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COVID can mimic prostate cancer symptoms
This patient has a strong likelihood of aggressive prostate cancer, right? If that same patient also presents with severe, burning bone pain with no precipitating trauma to the area and rest and over-the-counter painkillers are not helping, you’d think, “check for metastases,” right?
That patient was me in late January 2023.
As a research scientist member of the American Urological Association, I knew enough to know I had to consult my urologist ASAP.
With the above symptoms, I’ll admit I was scared. Fortunately, if that’s the right word, I was no stranger to a rapid, dramatic spike in PSA. In 2021 I was temporarily living in a new city, and I wanted to form a relationship with a good local urologist. The urologist that I was referred to gave me a thorough consultation, including a vigorous digital rectal exam (DRE) and sent me across the street for a blood draw.
To my shock, my PSA had spiked over 2 points, to 9.9 from 7.8 a few months earlier. I freaked. Had my 3-cm tumor burst out into an aggressive cancer? Research on PubMed provided an array of studies showing what could cause PSA to suddenly rise, including a DRE performed 72 hours before the blood draw.1 A week later, my PSA was back down to its normal 7.6.
But in January 2023, I had none of those previously reported experiences that could suddenly trigger a spike in PSA, like a DRE or riding on a thin bicycle seat for a few hours before the lab visit.
The COVID effect
I went back to PubMed and found a new circumstance that could cause a surge in PSA: COVID-19. A recent study2 of 91 men with benign prostatic hypertrophy by researchers in Turkey found that PSA spiked from 0 to 5 points during the COVID infection period and up to 2 points higher 3 months after the infection had cleared. I had tested positive for COVID-19 in mid-December 2022, 4 weeks before my 9.9 PSA reading.
Using Google translate, I communicated with the team in Turkey and found out that the PSA spike can last up to 6 months.
That study helps explain why my PSA dropped over 1.5 points to 8.5 just 2 weeks after the 9.9 reading, with the expectation that it would return to its previous normal of 7.8 within 6 months of infection with SARS-CoV-2. To be safe, my urologist scheduled another PSA test in May, along with an updated multiparametric MRI, which may be followed by an in-bore MRI-guided biopsy of the 3-cm tumor if the mass has enlarged.
COVID-19 pain
What about my burning bone pain in my upper right humerus and right rotator cuff that was not precipitated by trauma or strain? A radiograph found no evidence of metastasis, thank goodness. And my research showed that several studies3 have found that COVID-19 can cause burning musculoskeletal pain, including enthesopathy, which is what I had per the radiology report. So my PSA spike and searing pain were likely consequences of the infection.
To avoid the risk for a gross misdiagnosis after a radical spike in PSA, the informed urologist should ask the patient if he has had COVID-19 in the previous 6 months. Overlooking that question could lead to the wrong diagnostic decisions about a rapid jump in PSA or unexplained bone pain.
References
1. Bossens MM et al. Eur J Cancer. 1995;31A:682-5.
2. Cinislioglu AE et al. Urology. 2022;159:16-21.
3. Ciaffi J et al. Joint Bone Spine. 2021;88:105158.
Dr. Keller is founder of the Keller Research Institute, Jacksonville, Fla. He reported serving as a research scientist for the American Urological Association, serving on the advisory board of Active Surveillance Patient’s International, and serving on the boards of numerous nonprofit organizations.
A version of this article first appeared on Medscape.com.
This patient has a strong likelihood of aggressive prostate cancer, right? If that same patient also presents with severe, burning bone pain with no precipitating trauma to the area and rest and over-the-counter painkillers are not helping, you’d think, “check for metastases,” right?
That patient was me in late January 2023.
As a research scientist member of the American Urological Association, I knew enough to know I had to consult my urologist ASAP.
With the above symptoms, I’ll admit I was scared. Fortunately, if that’s the right word, I was no stranger to a rapid, dramatic spike in PSA. In 2021 I was temporarily living in a new city, and I wanted to form a relationship with a good local urologist. The urologist that I was referred to gave me a thorough consultation, including a vigorous digital rectal exam (DRE) and sent me across the street for a blood draw.
To my shock, my PSA had spiked over 2 points, to 9.9 from 7.8 a few months earlier. I freaked. Had my 3-cm tumor burst out into an aggressive cancer? Research on PubMed provided an array of studies showing what could cause PSA to suddenly rise, including a DRE performed 72 hours before the blood draw.1 A week later, my PSA was back down to its normal 7.6.
But in January 2023, I had none of those previously reported experiences that could suddenly trigger a spike in PSA, like a DRE or riding on a thin bicycle seat for a few hours before the lab visit.
The COVID effect
I went back to PubMed and found a new circumstance that could cause a surge in PSA: COVID-19. A recent study2 of 91 men with benign prostatic hypertrophy by researchers in Turkey found that PSA spiked from 0 to 5 points during the COVID infection period and up to 2 points higher 3 months after the infection had cleared. I had tested positive for COVID-19 in mid-December 2022, 4 weeks before my 9.9 PSA reading.
Using Google translate, I communicated with the team in Turkey and found out that the PSA spike can last up to 6 months.
That study helps explain why my PSA dropped over 1.5 points to 8.5 just 2 weeks after the 9.9 reading, with the expectation that it would return to its previous normal of 7.8 within 6 months of infection with SARS-CoV-2. To be safe, my urologist scheduled another PSA test in May, along with an updated multiparametric MRI, which may be followed by an in-bore MRI-guided biopsy of the 3-cm tumor if the mass has enlarged.
COVID-19 pain
What about my burning bone pain in my upper right humerus and right rotator cuff that was not precipitated by trauma or strain? A radiograph found no evidence of metastasis, thank goodness. And my research showed that several studies3 have found that COVID-19 can cause burning musculoskeletal pain, including enthesopathy, which is what I had per the radiology report. So my PSA spike and searing pain were likely consequences of the infection.
To avoid the risk for a gross misdiagnosis after a radical spike in PSA, the informed urologist should ask the patient if he has had COVID-19 in the previous 6 months. Overlooking that question could lead to the wrong diagnostic decisions about a rapid jump in PSA or unexplained bone pain.
References
1. Bossens MM et al. Eur J Cancer. 1995;31A:682-5.
2. Cinislioglu AE et al. Urology. 2022;159:16-21.
3. Ciaffi J et al. Joint Bone Spine. 2021;88:105158.
Dr. Keller is founder of the Keller Research Institute, Jacksonville, Fla. He reported serving as a research scientist for the American Urological Association, serving on the advisory board of Active Surveillance Patient’s International, and serving on the boards of numerous nonprofit organizations.
A version of this article first appeared on Medscape.com.
This patient has a strong likelihood of aggressive prostate cancer, right? If that same patient also presents with severe, burning bone pain with no precipitating trauma to the area and rest and over-the-counter painkillers are not helping, you’d think, “check for metastases,” right?
That patient was me in late January 2023.
As a research scientist member of the American Urological Association, I knew enough to know I had to consult my urologist ASAP.
With the above symptoms, I’ll admit I was scared. Fortunately, if that’s the right word, I was no stranger to a rapid, dramatic spike in PSA. In 2021 I was temporarily living in a new city, and I wanted to form a relationship with a good local urologist. The urologist that I was referred to gave me a thorough consultation, including a vigorous digital rectal exam (DRE) and sent me across the street for a blood draw.
To my shock, my PSA had spiked over 2 points, to 9.9 from 7.8 a few months earlier. I freaked. Had my 3-cm tumor burst out into an aggressive cancer? Research on PubMed provided an array of studies showing what could cause PSA to suddenly rise, including a DRE performed 72 hours before the blood draw.1 A week later, my PSA was back down to its normal 7.6.
But in January 2023, I had none of those previously reported experiences that could suddenly trigger a spike in PSA, like a DRE or riding on a thin bicycle seat for a few hours before the lab visit.
The COVID effect
I went back to PubMed and found a new circumstance that could cause a surge in PSA: COVID-19. A recent study2 of 91 men with benign prostatic hypertrophy by researchers in Turkey found that PSA spiked from 0 to 5 points during the COVID infection period and up to 2 points higher 3 months after the infection had cleared. I had tested positive for COVID-19 in mid-December 2022, 4 weeks before my 9.9 PSA reading.
Using Google translate, I communicated with the team in Turkey and found out that the PSA spike can last up to 6 months.
That study helps explain why my PSA dropped over 1.5 points to 8.5 just 2 weeks after the 9.9 reading, with the expectation that it would return to its previous normal of 7.8 within 6 months of infection with SARS-CoV-2. To be safe, my urologist scheduled another PSA test in May, along with an updated multiparametric MRI, which may be followed by an in-bore MRI-guided biopsy of the 3-cm tumor if the mass has enlarged.
COVID-19 pain
What about my burning bone pain in my upper right humerus and right rotator cuff that was not precipitated by trauma or strain? A radiograph found no evidence of metastasis, thank goodness. And my research showed that several studies3 have found that COVID-19 can cause burning musculoskeletal pain, including enthesopathy, which is what I had per the radiology report. So my PSA spike and searing pain were likely consequences of the infection.
To avoid the risk for a gross misdiagnosis after a radical spike in PSA, the informed urologist should ask the patient if he has had COVID-19 in the previous 6 months. Overlooking that question could lead to the wrong diagnostic decisions about a rapid jump in PSA or unexplained bone pain.
References
1. Bossens MM et al. Eur J Cancer. 1995;31A:682-5.
2. Cinislioglu AE et al. Urology. 2022;159:16-21.
3. Ciaffi J et al. Joint Bone Spine. 2021;88:105158.
Dr. Keller is founder of the Keller Research Institute, Jacksonville, Fla. He reported serving as a research scientist for the American Urological Association, serving on the advisory board of Active Surveillance Patient’s International, and serving on the boards of numerous nonprofit organizations.
A version of this article first appeared on Medscape.com.
Increased cancer in military pilots and ground crew: Pentagon
“Military aircrew and ground crew were overall more likely to be diagnosed with cancer, but less likely to die from cancer compared to the U.S. population,” the report concludes.
The study involved 156,050 aircrew and 737,891 ground crew. Participants were followed between 1992 and 2017. Both groups were predominantly male and non-Hispanic.
Data on cancer incidence and mortality for these two groups were compared with data from groups of similar age in the general population through use of the Surveillance, Epidemiology, and End Results (SEER) Database of the National Cancer Institute.
For aircrew, the study found an 87% higher rate of melanoma, a 39% higher rate of thyroid cancer, a 16% higher rate of prostate cancer, and a 24% higher rate of cancer for all sites combined.
A higher rate of melanoma and prostate cancer among aircrew has been reported previously, but the increased rate of thyroid cancer is a new finding, the authors note.
The uptick in melanoma has also been reported in studies of civilian pilots and cabin crew. It has been attributed to exposure to hazardous ultraviolet and cosmic radiation.
For ground crew members, the analysis found a 19% higher rate of cancers of the brain and nervous system, a 15% higher rate of thyroid cancer, a 9% higher rate of melanoma and of kidney and renal pelvis cancers, and a 3% higher rate of cancer for all sites combined.
There is little to compare these findings with: This is the first time that cancer risk has been evaluated in such a large population of military ground crew.
Lower rates of cancer mortality
In contrast to the increase in cancer incidence, the report found a decrease in cancer mortality.
When compared with a demographically similar U.S. population, the mortality rate among aircrew was 56% lower for all cancer sites; for ground crew, the mortality rate was 35% lower.
However, the report authors emphasize that “it is important to note that the military study population was relatively young.”
The median age at the end of follow-up for the cancer incidence analysis was 41 years for aircrew and 26 years for ground crew. The median age at the end of follow-up for the cancer mortality analysis was 48 years for aircrew and 41 years for ground crew.
“Results may have differed if additional older former Service members had been included in the study, since cancer risk and mortality rates increase with age,” the authors comment.
Other studies have found an increase in deaths from melanoma as well as an increase in the incidence of melanoma. A meta-analysis published in 2019 in the British Journal of Dermatology found that airline pilots and cabin crew have about twice the risk of melanoma and other skin cancers than the general population. Pilots are also more likely to die from melanoma.
Further study underway
The findings on military air and ground crew come from phase 1 of a study that was required by Congress in the 2021 defense bill. Because the investigators found an increase in the incidence of cancer, phase 2 of the study is now necessary.
The report authors explain that phase 2 will consist of identifying the carcinogenic toxicants or hazardous materials associated with military flight operations; identifying operating environments that could be associated with increased amounts of ionizing and nonionizing radiation; identifying specific duties, dates of service, and types of aircraft flown that could have increased the risk for cancer; identifying duty locations associated with a higher incidence of cancers; identifying potential exposures through military service that are not related to aviation; and determining the appropriate age to begin screening military aircrew and ground crew for cancers.
A version of this article first appeared on Medscape.com.
“Military aircrew and ground crew were overall more likely to be diagnosed with cancer, but less likely to die from cancer compared to the U.S. population,” the report concludes.
The study involved 156,050 aircrew and 737,891 ground crew. Participants were followed between 1992 and 2017. Both groups were predominantly male and non-Hispanic.
Data on cancer incidence and mortality for these two groups were compared with data from groups of similar age in the general population through use of the Surveillance, Epidemiology, and End Results (SEER) Database of the National Cancer Institute.
For aircrew, the study found an 87% higher rate of melanoma, a 39% higher rate of thyroid cancer, a 16% higher rate of prostate cancer, and a 24% higher rate of cancer for all sites combined.
A higher rate of melanoma and prostate cancer among aircrew has been reported previously, but the increased rate of thyroid cancer is a new finding, the authors note.
The uptick in melanoma has also been reported in studies of civilian pilots and cabin crew. It has been attributed to exposure to hazardous ultraviolet and cosmic radiation.
For ground crew members, the analysis found a 19% higher rate of cancers of the brain and nervous system, a 15% higher rate of thyroid cancer, a 9% higher rate of melanoma and of kidney and renal pelvis cancers, and a 3% higher rate of cancer for all sites combined.
There is little to compare these findings with: This is the first time that cancer risk has been evaluated in such a large population of military ground crew.
Lower rates of cancer mortality
In contrast to the increase in cancer incidence, the report found a decrease in cancer mortality.
When compared with a demographically similar U.S. population, the mortality rate among aircrew was 56% lower for all cancer sites; for ground crew, the mortality rate was 35% lower.
However, the report authors emphasize that “it is important to note that the military study population was relatively young.”
The median age at the end of follow-up for the cancer incidence analysis was 41 years for aircrew and 26 years for ground crew. The median age at the end of follow-up for the cancer mortality analysis was 48 years for aircrew and 41 years for ground crew.
“Results may have differed if additional older former Service members had been included in the study, since cancer risk and mortality rates increase with age,” the authors comment.
Other studies have found an increase in deaths from melanoma as well as an increase in the incidence of melanoma. A meta-analysis published in 2019 in the British Journal of Dermatology found that airline pilots and cabin crew have about twice the risk of melanoma and other skin cancers than the general population. Pilots are also more likely to die from melanoma.
Further study underway
The findings on military air and ground crew come from phase 1 of a study that was required by Congress in the 2021 defense bill. Because the investigators found an increase in the incidence of cancer, phase 2 of the study is now necessary.
The report authors explain that phase 2 will consist of identifying the carcinogenic toxicants or hazardous materials associated with military flight operations; identifying operating environments that could be associated with increased amounts of ionizing and nonionizing radiation; identifying specific duties, dates of service, and types of aircraft flown that could have increased the risk for cancer; identifying duty locations associated with a higher incidence of cancers; identifying potential exposures through military service that are not related to aviation; and determining the appropriate age to begin screening military aircrew and ground crew for cancers.
A version of this article first appeared on Medscape.com.
“Military aircrew and ground crew were overall more likely to be diagnosed with cancer, but less likely to die from cancer compared to the U.S. population,” the report concludes.
The study involved 156,050 aircrew and 737,891 ground crew. Participants were followed between 1992 and 2017. Both groups were predominantly male and non-Hispanic.
Data on cancer incidence and mortality for these two groups were compared with data from groups of similar age in the general population through use of the Surveillance, Epidemiology, and End Results (SEER) Database of the National Cancer Institute.
For aircrew, the study found an 87% higher rate of melanoma, a 39% higher rate of thyroid cancer, a 16% higher rate of prostate cancer, and a 24% higher rate of cancer for all sites combined.
A higher rate of melanoma and prostate cancer among aircrew has been reported previously, but the increased rate of thyroid cancer is a new finding, the authors note.
The uptick in melanoma has also been reported in studies of civilian pilots and cabin crew. It has been attributed to exposure to hazardous ultraviolet and cosmic radiation.
For ground crew members, the analysis found a 19% higher rate of cancers of the brain and nervous system, a 15% higher rate of thyroid cancer, a 9% higher rate of melanoma and of kidney and renal pelvis cancers, and a 3% higher rate of cancer for all sites combined.
There is little to compare these findings with: This is the first time that cancer risk has been evaluated in such a large population of military ground crew.
Lower rates of cancer mortality
In contrast to the increase in cancer incidence, the report found a decrease in cancer mortality.
When compared with a demographically similar U.S. population, the mortality rate among aircrew was 56% lower for all cancer sites; for ground crew, the mortality rate was 35% lower.
However, the report authors emphasize that “it is important to note that the military study population was relatively young.”
The median age at the end of follow-up for the cancer incidence analysis was 41 years for aircrew and 26 years for ground crew. The median age at the end of follow-up for the cancer mortality analysis was 48 years for aircrew and 41 years for ground crew.
“Results may have differed if additional older former Service members had been included in the study, since cancer risk and mortality rates increase with age,” the authors comment.
Other studies have found an increase in deaths from melanoma as well as an increase in the incidence of melanoma. A meta-analysis published in 2019 in the British Journal of Dermatology found that airline pilots and cabin crew have about twice the risk of melanoma and other skin cancers than the general population. Pilots are also more likely to die from melanoma.
Further study underway
The findings on military air and ground crew come from phase 1 of a study that was required by Congress in the 2021 defense bill. Because the investigators found an increase in the incidence of cancer, phase 2 of the study is now necessary.
The report authors explain that phase 2 will consist of identifying the carcinogenic toxicants or hazardous materials associated with military flight operations; identifying operating environments that could be associated with increased amounts of ionizing and nonionizing radiation; identifying specific duties, dates of service, and types of aircraft flown that could have increased the risk for cancer; identifying duty locations associated with a higher incidence of cancers; identifying potential exposures through military service that are not related to aviation; and determining the appropriate age to begin screening military aircrew and ground crew for cancers.
A version of this article first appeared on Medscape.com.
Digital rectal exam fails as screening tool for prostate cancer
, say investigators reporting the PROBASE study.
The study compared risk-adapted screening measures in men who had prostate-specific antigen (PSA) measured at age 45 with those who had PSA measurements plus DRE at age 50.
The results show that as a solitary screening tool, 99% of DREs did not raise suspicion for prostate cancer, and among the 57 cases where DRE did raise suspicion, only three men were found to have cancer, all of which were low-grade, reported Agne Krilaviciute, PhD, from the German Cancer Research Center in Heidelberg, and colleagues.
“We also see that the cancer detection rate by PSA is four times higher compared to the DRE detection. Around 18% of the tumors are located in the part of the prostate where DRE cannot detect them,” she said in an oral presentation at the European Association of Urology Congress.
The investigators found that the majority of prostate cancers that occurred in this relatively young population were International Society of Urological Pathology grade 1 (Gleason score 3 + 3 = 6) or grade 2 (Gleason 3 + 4 = 7). DRE yields positive results in only about 12% of cases of ISUP grade 1 or 2, they noted.
“We conclude that DRE as a solitary screening test does not lead to a significant PCa [prostate cancer] detection rate in young men,” Dr. Krilaviciute said.
Falling by the wayside
The study adds to the growing body of evidence that DRE may not be especially helpful as either a screening tool or when used in active surveillance of men with prostate cancer.
An international consensus panel found that DRE could be safely skipped for active surveillance when MRI and other more accurate and objective measures, such as biomarkers, are available.
A prostate cancer expert who was not involved in the PROBASE study told this news organization that when he was in medical school, it would have been considered a serious lapse of practice not to perform a DRE, but that things have changed considerably over the past several years.
“We have PSA now, we have technology with MRI, and the yield of digital rectal examination is very low,” commented Julio Pow-Sang, MD, chief of the genitourinary oncology program at Moffitt Cancer Center in Tampa, Fla.
“Empirically, it’s very rare to find positive cancer through rectal exam in this day and age of PSA,” he said, adding that the examination itself is highly subjective, with varying results depending on the skills of the particular examiner.
“I think that in time, with good studies like this, digital rectal exam specifically for prostate cancer is going to slowly fade away,” Dr. Pow-Sang said.
PROBASE results
PROBASE was a randomized screening study enrolling men at age 45 to test a risk-adapted screening strategy using a baseline PSA value with the additional offer of DRE in a large subcohort of participants.
The study was conducted in Germany, and the authors note that the “German statutory early detection program recommends DRE as a stand-alone screening test starting annually at age 45.”
The PROBASE investigators enrolled 46,495 men from February 2014 through December 2019.
Among the first 23,194 men enrolled, 6,537 underwent DRE at enrollment without a study PSA test.
In this group, 6,480 DREs (99%) were not suspicious for cancer, and 57 (1%) were. Of those with suspected prostate cancer, 37 underwent biopsy and 20 did not. Of those biopsied, only two were found to have prostate cancer. This translated into a cancer detection rate of 0.03% for DRE.
After a median of 6.6 years of follow-up, only one additional case of ISUP grade 2 prostate cancer was detected among the 6,357 men who had DREs at enrollment, translating into a prostate cancer detection rate of .05%.
The investigators also looked at men who suspicious DRE findings at baseline. They assumed that a DRE-detectable tumor at age 45 would still be manifest 5 years later and should be detectable with PSA at age 50. Of the 57 men with initially suspicious findings, 11 returned for PSA screening but refused biopsy, and of this group only one had an elevated PSA level. He then underwent biopsy, but the findings were negative.
Of those who underwent biopsy on the basis of DRE, 16 had prostatitis, 14 had benign prostatic hyperplasia, 1 had high-grade prostatic intraepithelial neoplasia, 1 had atypical small acinar proliferation, and 3 had equivocal findings.
In total, the investigators found 24 tumors among men screened with DRE. Of these, 3 occurred in men with results deemed suspicious and 21 were in men with unsuspicious digital exams. All of the tumors were ISUP grade 1, 2, or 3 tumors.
Among 245 men who had biopsies for a PSA level equal to or higher than 3 ng/mL, primarily Prostate Imaging Reporting and Data System (PI-RADS) 3-5 tumors, DRE findings at the time of biopsy were unsuspicious in about 82% of cases, Dr. Krilaviciute said.
“We also used MRI data to determine what proportion of tumors would be potentially detectable by DRE. We estimated that around 18% of tumors are located in the upper part of the prostate, which is not detectable by DRE,” she said. “Even excluding those tumors, still the DRE detection rate is low in palpable tumors.”
Although DRE performed better in higher-grade tumors, 80% of the tumors in the PROBASE participants were ISUP grade 1 or 2 and were likely to be undetected by DRE, she added.
“In Germany, the recommendations for the screening still include 45-year-olds to go with annual DRE. The PROBASE trial allowed us to evaluate for the first time what was the diagnostic performance for DRE at such a young age, and we see that 99% of men undergoing DRE have no suspicious findings, and among the 1% of suspicious findings having cancers extremely unlikely,” she said.
The study was supported by Deutsche Krebshilfe (German Cancer Aid). Dr. Krilaviciute and Dr. Pow-Sang reported having no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
, say investigators reporting the PROBASE study.
The study compared risk-adapted screening measures in men who had prostate-specific antigen (PSA) measured at age 45 with those who had PSA measurements plus DRE at age 50.
The results show that as a solitary screening tool, 99% of DREs did not raise suspicion for prostate cancer, and among the 57 cases where DRE did raise suspicion, only three men were found to have cancer, all of which were low-grade, reported Agne Krilaviciute, PhD, from the German Cancer Research Center in Heidelberg, and colleagues.
“We also see that the cancer detection rate by PSA is four times higher compared to the DRE detection. Around 18% of the tumors are located in the part of the prostate where DRE cannot detect them,” she said in an oral presentation at the European Association of Urology Congress.
The investigators found that the majority of prostate cancers that occurred in this relatively young population were International Society of Urological Pathology grade 1 (Gleason score 3 + 3 = 6) or grade 2 (Gleason 3 + 4 = 7). DRE yields positive results in only about 12% of cases of ISUP grade 1 or 2, they noted.
“We conclude that DRE as a solitary screening test does not lead to a significant PCa [prostate cancer] detection rate in young men,” Dr. Krilaviciute said.
Falling by the wayside
The study adds to the growing body of evidence that DRE may not be especially helpful as either a screening tool or when used in active surveillance of men with prostate cancer.
An international consensus panel found that DRE could be safely skipped for active surveillance when MRI and other more accurate and objective measures, such as biomarkers, are available.
A prostate cancer expert who was not involved in the PROBASE study told this news organization that when he was in medical school, it would have been considered a serious lapse of practice not to perform a DRE, but that things have changed considerably over the past several years.
“We have PSA now, we have technology with MRI, and the yield of digital rectal examination is very low,” commented Julio Pow-Sang, MD, chief of the genitourinary oncology program at Moffitt Cancer Center in Tampa, Fla.
“Empirically, it’s very rare to find positive cancer through rectal exam in this day and age of PSA,” he said, adding that the examination itself is highly subjective, with varying results depending on the skills of the particular examiner.
“I think that in time, with good studies like this, digital rectal exam specifically for prostate cancer is going to slowly fade away,” Dr. Pow-Sang said.
PROBASE results
PROBASE was a randomized screening study enrolling men at age 45 to test a risk-adapted screening strategy using a baseline PSA value with the additional offer of DRE in a large subcohort of participants.
The study was conducted in Germany, and the authors note that the “German statutory early detection program recommends DRE as a stand-alone screening test starting annually at age 45.”
The PROBASE investigators enrolled 46,495 men from February 2014 through December 2019.
Among the first 23,194 men enrolled, 6,537 underwent DRE at enrollment without a study PSA test.
In this group, 6,480 DREs (99%) were not suspicious for cancer, and 57 (1%) were. Of those with suspected prostate cancer, 37 underwent biopsy and 20 did not. Of those biopsied, only two were found to have prostate cancer. This translated into a cancer detection rate of 0.03% for DRE.
After a median of 6.6 years of follow-up, only one additional case of ISUP grade 2 prostate cancer was detected among the 6,357 men who had DREs at enrollment, translating into a prostate cancer detection rate of .05%.
The investigators also looked at men who suspicious DRE findings at baseline. They assumed that a DRE-detectable tumor at age 45 would still be manifest 5 years later and should be detectable with PSA at age 50. Of the 57 men with initially suspicious findings, 11 returned for PSA screening but refused biopsy, and of this group only one had an elevated PSA level. He then underwent biopsy, but the findings were negative.
Of those who underwent biopsy on the basis of DRE, 16 had prostatitis, 14 had benign prostatic hyperplasia, 1 had high-grade prostatic intraepithelial neoplasia, 1 had atypical small acinar proliferation, and 3 had equivocal findings.
In total, the investigators found 24 tumors among men screened with DRE. Of these, 3 occurred in men with results deemed suspicious and 21 were in men with unsuspicious digital exams. All of the tumors were ISUP grade 1, 2, or 3 tumors.
Among 245 men who had biopsies for a PSA level equal to or higher than 3 ng/mL, primarily Prostate Imaging Reporting and Data System (PI-RADS) 3-5 tumors, DRE findings at the time of biopsy were unsuspicious in about 82% of cases, Dr. Krilaviciute said.
“We also used MRI data to determine what proportion of tumors would be potentially detectable by DRE. We estimated that around 18% of tumors are located in the upper part of the prostate, which is not detectable by DRE,” she said. “Even excluding those tumors, still the DRE detection rate is low in palpable tumors.”
Although DRE performed better in higher-grade tumors, 80% of the tumors in the PROBASE participants were ISUP grade 1 or 2 and were likely to be undetected by DRE, she added.
“In Germany, the recommendations for the screening still include 45-year-olds to go with annual DRE. The PROBASE trial allowed us to evaluate for the first time what was the diagnostic performance for DRE at such a young age, and we see that 99% of men undergoing DRE have no suspicious findings, and among the 1% of suspicious findings having cancers extremely unlikely,” she said.
The study was supported by Deutsche Krebshilfe (German Cancer Aid). Dr. Krilaviciute and Dr. Pow-Sang reported having no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
, say investigators reporting the PROBASE study.
The study compared risk-adapted screening measures in men who had prostate-specific antigen (PSA) measured at age 45 with those who had PSA measurements plus DRE at age 50.
The results show that as a solitary screening tool, 99% of DREs did not raise suspicion for prostate cancer, and among the 57 cases where DRE did raise suspicion, only three men were found to have cancer, all of which were low-grade, reported Agne Krilaviciute, PhD, from the German Cancer Research Center in Heidelberg, and colleagues.
“We also see that the cancer detection rate by PSA is four times higher compared to the DRE detection. Around 18% of the tumors are located in the part of the prostate where DRE cannot detect them,” she said in an oral presentation at the European Association of Urology Congress.
The investigators found that the majority of prostate cancers that occurred in this relatively young population were International Society of Urological Pathology grade 1 (Gleason score 3 + 3 = 6) or grade 2 (Gleason 3 + 4 = 7). DRE yields positive results in only about 12% of cases of ISUP grade 1 or 2, they noted.
“We conclude that DRE as a solitary screening test does not lead to a significant PCa [prostate cancer] detection rate in young men,” Dr. Krilaviciute said.
Falling by the wayside
The study adds to the growing body of evidence that DRE may not be especially helpful as either a screening tool or when used in active surveillance of men with prostate cancer.
An international consensus panel found that DRE could be safely skipped for active surveillance when MRI and other more accurate and objective measures, such as biomarkers, are available.
A prostate cancer expert who was not involved in the PROBASE study told this news organization that when he was in medical school, it would have been considered a serious lapse of practice not to perform a DRE, but that things have changed considerably over the past several years.
“We have PSA now, we have technology with MRI, and the yield of digital rectal examination is very low,” commented Julio Pow-Sang, MD, chief of the genitourinary oncology program at Moffitt Cancer Center in Tampa, Fla.
“Empirically, it’s very rare to find positive cancer through rectal exam in this day and age of PSA,” he said, adding that the examination itself is highly subjective, with varying results depending on the skills of the particular examiner.
“I think that in time, with good studies like this, digital rectal exam specifically for prostate cancer is going to slowly fade away,” Dr. Pow-Sang said.
PROBASE results
PROBASE was a randomized screening study enrolling men at age 45 to test a risk-adapted screening strategy using a baseline PSA value with the additional offer of DRE in a large subcohort of participants.
The study was conducted in Germany, and the authors note that the “German statutory early detection program recommends DRE as a stand-alone screening test starting annually at age 45.”
The PROBASE investigators enrolled 46,495 men from February 2014 through December 2019.
Among the first 23,194 men enrolled, 6,537 underwent DRE at enrollment without a study PSA test.
In this group, 6,480 DREs (99%) were not suspicious for cancer, and 57 (1%) were. Of those with suspected prostate cancer, 37 underwent biopsy and 20 did not. Of those biopsied, only two were found to have prostate cancer. This translated into a cancer detection rate of 0.03% for DRE.
After a median of 6.6 years of follow-up, only one additional case of ISUP grade 2 prostate cancer was detected among the 6,357 men who had DREs at enrollment, translating into a prostate cancer detection rate of .05%.
The investigators also looked at men who suspicious DRE findings at baseline. They assumed that a DRE-detectable tumor at age 45 would still be manifest 5 years later and should be detectable with PSA at age 50. Of the 57 men with initially suspicious findings, 11 returned for PSA screening but refused biopsy, and of this group only one had an elevated PSA level. He then underwent biopsy, but the findings were negative.
Of those who underwent biopsy on the basis of DRE, 16 had prostatitis, 14 had benign prostatic hyperplasia, 1 had high-grade prostatic intraepithelial neoplasia, 1 had atypical small acinar proliferation, and 3 had equivocal findings.
In total, the investigators found 24 tumors among men screened with DRE. Of these, 3 occurred in men with results deemed suspicious and 21 were in men with unsuspicious digital exams. All of the tumors were ISUP grade 1, 2, or 3 tumors.
Among 245 men who had biopsies for a PSA level equal to or higher than 3 ng/mL, primarily Prostate Imaging Reporting and Data System (PI-RADS) 3-5 tumors, DRE findings at the time of biopsy were unsuspicious in about 82% of cases, Dr. Krilaviciute said.
“We also used MRI data to determine what proportion of tumors would be potentially detectable by DRE. We estimated that around 18% of tumors are located in the upper part of the prostate, which is not detectable by DRE,” she said. “Even excluding those tumors, still the DRE detection rate is low in palpable tumors.”
Although DRE performed better in higher-grade tumors, 80% of the tumors in the PROBASE participants were ISUP grade 1 or 2 and were likely to be undetected by DRE, she added.
“In Germany, the recommendations for the screening still include 45-year-olds to go with annual DRE. The PROBASE trial allowed us to evaluate for the first time what was the diagnostic performance for DRE at such a young age, and we see that 99% of men undergoing DRE have no suspicious findings, and among the 1% of suspicious findings having cancers extremely unlikely,” she said.
The study was supported by Deutsche Krebshilfe (German Cancer Aid). Dr. Krilaviciute and Dr. Pow-Sang reported having no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
FROM EAU 2023
Urine test predicts future bladder cancer 12 years before symptoms
an international team of researchers claims.
The test, if validated in further studies, has the potential to serve as a cancer screening tool for individuals at elevated risk for bladder cancer due to genetics, smoking, or from environmental exposures to known carcinogens, and it could help to reduce the frequency of unnecessary cystoscopies, say urologists who were not involved in the research.
The test involved was performed using a next-generation sequencing assay (UroAmp, Convergent Genomics, based in San Francisco) that identifies mutations in 60 genes associated with bladder cancer. New research reported at the annual congress of the European Association of Urology described the screening model that focused on 10 key genes covered in the assay.
In training and validation cohorts, the urinary comprehensive genomic profiling test accurately predicted future bladder cancer in 66% of patient urine samples, including some that had been collected more than a decade prior to being tested, reported Florence Le Calvez-Kelm, PhD, MSc, from the International Agency for Research on Cancer, Lyon, France.
“Our results provide first evidence from a population-based cohort study of preclinical urothelial cancer detection with urinary comprehensive genomic profiling,” she told the meeting.
The results were consistent both in individuals with known risk factors for bladder cancer who were undergoing cystoscopy and in those with no evidence of disease, she said.
“Research of this nature is very encouraging, as it shows that our ability to identify molecular alterations in liquid biopsies such as urine that might indicate cancer is constantly improving,” commented Joost Boormans, MD, PhD, a urologist at the Erasmus University Medical Center, Rotterdam, Netherlands, and a member of the EAU Scientific Congress Office.
“While we do need to develop more accurate diagnostics, it’s unlikely that we’ll have a mass screening program for bladder cancer in the near future,” he continued. “Where a urine test for genetic mutations could show its value is in reducing cystoscopies and scans in bladder cancer patients who are being monitored for recurrence, as well as those referred for blood in their urine. A simple urine test would be far easier for patients to undergo than invasive procedures or scans, as well as being less costly for health services.”
Dr. Le Calvez-Kelm and colleagues had previously shown that promoter mutations in the gene encoding for the enzyme telomerase reverse transcriptase (TERT) identified in urine were “promising noninvasive biomarkers” for early detection of bladder cancer.
They found that TERT mutations in urine could predict which patients were likely to develop urothelial cancer with 48% sensitivity and 100% specificity.
In the study presented at EAU23, they hypothesized that uCGP of DNA in urine could offer enhanced sensitivity for early detection of urothelial cancer.
They first used the 60-gene assay to create a training set using urine samples from 46 patients with de novo urothelial cancer, 40 with recurrent cancer, and 140 healthy controls.
They then tested the model in two validation cohorts. The first validation cohort consisted of samples from 22 patients with de novo cancer, 48 with recurrent urothelial cancer, and 96 controls from a case-control study conducted at Massachusetts General Hospital, Boston, and Ohio State University, Columbus.
The second validation cohort included 29 patients from the prospective Golestan Cohort Study who subsequently developed urothelial cancer, with 98 controls.
In all, 10 genes were identified as optimal for inclusion in a screening model, which was trained to an overall sensitivity of 88% and a 97% sensitivity for high-grade tumors, with a specificity of 94%.
In the MGH/OSU validation cohort the sensitivity of the models was 71%, and the specificity was 94%. In the Golestan cohort, the sensitivity was 66%, with a specificity of 94%. This compared favorably with the performance of the TERT-only screening model, which, as noted before, had a sensitivity of 48%, albeit with 100% specificity.
“Interestingly, when we broke down the analysis according to the lag time between urine collection and diagnosis, sensitivity increased as the time to diagnosis decreased, so the closer we got to the diagnosis, the higher was the sensitivity,” Dr. Le Calvez-Kelm said.
When the analysis was limited to urothelial cancers diagnosed within 7 years of sample collection, the sensitivity for detecting preclinical cancer improved to 86%, compared with 57% for a test of TERT promoter mutations alone.
Among the patients in the Golestan cohort, uCGP-predicted positive results were associated with a more than eightfold higher risk for worse cancer-free survival, compared with uCGP-predicted negatives (hazard ratio 8.5, P < .0001).
“Of course, further studies are needed to validate this finding and to assess the clinical utility in other longitudinal cohorts,” Dr. Le Calvez-Kelm concluded.
A version of this article first appeared on Medscape.com.
an international team of researchers claims.
The test, if validated in further studies, has the potential to serve as a cancer screening tool for individuals at elevated risk for bladder cancer due to genetics, smoking, or from environmental exposures to known carcinogens, and it could help to reduce the frequency of unnecessary cystoscopies, say urologists who were not involved in the research.
The test involved was performed using a next-generation sequencing assay (UroAmp, Convergent Genomics, based in San Francisco) that identifies mutations in 60 genes associated with bladder cancer. New research reported at the annual congress of the European Association of Urology described the screening model that focused on 10 key genes covered in the assay.
In training and validation cohorts, the urinary comprehensive genomic profiling test accurately predicted future bladder cancer in 66% of patient urine samples, including some that had been collected more than a decade prior to being tested, reported Florence Le Calvez-Kelm, PhD, MSc, from the International Agency for Research on Cancer, Lyon, France.
“Our results provide first evidence from a population-based cohort study of preclinical urothelial cancer detection with urinary comprehensive genomic profiling,” she told the meeting.
The results were consistent both in individuals with known risk factors for bladder cancer who were undergoing cystoscopy and in those with no evidence of disease, she said.
“Research of this nature is very encouraging, as it shows that our ability to identify molecular alterations in liquid biopsies such as urine that might indicate cancer is constantly improving,” commented Joost Boormans, MD, PhD, a urologist at the Erasmus University Medical Center, Rotterdam, Netherlands, and a member of the EAU Scientific Congress Office.
“While we do need to develop more accurate diagnostics, it’s unlikely that we’ll have a mass screening program for bladder cancer in the near future,” he continued. “Where a urine test for genetic mutations could show its value is in reducing cystoscopies and scans in bladder cancer patients who are being monitored for recurrence, as well as those referred for blood in their urine. A simple urine test would be far easier for patients to undergo than invasive procedures or scans, as well as being less costly for health services.”
Dr. Le Calvez-Kelm and colleagues had previously shown that promoter mutations in the gene encoding for the enzyme telomerase reverse transcriptase (TERT) identified in urine were “promising noninvasive biomarkers” for early detection of bladder cancer.
They found that TERT mutations in urine could predict which patients were likely to develop urothelial cancer with 48% sensitivity and 100% specificity.
In the study presented at EAU23, they hypothesized that uCGP of DNA in urine could offer enhanced sensitivity for early detection of urothelial cancer.
They first used the 60-gene assay to create a training set using urine samples from 46 patients with de novo urothelial cancer, 40 with recurrent cancer, and 140 healthy controls.
They then tested the model in two validation cohorts. The first validation cohort consisted of samples from 22 patients with de novo cancer, 48 with recurrent urothelial cancer, and 96 controls from a case-control study conducted at Massachusetts General Hospital, Boston, and Ohio State University, Columbus.
The second validation cohort included 29 patients from the prospective Golestan Cohort Study who subsequently developed urothelial cancer, with 98 controls.
In all, 10 genes were identified as optimal for inclusion in a screening model, which was trained to an overall sensitivity of 88% and a 97% sensitivity for high-grade tumors, with a specificity of 94%.
In the MGH/OSU validation cohort the sensitivity of the models was 71%, and the specificity was 94%. In the Golestan cohort, the sensitivity was 66%, with a specificity of 94%. This compared favorably with the performance of the TERT-only screening model, which, as noted before, had a sensitivity of 48%, albeit with 100% specificity.
“Interestingly, when we broke down the analysis according to the lag time between urine collection and diagnosis, sensitivity increased as the time to diagnosis decreased, so the closer we got to the diagnosis, the higher was the sensitivity,” Dr. Le Calvez-Kelm said.
When the analysis was limited to urothelial cancers diagnosed within 7 years of sample collection, the sensitivity for detecting preclinical cancer improved to 86%, compared with 57% for a test of TERT promoter mutations alone.
Among the patients in the Golestan cohort, uCGP-predicted positive results were associated with a more than eightfold higher risk for worse cancer-free survival, compared with uCGP-predicted negatives (hazard ratio 8.5, P < .0001).
“Of course, further studies are needed to validate this finding and to assess the clinical utility in other longitudinal cohorts,” Dr. Le Calvez-Kelm concluded.
A version of this article first appeared on Medscape.com.
an international team of researchers claims.
The test, if validated in further studies, has the potential to serve as a cancer screening tool for individuals at elevated risk for bladder cancer due to genetics, smoking, or from environmental exposures to known carcinogens, and it could help to reduce the frequency of unnecessary cystoscopies, say urologists who were not involved in the research.
The test involved was performed using a next-generation sequencing assay (UroAmp, Convergent Genomics, based in San Francisco) that identifies mutations in 60 genes associated with bladder cancer. New research reported at the annual congress of the European Association of Urology described the screening model that focused on 10 key genes covered in the assay.
In training and validation cohorts, the urinary comprehensive genomic profiling test accurately predicted future bladder cancer in 66% of patient urine samples, including some that had been collected more than a decade prior to being tested, reported Florence Le Calvez-Kelm, PhD, MSc, from the International Agency for Research on Cancer, Lyon, France.
“Our results provide first evidence from a population-based cohort study of preclinical urothelial cancer detection with urinary comprehensive genomic profiling,” she told the meeting.
The results were consistent both in individuals with known risk factors for bladder cancer who were undergoing cystoscopy and in those with no evidence of disease, she said.
“Research of this nature is very encouraging, as it shows that our ability to identify molecular alterations in liquid biopsies such as urine that might indicate cancer is constantly improving,” commented Joost Boormans, MD, PhD, a urologist at the Erasmus University Medical Center, Rotterdam, Netherlands, and a member of the EAU Scientific Congress Office.
“While we do need to develop more accurate diagnostics, it’s unlikely that we’ll have a mass screening program for bladder cancer in the near future,” he continued. “Where a urine test for genetic mutations could show its value is in reducing cystoscopies and scans in bladder cancer patients who are being monitored for recurrence, as well as those referred for blood in their urine. A simple urine test would be far easier for patients to undergo than invasive procedures or scans, as well as being less costly for health services.”
Dr. Le Calvez-Kelm and colleagues had previously shown that promoter mutations in the gene encoding for the enzyme telomerase reverse transcriptase (TERT) identified in urine were “promising noninvasive biomarkers” for early detection of bladder cancer.
They found that TERT mutations in urine could predict which patients were likely to develop urothelial cancer with 48% sensitivity and 100% specificity.
In the study presented at EAU23, they hypothesized that uCGP of DNA in urine could offer enhanced sensitivity for early detection of urothelial cancer.
They first used the 60-gene assay to create a training set using urine samples from 46 patients with de novo urothelial cancer, 40 with recurrent cancer, and 140 healthy controls.
They then tested the model in two validation cohorts. The first validation cohort consisted of samples from 22 patients with de novo cancer, 48 with recurrent urothelial cancer, and 96 controls from a case-control study conducted at Massachusetts General Hospital, Boston, and Ohio State University, Columbus.
The second validation cohort included 29 patients from the prospective Golestan Cohort Study who subsequently developed urothelial cancer, with 98 controls.
In all, 10 genes were identified as optimal for inclusion in a screening model, which was trained to an overall sensitivity of 88% and a 97% sensitivity for high-grade tumors, with a specificity of 94%.
In the MGH/OSU validation cohort the sensitivity of the models was 71%, and the specificity was 94%. In the Golestan cohort, the sensitivity was 66%, with a specificity of 94%. This compared favorably with the performance of the TERT-only screening model, which, as noted before, had a sensitivity of 48%, albeit with 100% specificity.
“Interestingly, when we broke down the analysis according to the lag time between urine collection and diagnosis, sensitivity increased as the time to diagnosis decreased, so the closer we got to the diagnosis, the higher was the sensitivity,” Dr. Le Calvez-Kelm said.
When the analysis was limited to urothelial cancers diagnosed within 7 years of sample collection, the sensitivity for detecting preclinical cancer improved to 86%, compared with 57% for a test of TERT promoter mutations alone.
Among the patients in the Golestan cohort, uCGP-predicted positive results were associated with a more than eightfold higher risk for worse cancer-free survival, compared with uCGP-predicted negatives (hazard ratio 8.5, P < .0001).
“Of course, further studies are needed to validate this finding and to assess the clinical utility in other longitudinal cohorts,” Dr. Le Calvez-Kelm concluded.
A version of this article first appeared on Medscape.com.
FROM EAU23
Prostate cancer subgroup may benefit from intensified therapy
SAN FRANCISCO – For patients with prostate cancer who have unfavorable features and a detectable PSA following a radical prostatectomy, the standard of care is treatment with 6 months of a gonadotropin-releasing hormone (GnRH) agonist with salvage radiation therapy (SRT), as established by the GETUG-AFU 16 trial.
A new trial, dubbed FORMULA-509, explored whether outcomes could be improved by intensifying the drug treatment by adding 6 months of abiraterone acetate plus prednisone as well as apalutamide on top of the GnRH agonist alongside the salvage radiotherapy.
However, the combination did significantly improve PFS and MFS in a subset of men with PSA levels greater than 0.5 ng/mL.
“Although this primary analysis did not meet the prespecified threshold for statistical significance, it does strongly suggest that the addition of abiraterone acetate/prednisone/apalutamide to salvage radiotherapy plus 6 months of ADT [androgen deprivation therapy] may improve progression-free survival and metastasis-free survival,” said lead author Paul L. Nguyen, MD, of the Dana-Farber Cancer Institute in Boston, and professor of radiation oncology at Harvard Medical School.
“This may be particularly evident in the subgroup of patients with PSA greater that 0.5 ng/mL where a preplanned subgroup analysis by stratification factors observed a statistically significant benefit for both progression-free survival and metastasis-free survival,” he said. “Six months of intensified ADT with next generation anti-androgens may provide an attractive alternative to lengthening ADT for patients with rising PSA and unfavorable features after radical prostatectomy.”
The study results were presented at the ASCO Genitourinary Cancers Symposium.
Benefit in subset
The FORMULA-509 trial included 305 patients with PSA ≥ 0.1 ng/mL who had undergone a radical prostatectomy, and who had one or more unfavorable risk features (Gleason 8-10 disease, PSA > 0.5 ng/mL, pT3/T4, pN1 or radiographic N1, PSA doubling time < 10 months, negative margins, persistent PSA, gross local/regional disease).
“This was a pretty high-risk population,” Dr. Nguyen emphasized, as 35% had Gleason score of 9, about a third (31%) a PSA >0.5, and 29% were pathologic node positive.
All patients received salvage radiotherapy plus 6 months of GnRH agonist (bicalutamide 50 mg), and half were randomly assigned to also receive abiraterone acetate/prednisone 1,000 mg/5 mg + apalutamide 240 mg daily.
At a median follow-up of 34 months, the 3-year PFS rate was 74.9% in the AAP-apalutamide arm vs. 68.5% for the control group (hazard ratio [HR], 0.71; P = .06), and the 3-year MFS rate was 90.6% vs. 87.2%, respectively (HR, 0.57; P = .05).
In the subset of patients with a PSA greater than 0.5 ng/mL, the 3-year PFS and MFS rates were significantly higher with in the AAP-apalutamide group: the 3-year PFS rate was 67.2% vs. 46.8% (HR, 0.50; P = .03), and the 3-year MFS rate was 84.3% vs. 66.1% (HR, 0.32; P = .02).
Adverse events were consistent with the known safety profiles of the agents being studied, Dr. Nguyen noted. The most common toxicities for AAP-apalutamide vs. controls were hypertension (21.8% vs. 13.3%), maculopapular rash (11.5% vs. 0.6%), diarrhea (8.5% vs. 4.8%), and fatigue (7.9% vs. 6.1%).
Dr. Nguyen noted that even though “we’re not supposed to compare clinical trials,” the results of this study appeared to compare favorably with those of another trial, RADICALS-HD, which was presented at the 2022 European Society of Medical Oncology Congress. That study showed that in patients undergoing postoperative radiation therapy, 24 months of ADT was superior to 6 months of ADT in improving both time to salvage ADT and MFS.
However, Dr. Nguyen emphasized that it would have to be formally tested, to see if “FORMULA-509 is performing in the ballpark of what 24 months of ADT would do.
“And I think that compared to 6 months of ADT, we can say it is certainly performing in the ballpark,” he said. “So, for patients with higher risk features, intensifying 6 months of ADT, I think, may be an appealing alternative to lengthening the ADT duration to 24 months.”
He added that this concept would be formally tested in the upcoming PROSTATE IQ study.
Strong evidence, standardization needed
In a discussion of the paper, Tyler Seibert, MD, PhD, of the University of California San Diego, said that “escalation by 24 months has the strongest evidence today, specifically from the RADICALS-HD trial, with more than 1,500 men with 10 years of follow-up and a clear statistically significant result.
“Intensification for 6 months is a very compelling concept, as most patients are not getting 2 years of androgen deprivation therapy at this point post prostatectomy,” he continued. “While we await the long term follow-up of this study and the pending PROSTATE IQ trial, and if only 6 months of therapy is acceptable or feasible, the FORMULA-509 [trial] provides convincing evidence that select patients would benefit from intensification with AAP and apalutamide.”
Another expert weighed in on the data. Approached by this news organization for an independent comment, Jeff M. Michalski, MD, MBA, professor of radiation oncology at Washington University, St Louis, and president of the American Society of Radiation Oncology, noted a few issues in the study.
He said that standards had changed since this study was first approved and had begun accrual several years ago. “In context of today’s era, the current standard is to do a PET scan if patients have a chemical failure after surgery,” he said. “The PSA levels of patients who were treated [in this trial] were very high, and many patients do not want to wait until they reach that level.”
Dr. Michalski also pointed out the number of patients getting radiation was less than the number who had node-positive disease. “This shows that patients had received suboptimal therapy late in the disease,” he said.
Overall, most patients in the study did not receive lymph node radiation, even though they had high-risk features. “A recent study of almost 1,800 patients that was published in The Lancet found that there is a benefit to pelvic lymph node radiation,” he said. “Because it wasn’t mandated, most of the patients did not receive pelvic lymph node radiation, which we now understand offers some benefit.”
The reasons for not giving pelvic radiation to these men is unclear. “Treatment was left at the discretion of the physician and this could create bias,” Dr. Michalski said. “It could drive one arm more than another.”
The study also wasn’t controlled for pelvic radiation. “Most of the nodal positive patients received it, but the other patients were undertreated,” he noted.
Dr. Michalski added that he hopes that in the forthcoming PROSTATE IQ study, lymph node radiation and imaging are standardized.
The trial was supported by Janssen Oncology. Dr. Nguyen disclosed relationships with, and/or support from, Volatilyx, Bayer, Blue Earth Diagnostics, Boston Scientific, Janssen Oncology, Myovant Sciences, Astellas Pharma, and Janssen. Dr. Seibert disclosed relationships with, and/or support from, CorTechs Labs, Varian Medical Systems, and GE Healthcare.
A version of this article first appeared on Medscape.com.
SAN FRANCISCO – For patients with prostate cancer who have unfavorable features and a detectable PSA following a radical prostatectomy, the standard of care is treatment with 6 months of a gonadotropin-releasing hormone (GnRH) agonist with salvage radiation therapy (SRT), as established by the GETUG-AFU 16 trial.
A new trial, dubbed FORMULA-509, explored whether outcomes could be improved by intensifying the drug treatment by adding 6 months of abiraterone acetate plus prednisone as well as apalutamide on top of the GnRH agonist alongside the salvage radiotherapy.
However, the combination did significantly improve PFS and MFS in a subset of men with PSA levels greater than 0.5 ng/mL.
“Although this primary analysis did not meet the prespecified threshold for statistical significance, it does strongly suggest that the addition of abiraterone acetate/prednisone/apalutamide to salvage radiotherapy plus 6 months of ADT [androgen deprivation therapy] may improve progression-free survival and metastasis-free survival,” said lead author Paul L. Nguyen, MD, of the Dana-Farber Cancer Institute in Boston, and professor of radiation oncology at Harvard Medical School.
“This may be particularly evident in the subgroup of patients with PSA greater that 0.5 ng/mL where a preplanned subgroup analysis by stratification factors observed a statistically significant benefit for both progression-free survival and metastasis-free survival,” he said. “Six months of intensified ADT with next generation anti-androgens may provide an attractive alternative to lengthening ADT for patients with rising PSA and unfavorable features after radical prostatectomy.”
The study results were presented at the ASCO Genitourinary Cancers Symposium.
Benefit in subset
The FORMULA-509 trial included 305 patients with PSA ≥ 0.1 ng/mL who had undergone a radical prostatectomy, and who had one or more unfavorable risk features (Gleason 8-10 disease, PSA > 0.5 ng/mL, pT3/T4, pN1 or radiographic N1, PSA doubling time < 10 months, negative margins, persistent PSA, gross local/regional disease).
“This was a pretty high-risk population,” Dr. Nguyen emphasized, as 35% had Gleason score of 9, about a third (31%) a PSA >0.5, and 29% were pathologic node positive.
All patients received salvage radiotherapy plus 6 months of GnRH agonist (bicalutamide 50 mg), and half were randomly assigned to also receive abiraterone acetate/prednisone 1,000 mg/5 mg + apalutamide 240 mg daily.
At a median follow-up of 34 months, the 3-year PFS rate was 74.9% in the AAP-apalutamide arm vs. 68.5% for the control group (hazard ratio [HR], 0.71; P = .06), and the 3-year MFS rate was 90.6% vs. 87.2%, respectively (HR, 0.57; P = .05).
In the subset of patients with a PSA greater than 0.5 ng/mL, the 3-year PFS and MFS rates were significantly higher with in the AAP-apalutamide group: the 3-year PFS rate was 67.2% vs. 46.8% (HR, 0.50; P = .03), and the 3-year MFS rate was 84.3% vs. 66.1% (HR, 0.32; P = .02).
Adverse events were consistent with the known safety profiles of the agents being studied, Dr. Nguyen noted. The most common toxicities for AAP-apalutamide vs. controls were hypertension (21.8% vs. 13.3%), maculopapular rash (11.5% vs. 0.6%), diarrhea (8.5% vs. 4.8%), and fatigue (7.9% vs. 6.1%).
Dr. Nguyen noted that even though “we’re not supposed to compare clinical trials,” the results of this study appeared to compare favorably with those of another trial, RADICALS-HD, which was presented at the 2022 European Society of Medical Oncology Congress. That study showed that in patients undergoing postoperative radiation therapy, 24 months of ADT was superior to 6 months of ADT in improving both time to salvage ADT and MFS.
However, Dr. Nguyen emphasized that it would have to be formally tested, to see if “FORMULA-509 is performing in the ballpark of what 24 months of ADT would do.
“And I think that compared to 6 months of ADT, we can say it is certainly performing in the ballpark,” he said. “So, for patients with higher risk features, intensifying 6 months of ADT, I think, may be an appealing alternative to lengthening the ADT duration to 24 months.”
He added that this concept would be formally tested in the upcoming PROSTATE IQ study.
Strong evidence, standardization needed
In a discussion of the paper, Tyler Seibert, MD, PhD, of the University of California San Diego, said that “escalation by 24 months has the strongest evidence today, specifically from the RADICALS-HD trial, with more than 1,500 men with 10 years of follow-up and a clear statistically significant result.
“Intensification for 6 months is a very compelling concept, as most patients are not getting 2 years of androgen deprivation therapy at this point post prostatectomy,” he continued. “While we await the long term follow-up of this study and the pending PROSTATE IQ trial, and if only 6 months of therapy is acceptable or feasible, the FORMULA-509 [trial] provides convincing evidence that select patients would benefit from intensification with AAP and apalutamide.”
Another expert weighed in on the data. Approached by this news organization for an independent comment, Jeff M. Michalski, MD, MBA, professor of radiation oncology at Washington University, St Louis, and president of the American Society of Radiation Oncology, noted a few issues in the study.
He said that standards had changed since this study was first approved and had begun accrual several years ago. “In context of today’s era, the current standard is to do a PET scan if patients have a chemical failure after surgery,” he said. “The PSA levels of patients who were treated [in this trial] were very high, and many patients do not want to wait until they reach that level.”
Dr. Michalski also pointed out the number of patients getting radiation was less than the number who had node-positive disease. “This shows that patients had received suboptimal therapy late in the disease,” he said.
Overall, most patients in the study did not receive lymph node radiation, even though they had high-risk features. “A recent study of almost 1,800 patients that was published in The Lancet found that there is a benefit to pelvic lymph node radiation,” he said. “Because it wasn’t mandated, most of the patients did not receive pelvic lymph node radiation, which we now understand offers some benefit.”
The reasons for not giving pelvic radiation to these men is unclear. “Treatment was left at the discretion of the physician and this could create bias,” Dr. Michalski said. “It could drive one arm more than another.”
The study also wasn’t controlled for pelvic radiation. “Most of the nodal positive patients received it, but the other patients were undertreated,” he noted.
Dr. Michalski added that he hopes that in the forthcoming PROSTATE IQ study, lymph node radiation and imaging are standardized.
The trial was supported by Janssen Oncology. Dr. Nguyen disclosed relationships with, and/or support from, Volatilyx, Bayer, Blue Earth Diagnostics, Boston Scientific, Janssen Oncology, Myovant Sciences, Astellas Pharma, and Janssen. Dr. Seibert disclosed relationships with, and/or support from, CorTechs Labs, Varian Medical Systems, and GE Healthcare.
A version of this article first appeared on Medscape.com.
SAN FRANCISCO – For patients with prostate cancer who have unfavorable features and a detectable PSA following a radical prostatectomy, the standard of care is treatment with 6 months of a gonadotropin-releasing hormone (GnRH) agonist with salvage radiation therapy (SRT), as established by the GETUG-AFU 16 trial.
A new trial, dubbed FORMULA-509, explored whether outcomes could be improved by intensifying the drug treatment by adding 6 months of abiraterone acetate plus prednisone as well as apalutamide on top of the GnRH agonist alongside the salvage radiotherapy.
However, the combination did significantly improve PFS and MFS in a subset of men with PSA levels greater than 0.5 ng/mL.
“Although this primary analysis did not meet the prespecified threshold for statistical significance, it does strongly suggest that the addition of abiraterone acetate/prednisone/apalutamide to salvage radiotherapy plus 6 months of ADT [androgen deprivation therapy] may improve progression-free survival and metastasis-free survival,” said lead author Paul L. Nguyen, MD, of the Dana-Farber Cancer Institute in Boston, and professor of radiation oncology at Harvard Medical School.
“This may be particularly evident in the subgroup of patients with PSA greater that 0.5 ng/mL where a preplanned subgroup analysis by stratification factors observed a statistically significant benefit for both progression-free survival and metastasis-free survival,” he said. “Six months of intensified ADT with next generation anti-androgens may provide an attractive alternative to lengthening ADT for patients with rising PSA and unfavorable features after radical prostatectomy.”
The study results were presented at the ASCO Genitourinary Cancers Symposium.
Benefit in subset
The FORMULA-509 trial included 305 patients with PSA ≥ 0.1 ng/mL who had undergone a radical prostatectomy, and who had one or more unfavorable risk features (Gleason 8-10 disease, PSA > 0.5 ng/mL, pT3/T4, pN1 or radiographic N1, PSA doubling time < 10 months, negative margins, persistent PSA, gross local/regional disease).
“This was a pretty high-risk population,” Dr. Nguyen emphasized, as 35% had Gleason score of 9, about a third (31%) a PSA >0.5, and 29% were pathologic node positive.
All patients received salvage radiotherapy plus 6 months of GnRH agonist (bicalutamide 50 mg), and half were randomly assigned to also receive abiraterone acetate/prednisone 1,000 mg/5 mg + apalutamide 240 mg daily.
At a median follow-up of 34 months, the 3-year PFS rate was 74.9% in the AAP-apalutamide arm vs. 68.5% for the control group (hazard ratio [HR], 0.71; P = .06), and the 3-year MFS rate was 90.6% vs. 87.2%, respectively (HR, 0.57; P = .05).
In the subset of patients with a PSA greater than 0.5 ng/mL, the 3-year PFS and MFS rates were significantly higher with in the AAP-apalutamide group: the 3-year PFS rate was 67.2% vs. 46.8% (HR, 0.50; P = .03), and the 3-year MFS rate was 84.3% vs. 66.1% (HR, 0.32; P = .02).
Adverse events were consistent with the known safety profiles of the agents being studied, Dr. Nguyen noted. The most common toxicities for AAP-apalutamide vs. controls were hypertension (21.8% vs. 13.3%), maculopapular rash (11.5% vs. 0.6%), diarrhea (8.5% vs. 4.8%), and fatigue (7.9% vs. 6.1%).
Dr. Nguyen noted that even though “we’re not supposed to compare clinical trials,” the results of this study appeared to compare favorably with those of another trial, RADICALS-HD, which was presented at the 2022 European Society of Medical Oncology Congress. That study showed that in patients undergoing postoperative radiation therapy, 24 months of ADT was superior to 6 months of ADT in improving both time to salvage ADT and MFS.
However, Dr. Nguyen emphasized that it would have to be formally tested, to see if “FORMULA-509 is performing in the ballpark of what 24 months of ADT would do.
“And I think that compared to 6 months of ADT, we can say it is certainly performing in the ballpark,” he said. “So, for patients with higher risk features, intensifying 6 months of ADT, I think, may be an appealing alternative to lengthening the ADT duration to 24 months.”
He added that this concept would be formally tested in the upcoming PROSTATE IQ study.
Strong evidence, standardization needed
In a discussion of the paper, Tyler Seibert, MD, PhD, of the University of California San Diego, said that “escalation by 24 months has the strongest evidence today, specifically from the RADICALS-HD trial, with more than 1,500 men with 10 years of follow-up and a clear statistically significant result.
“Intensification for 6 months is a very compelling concept, as most patients are not getting 2 years of androgen deprivation therapy at this point post prostatectomy,” he continued. “While we await the long term follow-up of this study and the pending PROSTATE IQ trial, and if only 6 months of therapy is acceptable or feasible, the FORMULA-509 [trial] provides convincing evidence that select patients would benefit from intensification with AAP and apalutamide.”
Another expert weighed in on the data. Approached by this news organization for an independent comment, Jeff M. Michalski, MD, MBA, professor of radiation oncology at Washington University, St Louis, and president of the American Society of Radiation Oncology, noted a few issues in the study.
He said that standards had changed since this study was first approved and had begun accrual several years ago. “In context of today’s era, the current standard is to do a PET scan if patients have a chemical failure after surgery,” he said. “The PSA levels of patients who were treated [in this trial] were very high, and many patients do not want to wait until they reach that level.”
Dr. Michalski also pointed out the number of patients getting radiation was less than the number who had node-positive disease. “This shows that patients had received suboptimal therapy late in the disease,” he said.
Overall, most patients in the study did not receive lymph node radiation, even though they had high-risk features. “A recent study of almost 1,800 patients that was published in The Lancet found that there is a benefit to pelvic lymph node radiation,” he said. “Because it wasn’t mandated, most of the patients did not receive pelvic lymph node radiation, which we now understand offers some benefit.”
The reasons for not giving pelvic radiation to these men is unclear. “Treatment was left at the discretion of the physician and this could create bias,” Dr. Michalski said. “It could drive one arm more than another.”
The study also wasn’t controlled for pelvic radiation. “Most of the nodal positive patients received it, but the other patients were undertreated,” he noted.
Dr. Michalski added that he hopes that in the forthcoming PROSTATE IQ study, lymph node radiation and imaging are standardized.
The trial was supported by Janssen Oncology. Dr. Nguyen disclosed relationships with, and/or support from, Volatilyx, Bayer, Blue Earth Diagnostics, Boston Scientific, Janssen Oncology, Myovant Sciences, Astellas Pharma, and Janssen. Dr. Seibert disclosed relationships with, and/or support from, CorTechs Labs, Varian Medical Systems, and GE Healthcare.
A version of this article first appeared on Medscape.com.
AT ASCO GU 2023
Talazoparib add-on improves outcomes in metastatic prostate cancer
in the TALAPRO-2 trial.
As determined on the basis of imaging, PFS was 37% better for talazoparib plus enzalutamide than for enzalutamide monotherapy. Combination therapy proved superior regardless of homologous recombination repair (HRR) pathway status, noted the authors.
“Not only did the combination therapy delay disease progression, it also significantly delayed progression of PSA [prostate-specific antigen] readings and the time until chemotherapy was needed compared to the control group,” said lead study author Neeraj Agarwal, MD, professor of medicine and director of the genitourinary oncology program at the Huntsman Cancer Institute, University of Utah, Salt Lake City.
“This is important because advanced prostate cancer can be associated with pain, fractures, suffering, and death. The current standard of care treatments were approved almost a decade ago, leaving a huge, unmet need for novel drugs in this setting,” he said.
The new results could pave the way for a prostate cancer indication for talazoparib; the company has said that it will submit these data to regulatory authorities. At present, the drug is approved only for use in BRCA+ breast cancer, an indication that was approved in 2018.
The findings were presented at the 2023 ASCO Genitourinary Cancers Symposium.
Overall, talazoparib plus enzalutamide resulted in a statistically significant and clinically meaningful improvement in PFS over placebo plus enzalutamide. “Results from the primary analysis of the TALAPRO-2 trial support the use of talazoparib plus enzalutamide as a first-line treatment in patients with mCRPC regardless of HRR gene alteration status,” Dr. Agarwal and colleagues concluded.
However, one expert disagreed with the authors’ conclusion regarding HHR pathway status. On the basis of imaging, PFS was 54% better in HHR-deficient patients in the combination therapy group. It was 30% better for patients with HHR-nondeficient tumors or tumors without known HHR status based on imaging and 34% better based on tumor tissue testing.
“There was a huge magnitude in benefit based on HHR, and I think HRR status matters,” commented Elena Castro, MD, PhD, Instituto de Investigación Biomédica de Málaga (Spain), who served as the invited discussant.
“We need to understand the benefit of ARPi [androgen receptor pathway inhibition] and PARP inhibitors better,” she said. “The balance between side effects and benefit depends on HRR status.”
Dr. Castro also noted that the treatment landscape has changed. ARPi is now a standard of care for metastatic prostate cancer, both for hormone-sensitive and castration-resistant disease. “So the question is, does the addition of a PARP inhibitor induce responses after progression to an ARPi in HHR-nondeficient tumors?”
Study details
In the TALAPRO-2 trial, Dr. Agarwal and colleagues randomly assigned 805 patients to receive either talazoparib 0.5 mg or placebo. All patients in the cohort received enzalutamide 160 mg daily.
Participants had mCRPC and were unselected for genetic alterations in DNA damage repair pathways directly or indirectly involved with HRR. They were aged 36-91 years (median age, 71). The cohort was enrolled from 25 countries, including the United States, Canada, Europe, South America, and countries in the Asia-Pacific region.
The men were stratified on the basis of prior use of abiraterone or docetaxel for castration-sensitive prostate cancer and HRR gene alteration status. The study’s primary endpoint was imaging-based PFS (ibPFS) by blinded independent central review (BICR).
Overall, median ibPFS by BICR was significantly improved in the combination group in comparison with the patients who received placebo; it was not reached versus 21.9 months (hazard ratio, 0.63; P < .001). It was also significantly improved among the HRR-deficient subgroup (HR, 0.46; P < .001) as well as in the HRR-nondeficient or unknown (HR, 0.70; P = .004) and HRR-nondeficient patients by tumor tissue testing (HR, 0.66; P = .009).
Talazoparib plus enzalutamide was also favored with regard to other endpoints. Dr. Agarwal noted that, while overall survival data are as yet immature, objective response rates, PSA response of at least 50%, and time to PSA progression and use of subsequent cytotoxic chemotherapy and antineoplastic therapy significantly favored the talazoparib group.
The objective response rate was 61.7% versus 43.9% (P = .005), with 37.5% versus 18.2% complete responses.
“The higher rates of complete response suggest a cooperative effect of talazoparib plus enzalutamide treatment,” he explained.
High rate of adverse events
The rate of treatment-emergent adverse events was higher among patients who received talazoparib plus enzalutamide; 71.9% of the patients who received talazoparib plus enzalutamide experienced grade 3-4 TEAEs versus 40.6%. The most common grade 3 or greater TEAEs in the talazoparib group were anemia, low neutrophil counts, and low platelet counts. Hypertension, anemia, and fatigue were the most common in the placebo group. Talazoparib was discontinued in 19.1% of patients because of TEAEs. Enzalutamide was discontinued in 10.8% of patients in the combination group versus 11.0% in the placebo group.
Dr. Agarwal pointed out that there were TEAEs of special interest for talazoparib. “Myelodysplastic syndrome was reported in one patient during the safety reporting period, and acute myeloid leukemia was reported in one patient during the follow-up period,” he said.
Additionally, pulmonary embolism was reported in 10 (2.5%) patients (grade 3 in 9 patients) in the talazoparib arm and in 3 (0.7%) patients (all grade 3) in the placebo arm.
Results less relevant
Commenting on the study, Matthew Zibelman, MD, associate professor, department of hematology/oncology, Fox Chase Cancer Center, Philadelphia, noted that these results represent an “intriguing finding for men with mCRPC, particularly in conjunction with the previously reported PROPEL study results.
“However, given that many patients receive an androgen receptor inhibitor now for metastatic castration-sensitive prostate cancer, these results are less relevant to current practice,” Dr. Zibelman said.
“Demonstration of an overall survival benefit of the combination would be optimal to change standard of care vs potential sequential therapy.”
The study was sponsored by Pfizer, manufacturer of enzalutamide and talazoparib. Dr. Agarwal has relationships with numerous pharmaceutical companies. Dr. Castro has relationships with Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Janssen-Cilag, Merck, MSD Oncology, Novartis and Pfizer, and Roche. Dr. Zibelman has relationships with Bristol-Myers Squibb, Exelixis, Pfizer, Jannsen, EMD Serono, and Blue Earth.
A version of this article first appeared on Medscape.com.
in the TALAPRO-2 trial.
As determined on the basis of imaging, PFS was 37% better for talazoparib plus enzalutamide than for enzalutamide monotherapy. Combination therapy proved superior regardless of homologous recombination repair (HRR) pathway status, noted the authors.
“Not only did the combination therapy delay disease progression, it also significantly delayed progression of PSA [prostate-specific antigen] readings and the time until chemotherapy was needed compared to the control group,” said lead study author Neeraj Agarwal, MD, professor of medicine and director of the genitourinary oncology program at the Huntsman Cancer Institute, University of Utah, Salt Lake City.
“This is important because advanced prostate cancer can be associated with pain, fractures, suffering, and death. The current standard of care treatments were approved almost a decade ago, leaving a huge, unmet need for novel drugs in this setting,” he said.
The new results could pave the way for a prostate cancer indication for talazoparib; the company has said that it will submit these data to regulatory authorities. At present, the drug is approved only for use in BRCA+ breast cancer, an indication that was approved in 2018.
The findings were presented at the 2023 ASCO Genitourinary Cancers Symposium.
Overall, talazoparib plus enzalutamide resulted in a statistically significant and clinically meaningful improvement in PFS over placebo plus enzalutamide. “Results from the primary analysis of the TALAPRO-2 trial support the use of talazoparib plus enzalutamide as a first-line treatment in patients with mCRPC regardless of HRR gene alteration status,” Dr. Agarwal and colleagues concluded.
However, one expert disagreed with the authors’ conclusion regarding HHR pathway status. On the basis of imaging, PFS was 54% better in HHR-deficient patients in the combination therapy group. It was 30% better for patients with HHR-nondeficient tumors or tumors without known HHR status based on imaging and 34% better based on tumor tissue testing.
“There was a huge magnitude in benefit based on HHR, and I think HRR status matters,” commented Elena Castro, MD, PhD, Instituto de Investigación Biomédica de Málaga (Spain), who served as the invited discussant.
“We need to understand the benefit of ARPi [androgen receptor pathway inhibition] and PARP inhibitors better,” she said. “The balance between side effects and benefit depends on HRR status.”
Dr. Castro also noted that the treatment landscape has changed. ARPi is now a standard of care for metastatic prostate cancer, both for hormone-sensitive and castration-resistant disease. “So the question is, does the addition of a PARP inhibitor induce responses after progression to an ARPi in HHR-nondeficient tumors?”
Study details
In the TALAPRO-2 trial, Dr. Agarwal and colleagues randomly assigned 805 patients to receive either talazoparib 0.5 mg or placebo. All patients in the cohort received enzalutamide 160 mg daily.
Participants had mCRPC and were unselected for genetic alterations in DNA damage repair pathways directly or indirectly involved with HRR. They were aged 36-91 years (median age, 71). The cohort was enrolled from 25 countries, including the United States, Canada, Europe, South America, and countries in the Asia-Pacific region.
The men were stratified on the basis of prior use of abiraterone or docetaxel for castration-sensitive prostate cancer and HRR gene alteration status. The study’s primary endpoint was imaging-based PFS (ibPFS) by blinded independent central review (BICR).
Overall, median ibPFS by BICR was significantly improved in the combination group in comparison with the patients who received placebo; it was not reached versus 21.9 months (hazard ratio, 0.63; P < .001). It was also significantly improved among the HRR-deficient subgroup (HR, 0.46; P < .001) as well as in the HRR-nondeficient or unknown (HR, 0.70; P = .004) and HRR-nondeficient patients by tumor tissue testing (HR, 0.66; P = .009).
Talazoparib plus enzalutamide was also favored with regard to other endpoints. Dr. Agarwal noted that, while overall survival data are as yet immature, objective response rates, PSA response of at least 50%, and time to PSA progression and use of subsequent cytotoxic chemotherapy and antineoplastic therapy significantly favored the talazoparib group.
The objective response rate was 61.7% versus 43.9% (P = .005), with 37.5% versus 18.2% complete responses.
“The higher rates of complete response suggest a cooperative effect of talazoparib plus enzalutamide treatment,” he explained.
High rate of adverse events
The rate of treatment-emergent adverse events was higher among patients who received talazoparib plus enzalutamide; 71.9% of the patients who received talazoparib plus enzalutamide experienced grade 3-4 TEAEs versus 40.6%. The most common grade 3 or greater TEAEs in the talazoparib group were anemia, low neutrophil counts, and low platelet counts. Hypertension, anemia, and fatigue were the most common in the placebo group. Talazoparib was discontinued in 19.1% of patients because of TEAEs. Enzalutamide was discontinued in 10.8% of patients in the combination group versus 11.0% in the placebo group.
Dr. Agarwal pointed out that there were TEAEs of special interest for talazoparib. “Myelodysplastic syndrome was reported in one patient during the safety reporting period, and acute myeloid leukemia was reported in one patient during the follow-up period,” he said.
Additionally, pulmonary embolism was reported in 10 (2.5%) patients (grade 3 in 9 patients) in the talazoparib arm and in 3 (0.7%) patients (all grade 3) in the placebo arm.
Results less relevant
Commenting on the study, Matthew Zibelman, MD, associate professor, department of hematology/oncology, Fox Chase Cancer Center, Philadelphia, noted that these results represent an “intriguing finding for men with mCRPC, particularly in conjunction with the previously reported PROPEL study results.
“However, given that many patients receive an androgen receptor inhibitor now for metastatic castration-sensitive prostate cancer, these results are less relevant to current practice,” Dr. Zibelman said.
“Demonstration of an overall survival benefit of the combination would be optimal to change standard of care vs potential sequential therapy.”
The study was sponsored by Pfizer, manufacturer of enzalutamide and talazoparib. Dr. Agarwal has relationships with numerous pharmaceutical companies. Dr. Castro has relationships with Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Janssen-Cilag, Merck, MSD Oncology, Novartis and Pfizer, and Roche. Dr. Zibelman has relationships with Bristol-Myers Squibb, Exelixis, Pfizer, Jannsen, EMD Serono, and Blue Earth.
A version of this article first appeared on Medscape.com.
in the TALAPRO-2 trial.
As determined on the basis of imaging, PFS was 37% better for talazoparib plus enzalutamide than for enzalutamide monotherapy. Combination therapy proved superior regardless of homologous recombination repair (HRR) pathway status, noted the authors.
“Not only did the combination therapy delay disease progression, it also significantly delayed progression of PSA [prostate-specific antigen] readings and the time until chemotherapy was needed compared to the control group,” said lead study author Neeraj Agarwal, MD, professor of medicine and director of the genitourinary oncology program at the Huntsman Cancer Institute, University of Utah, Salt Lake City.
“This is important because advanced prostate cancer can be associated with pain, fractures, suffering, and death. The current standard of care treatments were approved almost a decade ago, leaving a huge, unmet need for novel drugs in this setting,” he said.
The new results could pave the way for a prostate cancer indication for talazoparib; the company has said that it will submit these data to regulatory authorities. At present, the drug is approved only for use in BRCA+ breast cancer, an indication that was approved in 2018.
The findings were presented at the 2023 ASCO Genitourinary Cancers Symposium.
Overall, talazoparib plus enzalutamide resulted in a statistically significant and clinically meaningful improvement in PFS over placebo plus enzalutamide. “Results from the primary analysis of the TALAPRO-2 trial support the use of talazoparib plus enzalutamide as a first-line treatment in patients with mCRPC regardless of HRR gene alteration status,” Dr. Agarwal and colleagues concluded.
However, one expert disagreed with the authors’ conclusion regarding HHR pathway status. On the basis of imaging, PFS was 54% better in HHR-deficient patients in the combination therapy group. It was 30% better for patients with HHR-nondeficient tumors or tumors without known HHR status based on imaging and 34% better based on tumor tissue testing.
“There was a huge magnitude in benefit based on HHR, and I think HRR status matters,” commented Elena Castro, MD, PhD, Instituto de Investigación Biomédica de Málaga (Spain), who served as the invited discussant.
“We need to understand the benefit of ARPi [androgen receptor pathway inhibition] and PARP inhibitors better,” she said. “The balance between side effects and benefit depends on HRR status.”
Dr. Castro also noted that the treatment landscape has changed. ARPi is now a standard of care for metastatic prostate cancer, both for hormone-sensitive and castration-resistant disease. “So the question is, does the addition of a PARP inhibitor induce responses after progression to an ARPi in HHR-nondeficient tumors?”
Study details
In the TALAPRO-2 trial, Dr. Agarwal and colleagues randomly assigned 805 patients to receive either talazoparib 0.5 mg or placebo. All patients in the cohort received enzalutamide 160 mg daily.
Participants had mCRPC and were unselected for genetic alterations in DNA damage repair pathways directly or indirectly involved with HRR. They were aged 36-91 years (median age, 71). The cohort was enrolled from 25 countries, including the United States, Canada, Europe, South America, and countries in the Asia-Pacific region.
The men were stratified on the basis of prior use of abiraterone or docetaxel for castration-sensitive prostate cancer and HRR gene alteration status. The study’s primary endpoint was imaging-based PFS (ibPFS) by blinded independent central review (BICR).
Overall, median ibPFS by BICR was significantly improved in the combination group in comparison with the patients who received placebo; it was not reached versus 21.9 months (hazard ratio, 0.63; P < .001). It was also significantly improved among the HRR-deficient subgroup (HR, 0.46; P < .001) as well as in the HRR-nondeficient or unknown (HR, 0.70; P = .004) and HRR-nondeficient patients by tumor tissue testing (HR, 0.66; P = .009).
Talazoparib plus enzalutamide was also favored with regard to other endpoints. Dr. Agarwal noted that, while overall survival data are as yet immature, objective response rates, PSA response of at least 50%, and time to PSA progression and use of subsequent cytotoxic chemotherapy and antineoplastic therapy significantly favored the talazoparib group.
The objective response rate was 61.7% versus 43.9% (P = .005), with 37.5% versus 18.2% complete responses.
“The higher rates of complete response suggest a cooperative effect of talazoparib plus enzalutamide treatment,” he explained.
High rate of adverse events
The rate of treatment-emergent adverse events was higher among patients who received talazoparib plus enzalutamide; 71.9% of the patients who received talazoparib plus enzalutamide experienced grade 3-4 TEAEs versus 40.6%. The most common grade 3 or greater TEAEs in the talazoparib group were anemia, low neutrophil counts, and low platelet counts. Hypertension, anemia, and fatigue were the most common in the placebo group. Talazoparib was discontinued in 19.1% of patients because of TEAEs. Enzalutamide was discontinued in 10.8% of patients in the combination group versus 11.0% in the placebo group.
Dr. Agarwal pointed out that there were TEAEs of special interest for talazoparib. “Myelodysplastic syndrome was reported in one patient during the safety reporting period, and acute myeloid leukemia was reported in one patient during the follow-up period,” he said.
Additionally, pulmonary embolism was reported in 10 (2.5%) patients (grade 3 in 9 patients) in the talazoparib arm and in 3 (0.7%) patients (all grade 3) in the placebo arm.
Results less relevant
Commenting on the study, Matthew Zibelman, MD, associate professor, department of hematology/oncology, Fox Chase Cancer Center, Philadelphia, noted that these results represent an “intriguing finding for men with mCRPC, particularly in conjunction with the previously reported PROPEL study results.
“However, given that many patients receive an androgen receptor inhibitor now for metastatic castration-sensitive prostate cancer, these results are less relevant to current practice,” Dr. Zibelman said.
“Demonstration of an overall survival benefit of the combination would be optimal to change standard of care vs potential sequential therapy.”
The study was sponsored by Pfizer, manufacturer of enzalutamide and talazoparib. Dr. Agarwal has relationships with numerous pharmaceutical companies. Dr. Castro has relationships with Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Janssen-Cilag, Merck, MSD Oncology, Novartis and Pfizer, and Roche. Dr. Zibelman has relationships with Bristol-Myers Squibb, Exelixis, Pfizer, Jannsen, EMD Serono, and Blue Earth.
A version of this article first appeared on Medscape.com.
AT ASCO GU 2023
Adjuvant nivolumab as standard of care in resected bladder cancer
Extended follow-up data from the phase 3 CheckMate 274 trial continue to show that, compared with placebo, nivolumab improves disease-free survival, nonurothelial tract recurrence-free survival (NUTRFS), and distant metastasis-free survival (DMFS) in patients with high-risk, muscle-invasive urothelial cancer after undergoing radical surgery.
The benefit was observed in both in the intent-to-treat population (ITT) and in the subset of patients with programmed death–ligand 1 (PD-L1) expression of at least 1%.
“In the ITT population, median disease-free survival with nivolumab was doubled compared to placebo,” said lead author Matthew Galsky, MD, director of genitourinary medical oncology and codirector of the Center of Excellence for Bladder Cancer at Tisch Cancer Institute, New York. “For the patients with high PD-L1 expression, the median disease-free survival with nivolumab reached 52.6 months, more than six times that of the placebo arm.
“These results further support adjuvant nivolumab as a standard of care in high-risk muscle-invasive urothelial cancer after resection,” he concluded.
Dr. Galsky presented the findings at the 2023 ASCO Genitourinary Cancers Symposium.
Practice changing
The earlier results of this study have already led to an approval from the Food and Drug Administration. In August 2021, nivolumab became the first adjuvant immunotherapy for use in patients with urothelial carcinoma at high risk for recurrence after radical resection
“This is a practice-changing study,” said Scot Niglio, MD, medical oncologist, New York University Perlmutter Cancer Center, who was approached for an independent comment.
“For decades, there were limited to zero treatment options in the postsurgical setting for urothelial cancer patients with a high recurrence risk,” he said.
The standard of care for muscle-invasive urothelial carcinoma is surgery, which may include neoadjuvant cisplatin-based chemotherapy, but most patients will experience disease recurrence, he explained.
“When urothelial cancer recurs outside the urinary tract, the prognosis quickly changes from curable to incurable,” he said, “making this area of research paramount.”
Dr. Niglio emphasized that these updated results show continued benefit from nivolumab on disease-free survival, as well as nonurothelial tract recurrence-free survival and distant metastasis-free survival, supporting its use as standard of care therapy.
“Even though the overall survival data is still maturing, the current data remains promising,” he said. “Patients with urothelial cancer meeting the criteria for high risk now have a treatment option to mitigate the potential of distant recurrence.”
In his own practice, Dr. Niglio added that he will “continue to discuss adjuvant nivolumab as a potential treatment option with all patients who are eligible based on this study.”
Met all endpoints
The Checkmate 274 trial involved 353 patients (of whom 140 patients had PD-L1 ≥ 1%) randomly assigned to take nivolumab 240 mg every 2 weeks and 356 patients (with 142 patients with PD-L1 ≥ 1%) randomized to placebo. All patients had pathologic evidence of urothelial cancer at high risk of recurrence and Eastern Cooperative Oncology Group performance status (ECOG PS) of1 or less.
Previous results, at a median follow-up of about 20 months, show that the study met its primary endpoint, showing significant prolongation of disease-free survival in the intention-to-treat population, with nivolumab at 21 months versus placebo at 10.9 months (hazard ratio, 0.70; P < .001).
When the analysis considered only patients with tumors expressing PD-L1 of at least 1%, the median disease-free survival was even higher (not reached vs. 10.8 months; HR, 0.53; P < .001).
Nivolumab was also superior to placebo for NUTRFS, in both in the entire ITT population and in the subset with PD-L1–positive tumors.
The latest results come from a median follow-up of 36.1 months. The median disease-free survival was 22 months with nivolumab, compared with 10.9 months with placebo in ITT patients and 52.6 months on nivolumab versus 8.4 months in patients with PD-L1 of at least 1%.
Nivolumab was superior to placebo for secondary and exploratory endpoints, NUTRFS (ITT: HR, 0.72 and PD-L1 ≥ 1%: HR, 0.53) and DMFS (ITT: HR, 0.74; PD-L1 ≥ 1%: HR, 0.58). However, overall survival data remained immature and will be assessed as a future data cutoff, Dr. Galsky explained.
The updated analysis also included another exploratory endpoint, progression-free survival 2 (PFS2), defined as time from randomization to disease progression after subsequent next-line systemic therapy, start of second subsequent next-line systemic therapy, or death.
Median PFS2 was 61.2 months for all-patients who received nivolumab versus 47.1 months with placebo (HR, 0.79). In the PD-L1 of 1% or greater subgroup, median PFS2 was not reached with nivolumab versus 39.4 months with placebo (HR, 0.54).
Grade 3-4 treatment-related adverse events occurred in 18.2% and 7.2% of patients (nivolumab vs. placebo), and this was consistent with the primary analysis. “No new safety signals were identified,” said Dr. Galsky.
The CheckMate 274 trial was funded by Bristol-Myers Squibb, manufacturer of nivolumab. Dr. Galsky reported relationships with numerous pharmaceutical companies.
A version of this article first appeared on Medscape.com.
Extended follow-up data from the phase 3 CheckMate 274 trial continue to show that, compared with placebo, nivolumab improves disease-free survival, nonurothelial tract recurrence-free survival (NUTRFS), and distant metastasis-free survival (DMFS) in patients with high-risk, muscle-invasive urothelial cancer after undergoing radical surgery.
The benefit was observed in both in the intent-to-treat population (ITT) and in the subset of patients with programmed death–ligand 1 (PD-L1) expression of at least 1%.
“In the ITT population, median disease-free survival with nivolumab was doubled compared to placebo,” said lead author Matthew Galsky, MD, director of genitourinary medical oncology and codirector of the Center of Excellence for Bladder Cancer at Tisch Cancer Institute, New York. “For the patients with high PD-L1 expression, the median disease-free survival with nivolumab reached 52.6 months, more than six times that of the placebo arm.
“These results further support adjuvant nivolumab as a standard of care in high-risk muscle-invasive urothelial cancer after resection,” he concluded.
Dr. Galsky presented the findings at the 2023 ASCO Genitourinary Cancers Symposium.
Practice changing
The earlier results of this study have already led to an approval from the Food and Drug Administration. In August 2021, nivolumab became the first adjuvant immunotherapy for use in patients with urothelial carcinoma at high risk for recurrence after radical resection
“This is a practice-changing study,” said Scot Niglio, MD, medical oncologist, New York University Perlmutter Cancer Center, who was approached for an independent comment.
“For decades, there were limited to zero treatment options in the postsurgical setting for urothelial cancer patients with a high recurrence risk,” he said.
The standard of care for muscle-invasive urothelial carcinoma is surgery, which may include neoadjuvant cisplatin-based chemotherapy, but most patients will experience disease recurrence, he explained.
“When urothelial cancer recurs outside the urinary tract, the prognosis quickly changes from curable to incurable,” he said, “making this area of research paramount.”
Dr. Niglio emphasized that these updated results show continued benefit from nivolumab on disease-free survival, as well as nonurothelial tract recurrence-free survival and distant metastasis-free survival, supporting its use as standard of care therapy.
“Even though the overall survival data is still maturing, the current data remains promising,” he said. “Patients with urothelial cancer meeting the criteria for high risk now have a treatment option to mitigate the potential of distant recurrence.”
In his own practice, Dr. Niglio added that he will “continue to discuss adjuvant nivolumab as a potential treatment option with all patients who are eligible based on this study.”
Met all endpoints
The Checkmate 274 trial involved 353 patients (of whom 140 patients had PD-L1 ≥ 1%) randomly assigned to take nivolumab 240 mg every 2 weeks and 356 patients (with 142 patients with PD-L1 ≥ 1%) randomized to placebo. All patients had pathologic evidence of urothelial cancer at high risk of recurrence and Eastern Cooperative Oncology Group performance status (ECOG PS) of1 or less.
Previous results, at a median follow-up of about 20 months, show that the study met its primary endpoint, showing significant prolongation of disease-free survival in the intention-to-treat population, with nivolumab at 21 months versus placebo at 10.9 months (hazard ratio, 0.70; P < .001).
When the analysis considered only patients with tumors expressing PD-L1 of at least 1%, the median disease-free survival was even higher (not reached vs. 10.8 months; HR, 0.53; P < .001).
Nivolumab was also superior to placebo for NUTRFS, in both in the entire ITT population and in the subset with PD-L1–positive tumors.
The latest results come from a median follow-up of 36.1 months. The median disease-free survival was 22 months with nivolumab, compared with 10.9 months with placebo in ITT patients and 52.6 months on nivolumab versus 8.4 months in patients with PD-L1 of at least 1%.
Nivolumab was superior to placebo for secondary and exploratory endpoints, NUTRFS (ITT: HR, 0.72 and PD-L1 ≥ 1%: HR, 0.53) and DMFS (ITT: HR, 0.74; PD-L1 ≥ 1%: HR, 0.58). However, overall survival data remained immature and will be assessed as a future data cutoff, Dr. Galsky explained.
The updated analysis also included another exploratory endpoint, progression-free survival 2 (PFS2), defined as time from randomization to disease progression after subsequent next-line systemic therapy, start of second subsequent next-line systemic therapy, or death.
Median PFS2 was 61.2 months for all-patients who received nivolumab versus 47.1 months with placebo (HR, 0.79). In the PD-L1 of 1% or greater subgroup, median PFS2 was not reached with nivolumab versus 39.4 months with placebo (HR, 0.54).
Grade 3-4 treatment-related adverse events occurred in 18.2% and 7.2% of patients (nivolumab vs. placebo), and this was consistent with the primary analysis. “No new safety signals were identified,” said Dr. Galsky.
The CheckMate 274 trial was funded by Bristol-Myers Squibb, manufacturer of nivolumab. Dr. Galsky reported relationships with numerous pharmaceutical companies.
A version of this article first appeared on Medscape.com.
Extended follow-up data from the phase 3 CheckMate 274 trial continue to show that, compared with placebo, nivolumab improves disease-free survival, nonurothelial tract recurrence-free survival (NUTRFS), and distant metastasis-free survival (DMFS) in patients with high-risk, muscle-invasive urothelial cancer after undergoing radical surgery.
The benefit was observed in both in the intent-to-treat population (ITT) and in the subset of patients with programmed death–ligand 1 (PD-L1) expression of at least 1%.
“In the ITT population, median disease-free survival with nivolumab was doubled compared to placebo,” said lead author Matthew Galsky, MD, director of genitourinary medical oncology and codirector of the Center of Excellence for Bladder Cancer at Tisch Cancer Institute, New York. “For the patients with high PD-L1 expression, the median disease-free survival with nivolumab reached 52.6 months, more than six times that of the placebo arm.
“These results further support adjuvant nivolumab as a standard of care in high-risk muscle-invasive urothelial cancer after resection,” he concluded.
Dr. Galsky presented the findings at the 2023 ASCO Genitourinary Cancers Symposium.
Practice changing
The earlier results of this study have already led to an approval from the Food and Drug Administration. In August 2021, nivolumab became the first adjuvant immunotherapy for use in patients with urothelial carcinoma at high risk for recurrence after radical resection
“This is a practice-changing study,” said Scot Niglio, MD, medical oncologist, New York University Perlmutter Cancer Center, who was approached for an independent comment.
“For decades, there were limited to zero treatment options in the postsurgical setting for urothelial cancer patients with a high recurrence risk,” he said.
The standard of care for muscle-invasive urothelial carcinoma is surgery, which may include neoadjuvant cisplatin-based chemotherapy, but most patients will experience disease recurrence, he explained.
“When urothelial cancer recurs outside the urinary tract, the prognosis quickly changes from curable to incurable,” he said, “making this area of research paramount.”
Dr. Niglio emphasized that these updated results show continued benefit from nivolumab on disease-free survival, as well as nonurothelial tract recurrence-free survival and distant metastasis-free survival, supporting its use as standard of care therapy.
“Even though the overall survival data is still maturing, the current data remains promising,” he said. “Patients with urothelial cancer meeting the criteria for high risk now have a treatment option to mitigate the potential of distant recurrence.”
In his own practice, Dr. Niglio added that he will “continue to discuss adjuvant nivolumab as a potential treatment option with all patients who are eligible based on this study.”
Met all endpoints
The Checkmate 274 trial involved 353 patients (of whom 140 patients had PD-L1 ≥ 1%) randomly assigned to take nivolumab 240 mg every 2 weeks and 356 patients (with 142 patients with PD-L1 ≥ 1%) randomized to placebo. All patients had pathologic evidence of urothelial cancer at high risk of recurrence and Eastern Cooperative Oncology Group performance status (ECOG PS) of1 or less.
Previous results, at a median follow-up of about 20 months, show that the study met its primary endpoint, showing significant prolongation of disease-free survival in the intention-to-treat population, with nivolumab at 21 months versus placebo at 10.9 months (hazard ratio, 0.70; P < .001).
When the analysis considered only patients with tumors expressing PD-L1 of at least 1%, the median disease-free survival was even higher (not reached vs. 10.8 months; HR, 0.53; P < .001).
Nivolumab was also superior to placebo for NUTRFS, in both in the entire ITT population and in the subset with PD-L1–positive tumors.
The latest results come from a median follow-up of 36.1 months. The median disease-free survival was 22 months with nivolumab, compared with 10.9 months with placebo in ITT patients and 52.6 months on nivolumab versus 8.4 months in patients with PD-L1 of at least 1%.
Nivolumab was superior to placebo for secondary and exploratory endpoints, NUTRFS (ITT: HR, 0.72 and PD-L1 ≥ 1%: HR, 0.53) and DMFS (ITT: HR, 0.74; PD-L1 ≥ 1%: HR, 0.58). However, overall survival data remained immature and will be assessed as a future data cutoff, Dr. Galsky explained.
The updated analysis also included another exploratory endpoint, progression-free survival 2 (PFS2), defined as time from randomization to disease progression after subsequent next-line systemic therapy, start of second subsequent next-line systemic therapy, or death.
Median PFS2 was 61.2 months for all-patients who received nivolumab versus 47.1 months with placebo (HR, 0.79). In the PD-L1 of 1% or greater subgroup, median PFS2 was not reached with nivolumab versus 39.4 months with placebo (HR, 0.54).
Grade 3-4 treatment-related adverse events occurred in 18.2% and 7.2% of patients (nivolumab vs. placebo), and this was consistent with the primary analysis. “No new safety signals were identified,” said Dr. Galsky.
The CheckMate 274 trial was funded by Bristol-Myers Squibb, manufacturer of nivolumab. Dr. Galsky reported relationships with numerous pharmaceutical companies.
A version of this article first appeared on Medscape.com.
AT ASCO GU 2023
Rucaparib benefit in BRCA+ prostate cancer confirmed
The finding, which comes from the TRITON3 clinical trial, provides evidence of clinical benefit for an indication for rucaparib that was granted an accelerated approval in May 2020.
“Rucaparib reduced the risk of progression or death by half in patients with BRCA alterations,” said lead author Alan H. Bryce, MD, medical director of the Genomic Oncology Clinic at Mayo Clinic Arizona, in Phoenix.
For the subgroup of patients with BRCA alterations, the median PFS was 11.2 months with rucaparib vs. 6.4 months (hazard ratio, 0.50; P < .001) among those who received physician’s choice of therapy, which included docetaxel or a second-generation ARPI, such as abiraterone or enzalutamide.
In another subgroup of patients whose disease had ATM alterations, the median PFS was 8.1 months with rucaparib vs. 6.8 months with physician’s choice of drug. The difference was not statistically significant.
However, the difference was significant in the intention-to-treat (ITT) population (comprising both subgroups), for whom the median PFS was 10.2 months with rucaparib vs. 6.4 months with physician’s choice of drug (HR, 0.61; P < .001 by log-rank test).
Dr. Bryce pointed out that three-quarters of the patients in the physician’s-choice arm who had progressive disease crossed over to rucaparib upon progression and that overall survival (OS) results are immature. At 62 months, median OS did not significantly differ in the BRCA subgroup (24.3 vs. 20.8 months favoring rucaparib; P = .21) or in the ITT group (23.6 vs. 20.9 months; P = .67).
Importantly, rucaparib was well tolerated. In all treatment groups, the most frequent adverse events were asthenia and fatigue, Bryce said. “There were no cases of myelodysplastic syndrome or acute myeloid leukemia reported.”
These results from the TRITON3 trial were presented at the 2023 ASCO Genitourinary Cancers Symposium and were published simultaneously in the New England Journal of Medicine.
Suggested benefit
Rucaparib is the first PARP inhibitor approved for use in patients with mCRPC that harbors deleterious BRCA mutations (germline and/or somatic) who have already been treated with androgen receptor–directed therapy and a taxane-based chemotherapy. This prostate cancer indication was granted an accelerated approval in May 2020 by the U.S. Food and Drug Administration on the basis of response rates and effect on levels of prostate-specific antigen (PSA) from the TRITON2 clinical trial, the forerunner of the current study.
The TRITON2 study was a single-arm clinical trial that involved three cohorts: 62 patients with a BRCA mutation (germline and/or somatic) and measurable disease; 115 patients with a BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease; and 209 patients with homologous recombination deficiency–positive mCRPC.
In an analysis of 115 patients with a deleterious BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease, the confirmed PSA response rate was 55%. For the patients with measurable disease and a BRCA mutation, the objective response rate was 44%. The objective response rate was similar for those with a germline BRCA mutation.
Study details
The current phase 3 randomized TRITON3 clinical trial was conducted to confirm the earlier findings and to expand upon the data in mCRPC. The participants in this trial were patients with mCRPC who had specific gene alterations, including BRCA and ATM alterations, who had experienced disease progression after androgen receptor–directed therapy but who had not yet received chemotherapy.
A total of 270 men were assigned to receive rucaparib (600 mg twice daily); 135 patients received their physician’s choice of medication. Within the two study arms, 302 patients had a BRCA alteration, and 103 patients had an ATM alteration. The ITT population consisted of all the patients who had been randomly assigned to either of the two groups. A prespecified subgroup included patients with a BRCA alteration.
The primary outcome was the median duration of imaging-based PSF, as determined through independent review. Key secondary outcomes were overall survival and objective response rate.
The most common adverse events in the rucaparib group were fatigue, nausea, and anemia or decreased hemoglobin. In the control group, the most common adverse events were fatigue, diarrhea, and neuropathy. The most common events of grade 3 or higher were anemia or decreased hemoglobin, neutropenia or a decreased neutrophil count, and fatigue in the rucaparib group, and fatigue and neutropenia or a decreased neutrophil count among control patients.
No changes in standard of care
In a discussion of the study, Elena Castro, MD, PhD, of the Instituto de Investigación Biomédica de Málaga, Campanillas, Spain, emphasized that there is a clear benefit from the use of PARP inhibitors (such as rucaparib) for patients with BRCA alterations.
However, she highlighted the absence of convincing overall survival data and the absence of a clear benefit on PFS in the subgroup of patients with ATM alterations.
“These data raise several questions,” she noted, “such as, do patients with ATM alterations benefit at all? And should PARP inhibitors [such as rucaparib] precede or follow docetaxel therapy?”
Because of the high crossover rate, it may be possible to evaluate the directionality of docetaxel followed by PARP inhibitors and the other way around, she suggested.
Dr. Castro said that patients with BRCA alterations benefit from PARP inhibitors and are likely to derive more benefit from them than from taxanes.
“But those with ATM alterations are unlikely to benefit from rucaparib more than from taxanes,” she said.
In a comment, Hank Ng, MD, medical oncologist, NYU Langone Perlmutter Cancer Center, New York, said he is not convinced that the findings from TRITON 3 represent a new standard of care in BRCA 1/2 mutations or ATM.
“Currently, we know that, for patients with prostate cancer with BRCA1/2 or ATM, the standard of care is an androgen receptor pathway inhibitor (ARPI), such as abiraterone or enzalutamide, then docetaxel, and then a PARP inhibitor like rucaparib,” he said.
(Currently, rucaparib is indicated for use in patients with mCRPC with BRCA alterations after they have already received an ARPI and taxane-based chemotherapy.)
Dr. Ng also questioned the control arm of the TRITON 3 trial. All the participants in the trial had already experienced disease progression after treatment with a second-generation ARPI. But the physician’s choice of therapy allowed them to move on to another ARPI or to docetaxel.
Dr. NG commented that, “in almost all cases, after progression of one ARPI, switching to another ARPI does not provide much benefit – from what is visible from this abstract – and only 56% patients received docetaxel, and thus 44% received a not-beneficial treatment,” he said.
“I am not sure what the docetaxel subgroup showed, but potentially, if those numbers are convincing, we could move this [rucaparib] ahead of docetaxel,” he speculated.
However, he also pointed out that an overall survival benefit has not yet been shown; so far, the benefit that has been shown is with respect to imaging-based PFS.
Dr. Ng does agree that rucaparib is indicated in the second line after progression with one ARPI for patients who are not candidates for chemotherapy. “But this has not yet shown me that we should absolutely be offering rucaparib before docetaxel,” he said.
TRITON3 was supported by Clovis Oncology, manufacturer of rucaparib. Dr. Bryce has relationships with Bayer, Foundation Medicine, Janssen, Merck, Myovant Sciences, and Novartis and holds a patent for therapeutic targeting of cancer patients with NRG1 rearrangements. Dr. Castro has relationships with Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Janssen-Cilag, Merck, MSD Oncology, Novartis, Pfizer, and Roche.
A version of this article first appeared on Medscape.com.
The finding, which comes from the TRITON3 clinical trial, provides evidence of clinical benefit for an indication for rucaparib that was granted an accelerated approval in May 2020.
“Rucaparib reduced the risk of progression or death by half in patients with BRCA alterations,” said lead author Alan H. Bryce, MD, medical director of the Genomic Oncology Clinic at Mayo Clinic Arizona, in Phoenix.
For the subgroup of patients with BRCA alterations, the median PFS was 11.2 months with rucaparib vs. 6.4 months (hazard ratio, 0.50; P < .001) among those who received physician’s choice of therapy, which included docetaxel or a second-generation ARPI, such as abiraterone or enzalutamide.
In another subgroup of patients whose disease had ATM alterations, the median PFS was 8.1 months with rucaparib vs. 6.8 months with physician’s choice of drug. The difference was not statistically significant.
However, the difference was significant in the intention-to-treat (ITT) population (comprising both subgroups), for whom the median PFS was 10.2 months with rucaparib vs. 6.4 months with physician’s choice of drug (HR, 0.61; P < .001 by log-rank test).
Dr. Bryce pointed out that three-quarters of the patients in the physician’s-choice arm who had progressive disease crossed over to rucaparib upon progression and that overall survival (OS) results are immature. At 62 months, median OS did not significantly differ in the BRCA subgroup (24.3 vs. 20.8 months favoring rucaparib; P = .21) or in the ITT group (23.6 vs. 20.9 months; P = .67).
Importantly, rucaparib was well tolerated. In all treatment groups, the most frequent adverse events were asthenia and fatigue, Bryce said. “There were no cases of myelodysplastic syndrome or acute myeloid leukemia reported.”
These results from the TRITON3 trial were presented at the 2023 ASCO Genitourinary Cancers Symposium and were published simultaneously in the New England Journal of Medicine.
Suggested benefit
Rucaparib is the first PARP inhibitor approved for use in patients with mCRPC that harbors deleterious BRCA mutations (germline and/or somatic) who have already been treated with androgen receptor–directed therapy and a taxane-based chemotherapy. This prostate cancer indication was granted an accelerated approval in May 2020 by the U.S. Food and Drug Administration on the basis of response rates and effect on levels of prostate-specific antigen (PSA) from the TRITON2 clinical trial, the forerunner of the current study.
The TRITON2 study was a single-arm clinical trial that involved three cohorts: 62 patients with a BRCA mutation (germline and/or somatic) and measurable disease; 115 patients with a BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease; and 209 patients with homologous recombination deficiency–positive mCRPC.
In an analysis of 115 patients with a deleterious BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease, the confirmed PSA response rate was 55%. For the patients with measurable disease and a BRCA mutation, the objective response rate was 44%. The objective response rate was similar for those with a germline BRCA mutation.
Study details
The current phase 3 randomized TRITON3 clinical trial was conducted to confirm the earlier findings and to expand upon the data in mCRPC. The participants in this trial were patients with mCRPC who had specific gene alterations, including BRCA and ATM alterations, who had experienced disease progression after androgen receptor–directed therapy but who had not yet received chemotherapy.
A total of 270 men were assigned to receive rucaparib (600 mg twice daily); 135 patients received their physician’s choice of medication. Within the two study arms, 302 patients had a BRCA alteration, and 103 patients had an ATM alteration. The ITT population consisted of all the patients who had been randomly assigned to either of the two groups. A prespecified subgroup included patients with a BRCA alteration.
The primary outcome was the median duration of imaging-based PSF, as determined through independent review. Key secondary outcomes were overall survival and objective response rate.
The most common adverse events in the rucaparib group were fatigue, nausea, and anemia or decreased hemoglobin. In the control group, the most common adverse events were fatigue, diarrhea, and neuropathy. The most common events of grade 3 or higher were anemia or decreased hemoglobin, neutropenia or a decreased neutrophil count, and fatigue in the rucaparib group, and fatigue and neutropenia or a decreased neutrophil count among control patients.
No changes in standard of care
In a discussion of the study, Elena Castro, MD, PhD, of the Instituto de Investigación Biomédica de Málaga, Campanillas, Spain, emphasized that there is a clear benefit from the use of PARP inhibitors (such as rucaparib) for patients with BRCA alterations.
However, she highlighted the absence of convincing overall survival data and the absence of a clear benefit on PFS in the subgroup of patients with ATM alterations.
“These data raise several questions,” she noted, “such as, do patients with ATM alterations benefit at all? And should PARP inhibitors [such as rucaparib] precede or follow docetaxel therapy?”
Because of the high crossover rate, it may be possible to evaluate the directionality of docetaxel followed by PARP inhibitors and the other way around, she suggested.
Dr. Castro said that patients with BRCA alterations benefit from PARP inhibitors and are likely to derive more benefit from them than from taxanes.
“But those with ATM alterations are unlikely to benefit from rucaparib more than from taxanes,” she said.
In a comment, Hank Ng, MD, medical oncologist, NYU Langone Perlmutter Cancer Center, New York, said he is not convinced that the findings from TRITON 3 represent a new standard of care in BRCA 1/2 mutations or ATM.
“Currently, we know that, for patients with prostate cancer with BRCA1/2 or ATM, the standard of care is an androgen receptor pathway inhibitor (ARPI), such as abiraterone or enzalutamide, then docetaxel, and then a PARP inhibitor like rucaparib,” he said.
(Currently, rucaparib is indicated for use in patients with mCRPC with BRCA alterations after they have already received an ARPI and taxane-based chemotherapy.)
Dr. Ng also questioned the control arm of the TRITON 3 trial. All the participants in the trial had already experienced disease progression after treatment with a second-generation ARPI. But the physician’s choice of therapy allowed them to move on to another ARPI or to docetaxel.
Dr. NG commented that, “in almost all cases, after progression of one ARPI, switching to another ARPI does not provide much benefit – from what is visible from this abstract – and only 56% patients received docetaxel, and thus 44% received a not-beneficial treatment,” he said.
“I am not sure what the docetaxel subgroup showed, but potentially, if those numbers are convincing, we could move this [rucaparib] ahead of docetaxel,” he speculated.
However, he also pointed out that an overall survival benefit has not yet been shown; so far, the benefit that has been shown is with respect to imaging-based PFS.
Dr. Ng does agree that rucaparib is indicated in the second line after progression with one ARPI for patients who are not candidates for chemotherapy. “But this has not yet shown me that we should absolutely be offering rucaparib before docetaxel,” he said.
TRITON3 was supported by Clovis Oncology, manufacturer of rucaparib. Dr. Bryce has relationships with Bayer, Foundation Medicine, Janssen, Merck, Myovant Sciences, and Novartis and holds a patent for therapeutic targeting of cancer patients with NRG1 rearrangements. Dr. Castro has relationships with Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Janssen-Cilag, Merck, MSD Oncology, Novartis, Pfizer, and Roche.
A version of this article first appeared on Medscape.com.
The finding, which comes from the TRITON3 clinical trial, provides evidence of clinical benefit for an indication for rucaparib that was granted an accelerated approval in May 2020.
“Rucaparib reduced the risk of progression or death by half in patients with BRCA alterations,” said lead author Alan H. Bryce, MD, medical director of the Genomic Oncology Clinic at Mayo Clinic Arizona, in Phoenix.
For the subgroup of patients with BRCA alterations, the median PFS was 11.2 months with rucaparib vs. 6.4 months (hazard ratio, 0.50; P < .001) among those who received physician’s choice of therapy, which included docetaxel or a second-generation ARPI, such as abiraterone or enzalutamide.
In another subgroup of patients whose disease had ATM alterations, the median PFS was 8.1 months with rucaparib vs. 6.8 months with physician’s choice of drug. The difference was not statistically significant.
However, the difference was significant in the intention-to-treat (ITT) population (comprising both subgroups), for whom the median PFS was 10.2 months with rucaparib vs. 6.4 months with physician’s choice of drug (HR, 0.61; P < .001 by log-rank test).
Dr. Bryce pointed out that three-quarters of the patients in the physician’s-choice arm who had progressive disease crossed over to rucaparib upon progression and that overall survival (OS) results are immature. At 62 months, median OS did not significantly differ in the BRCA subgroup (24.3 vs. 20.8 months favoring rucaparib; P = .21) or in the ITT group (23.6 vs. 20.9 months; P = .67).
Importantly, rucaparib was well tolerated. In all treatment groups, the most frequent adverse events were asthenia and fatigue, Bryce said. “There were no cases of myelodysplastic syndrome or acute myeloid leukemia reported.”
These results from the TRITON3 trial were presented at the 2023 ASCO Genitourinary Cancers Symposium and were published simultaneously in the New England Journal of Medicine.
Suggested benefit
Rucaparib is the first PARP inhibitor approved for use in patients with mCRPC that harbors deleterious BRCA mutations (germline and/or somatic) who have already been treated with androgen receptor–directed therapy and a taxane-based chemotherapy. This prostate cancer indication was granted an accelerated approval in May 2020 by the U.S. Food and Drug Administration on the basis of response rates and effect on levels of prostate-specific antigen (PSA) from the TRITON2 clinical trial, the forerunner of the current study.
The TRITON2 study was a single-arm clinical trial that involved three cohorts: 62 patients with a BRCA mutation (germline and/or somatic) and measurable disease; 115 patients with a BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease; and 209 patients with homologous recombination deficiency–positive mCRPC.
In an analysis of 115 patients with a deleterious BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease, the confirmed PSA response rate was 55%. For the patients with measurable disease and a BRCA mutation, the objective response rate was 44%. The objective response rate was similar for those with a germline BRCA mutation.
Study details
The current phase 3 randomized TRITON3 clinical trial was conducted to confirm the earlier findings and to expand upon the data in mCRPC. The participants in this trial were patients with mCRPC who had specific gene alterations, including BRCA and ATM alterations, who had experienced disease progression after androgen receptor–directed therapy but who had not yet received chemotherapy.
A total of 270 men were assigned to receive rucaparib (600 mg twice daily); 135 patients received their physician’s choice of medication. Within the two study arms, 302 patients had a BRCA alteration, and 103 patients had an ATM alteration. The ITT population consisted of all the patients who had been randomly assigned to either of the two groups. A prespecified subgroup included patients with a BRCA alteration.
The primary outcome was the median duration of imaging-based PSF, as determined through independent review. Key secondary outcomes were overall survival and objective response rate.
The most common adverse events in the rucaparib group were fatigue, nausea, and anemia or decreased hemoglobin. In the control group, the most common adverse events were fatigue, diarrhea, and neuropathy. The most common events of grade 3 or higher were anemia or decreased hemoglobin, neutropenia or a decreased neutrophil count, and fatigue in the rucaparib group, and fatigue and neutropenia or a decreased neutrophil count among control patients.
No changes in standard of care
In a discussion of the study, Elena Castro, MD, PhD, of the Instituto de Investigación Biomédica de Málaga, Campanillas, Spain, emphasized that there is a clear benefit from the use of PARP inhibitors (such as rucaparib) for patients with BRCA alterations.
However, she highlighted the absence of convincing overall survival data and the absence of a clear benefit on PFS in the subgroup of patients with ATM alterations.
“These data raise several questions,” she noted, “such as, do patients with ATM alterations benefit at all? And should PARP inhibitors [such as rucaparib] precede or follow docetaxel therapy?”
Because of the high crossover rate, it may be possible to evaluate the directionality of docetaxel followed by PARP inhibitors and the other way around, she suggested.
Dr. Castro said that patients with BRCA alterations benefit from PARP inhibitors and are likely to derive more benefit from them than from taxanes.
“But those with ATM alterations are unlikely to benefit from rucaparib more than from taxanes,” she said.
In a comment, Hank Ng, MD, medical oncologist, NYU Langone Perlmutter Cancer Center, New York, said he is not convinced that the findings from TRITON 3 represent a new standard of care in BRCA 1/2 mutations or ATM.
“Currently, we know that, for patients with prostate cancer with BRCA1/2 or ATM, the standard of care is an androgen receptor pathway inhibitor (ARPI), such as abiraterone or enzalutamide, then docetaxel, and then a PARP inhibitor like rucaparib,” he said.
(Currently, rucaparib is indicated for use in patients with mCRPC with BRCA alterations after they have already received an ARPI and taxane-based chemotherapy.)
Dr. Ng also questioned the control arm of the TRITON 3 trial. All the participants in the trial had already experienced disease progression after treatment with a second-generation ARPI. But the physician’s choice of therapy allowed them to move on to another ARPI or to docetaxel.
Dr. NG commented that, “in almost all cases, after progression of one ARPI, switching to another ARPI does not provide much benefit – from what is visible from this abstract – and only 56% patients received docetaxel, and thus 44% received a not-beneficial treatment,” he said.
“I am not sure what the docetaxel subgroup showed, but potentially, if those numbers are convincing, we could move this [rucaparib] ahead of docetaxel,” he speculated.
However, he also pointed out that an overall survival benefit has not yet been shown; so far, the benefit that has been shown is with respect to imaging-based PFS.
Dr. Ng does agree that rucaparib is indicated in the second line after progression with one ARPI for patients who are not candidates for chemotherapy. “But this has not yet shown me that we should absolutely be offering rucaparib before docetaxel,” he said.
TRITON3 was supported by Clovis Oncology, manufacturer of rucaparib. Dr. Bryce has relationships with Bayer, Foundation Medicine, Janssen, Merck, Myovant Sciences, and Novartis and holds a patent for therapeutic targeting of cancer patients with NRG1 rearrangements. Dr. Castro has relationships with Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Janssen-Cilag, Merck, MSD Oncology, Novartis, Pfizer, and Roche.
A version of this article first appeared on Medscape.com.
AT ASCO GU 2023
Key factors predict gallbladder cancer on routine cholecystectomy
The study covered in this summary was published on researchsquare.com as a preprint and has not yet been peer reviewed.
Key takeaway
Why this matters
- More than 60% of gallbladder cancers are diagnosed incidentally following cholecystectomy for benign reasons.
- Identifying predictors allows surgeons to send high-risk individuals for oncologic evaluation beforehand and to prepare for intraoperative frozen pathology and more appropriate surgery, including extended cholecystectomy and lymph node dissection.
Study design
- The investigators analyzed 403,443 cholecystectomies in the American College of Surgeons’ NSQIP database from 2007 to 2017.
- They used multivariable logistic regression to identify risk factors for gallbladder cancers.
- Patients undergoing cholecystectomy for suspected or confirmed gallbladder cancer were excluded.
Key results
- The incidence of gallbladder cancer was 0.11% (441 of 403,443 patients).
- Preoperative factors significantly associated with gallbladder cancer included age older than 60 years (odds ratio [OR], 6.51), female sex (OR, 1.75), weight loss (OR, 2.58), and elevated alkaline phosphatase level (OR, 1.67).
- Starting with or converting to an open approach – both potential indicators of more complex disease – were associated with seven times’ higher odds of gallbladder cancer (OR, 7.33; P < .001), as were longer operative times (127 minutes vs. 70.7 minutes; P < .001).
Limitations
- There is a risk of selection bias regarding which patients were included in the database.
- Presenting symptoms, preoperative imaging findings, and pathologic staging were not available.
- The database did not record the reasons for choosing open surgery rather than laparoscopic surgery or for converting to an open approach.
Disclosures
- There was no funding for the work, and the investigators did not disclose any relevant financial relationships.
This is a summary of a preprint research study, “Gallbladder Cancer Incidentally Found at Cholecystectomy: Perioperative Risk Factors,” led by Elizabeth Olecki of Penn State University, State College. The study has not been peer reviewed. The full text can be found at researchsquare.com. A version of this article first appeared on Medscape.com.
The study covered in this summary was published on researchsquare.com as a preprint and has not yet been peer reviewed.
Key takeaway
Why this matters
- More than 60% of gallbladder cancers are diagnosed incidentally following cholecystectomy for benign reasons.
- Identifying predictors allows surgeons to send high-risk individuals for oncologic evaluation beforehand and to prepare for intraoperative frozen pathology and more appropriate surgery, including extended cholecystectomy and lymph node dissection.
Study design
- The investigators analyzed 403,443 cholecystectomies in the American College of Surgeons’ NSQIP database from 2007 to 2017.
- They used multivariable logistic regression to identify risk factors for gallbladder cancers.
- Patients undergoing cholecystectomy for suspected or confirmed gallbladder cancer were excluded.
Key results
- The incidence of gallbladder cancer was 0.11% (441 of 403,443 patients).
- Preoperative factors significantly associated with gallbladder cancer included age older than 60 years (odds ratio [OR], 6.51), female sex (OR, 1.75), weight loss (OR, 2.58), and elevated alkaline phosphatase level (OR, 1.67).
- Starting with or converting to an open approach – both potential indicators of more complex disease – were associated with seven times’ higher odds of gallbladder cancer (OR, 7.33; P < .001), as were longer operative times (127 minutes vs. 70.7 minutes; P < .001).
Limitations
- There is a risk of selection bias regarding which patients were included in the database.
- Presenting symptoms, preoperative imaging findings, and pathologic staging were not available.
- The database did not record the reasons for choosing open surgery rather than laparoscopic surgery or for converting to an open approach.
Disclosures
- There was no funding for the work, and the investigators did not disclose any relevant financial relationships.
This is a summary of a preprint research study, “Gallbladder Cancer Incidentally Found at Cholecystectomy: Perioperative Risk Factors,” led by Elizabeth Olecki of Penn State University, State College. The study has not been peer reviewed. The full text can be found at researchsquare.com. A version of this article first appeared on Medscape.com.
The study covered in this summary was published on researchsquare.com as a preprint and has not yet been peer reviewed.
Key takeaway
Why this matters
- More than 60% of gallbladder cancers are diagnosed incidentally following cholecystectomy for benign reasons.
- Identifying predictors allows surgeons to send high-risk individuals for oncologic evaluation beforehand and to prepare for intraoperative frozen pathology and more appropriate surgery, including extended cholecystectomy and lymph node dissection.
Study design
- The investigators analyzed 403,443 cholecystectomies in the American College of Surgeons’ NSQIP database from 2007 to 2017.
- They used multivariable logistic regression to identify risk factors for gallbladder cancers.
- Patients undergoing cholecystectomy for suspected or confirmed gallbladder cancer were excluded.
Key results
- The incidence of gallbladder cancer was 0.11% (441 of 403,443 patients).
- Preoperative factors significantly associated with gallbladder cancer included age older than 60 years (odds ratio [OR], 6.51), female sex (OR, 1.75), weight loss (OR, 2.58), and elevated alkaline phosphatase level (OR, 1.67).
- Starting with or converting to an open approach – both potential indicators of more complex disease – were associated with seven times’ higher odds of gallbladder cancer (OR, 7.33; P < .001), as were longer operative times (127 minutes vs. 70.7 minutes; P < .001).
Limitations
- There is a risk of selection bias regarding which patients were included in the database.
- Presenting symptoms, preoperative imaging findings, and pathologic staging were not available.
- The database did not record the reasons for choosing open surgery rather than laparoscopic surgery or for converting to an open approach.
Disclosures
- There was no funding for the work, and the investigators did not disclose any relevant financial relationships.
This is a summary of a preprint research study, “Gallbladder Cancer Incidentally Found at Cholecystectomy: Perioperative Risk Factors,” led by Elizabeth Olecki of Penn State University, State College. The study has not been peer reviewed. The full text can be found at researchsquare.com. A version of this article first appeared on Medscape.com.
Local therapies show promise for metastatic lung cancer
“Don’t close the barn door after the horse is gone,” the old proverb goes. In other words, there’s no sense in trying to prevent something when it’s already too late.
In many ways and for many years, this saying has applied to providing local therapies to treat cancers that have metastasized to distant sites. I learned this lesson early on from my mentors and have relayed it to countless patients with advanced cancer over the past several decades.
But a growing body of evidence, alongside promising new therapies, highlights more and more exceptions to this long-held belief.
This concept was outlined decades ago for oligometastatic disease and has since been studied in greater depth, and is even being applied in practice. Local therapy for colorectal cancer with limited liver-only metastases is now established as a path to potentially excellent long-term survival. And prospective randomized trials of local therapies for oligometastatic lung cancer or prostate cancer have also demonstrated improvements in clinical outcomes that should lead us to strongly consider integrating local therapy for appropriately selected patients.
In addition, early retrospective studies have provided a proof of principle that patients with solitary brain or adrenal metastases from non–small cell lung cancer (NSCLC) can do exceptionally well and even remain disease-free for many years after definitive local therapy to the primary tumor and oligometastatic disease. For example, a recent press release on the LUNAR trial reported an improvement in overall survival with tumor-treating fields (TTFs), a local therapy, compared with docetaxel as second-line therapy for patients with advanced NSCLC.
That said, the selection process for who receives local therapy remains subjective. In practice, I see patients who fall well outside of conventional oligometastatic parameters but who are directed to local therapy, commonly when systemic therapy is considered futile or prohibitively toxic.
At the same time, however, I also see many patients who would be appropriate candidates for local therapy for oligometastatic disease for whom this strategy is not pursued, perhaps because some oncologists remain dubious about the value of local therapy in this setting. And although we await the full data from the LUNAR trial, I would expect TTFs to face challenges in broad adoption because it is a novel platform with cumbersome practical application, particularly outside of larger centers.
But beyond the potential for TTFs to change management of previously treated advanced NSCLC, I think the findings are more significant because they represent a step, perhaps even a quantum leap, in the role that local therapy could play in improving survival in a broad, unselected population with advanced disease. That is a far more meaningful prospect than conferring benefits in well-selected patients with a narrow subtype of lung cancer. It will be important to determine whether certain subgroups from the LUNAR trial are driving this overall survival benefit.
Local therapy may even have value in the advanced cancer setting beyond oligometastatic disease. That potential is being explored in the SABR-COMET-10 trial, which randomly assigned 159 patients with 4-10 metastatic lesions from various cancers to stereotactic ablative body radiation with standard systemic therapy or the latter alone. With overall survival as the primary endpoint, this study could further revise our understanding of the use of local therapy for treating patients whose cancer biology does not fit the definition of oligometastatic disease.
Does this evolving landscape mean that we were wrong to minimize the role of local therapy?
I don’t think so. The risk/benefit of local therapy today is predicated on two key factors that were absent a few decades ago. First, local therapies such as stereotactic ablative body radiation, minimally invasive surgery, and TTFs now offer disease control with far less attendant toxicity than conventional external beam radiation therapy or open surgery. Second, newer systemic therapies that include targeted therapies and immunotherapy confer remarkably greater disease control for far more patients than does conventional chemotherapy alone.
It is this combination of local therapy’s excellent therapeutic index applied against a background of far better systemic disease control that makes the interplay of local and systemic treatments a newly relevant, open question.
We have yet to see the details of several pivotal trials, but I feel that we should be prepared to question some of the historic dogma in our field to achieve better outcomes not just for selected, narrow subgroups but for a broader population with different types of metastatic cancer.
Dr. West is clinical associate professor, department of medical oncology, City of Hope Comprehensive Cancer Care, Duarte, Calif. He disclosed ties with Ariad/Takeda, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech/Roche, Merck, Pfizer, and Spectrum. A version of this article originally appeared on Medscape.com.
“Don’t close the barn door after the horse is gone,” the old proverb goes. In other words, there’s no sense in trying to prevent something when it’s already too late.
In many ways and for many years, this saying has applied to providing local therapies to treat cancers that have metastasized to distant sites. I learned this lesson early on from my mentors and have relayed it to countless patients with advanced cancer over the past several decades.
But a growing body of evidence, alongside promising new therapies, highlights more and more exceptions to this long-held belief.
This concept was outlined decades ago for oligometastatic disease and has since been studied in greater depth, and is even being applied in practice. Local therapy for colorectal cancer with limited liver-only metastases is now established as a path to potentially excellent long-term survival. And prospective randomized trials of local therapies for oligometastatic lung cancer or prostate cancer have also demonstrated improvements in clinical outcomes that should lead us to strongly consider integrating local therapy for appropriately selected patients.
In addition, early retrospective studies have provided a proof of principle that patients with solitary brain or adrenal metastases from non–small cell lung cancer (NSCLC) can do exceptionally well and even remain disease-free for many years after definitive local therapy to the primary tumor and oligometastatic disease. For example, a recent press release on the LUNAR trial reported an improvement in overall survival with tumor-treating fields (TTFs), a local therapy, compared with docetaxel as second-line therapy for patients with advanced NSCLC.
That said, the selection process for who receives local therapy remains subjective. In practice, I see patients who fall well outside of conventional oligometastatic parameters but who are directed to local therapy, commonly when systemic therapy is considered futile or prohibitively toxic.
At the same time, however, I also see many patients who would be appropriate candidates for local therapy for oligometastatic disease for whom this strategy is not pursued, perhaps because some oncologists remain dubious about the value of local therapy in this setting. And although we await the full data from the LUNAR trial, I would expect TTFs to face challenges in broad adoption because it is a novel platform with cumbersome practical application, particularly outside of larger centers.
But beyond the potential for TTFs to change management of previously treated advanced NSCLC, I think the findings are more significant because they represent a step, perhaps even a quantum leap, in the role that local therapy could play in improving survival in a broad, unselected population with advanced disease. That is a far more meaningful prospect than conferring benefits in well-selected patients with a narrow subtype of lung cancer. It will be important to determine whether certain subgroups from the LUNAR trial are driving this overall survival benefit.
Local therapy may even have value in the advanced cancer setting beyond oligometastatic disease. That potential is being explored in the SABR-COMET-10 trial, which randomly assigned 159 patients with 4-10 metastatic lesions from various cancers to stereotactic ablative body radiation with standard systemic therapy or the latter alone. With overall survival as the primary endpoint, this study could further revise our understanding of the use of local therapy for treating patients whose cancer biology does not fit the definition of oligometastatic disease.
Does this evolving landscape mean that we were wrong to minimize the role of local therapy?
I don’t think so. The risk/benefit of local therapy today is predicated on two key factors that were absent a few decades ago. First, local therapies such as stereotactic ablative body radiation, minimally invasive surgery, and TTFs now offer disease control with far less attendant toxicity than conventional external beam radiation therapy or open surgery. Second, newer systemic therapies that include targeted therapies and immunotherapy confer remarkably greater disease control for far more patients than does conventional chemotherapy alone.
It is this combination of local therapy’s excellent therapeutic index applied against a background of far better systemic disease control that makes the interplay of local and systemic treatments a newly relevant, open question.
We have yet to see the details of several pivotal trials, but I feel that we should be prepared to question some of the historic dogma in our field to achieve better outcomes not just for selected, narrow subgroups but for a broader population with different types of metastatic cancer.
Dr. West is clinical associate professor, department of medical oncology, City of Hope Comprehensive Cancer Care, Duarte, Calif. He disclosed ties with Ariad/Takeda, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech/Roche, Merck, Pfizer, and Spectrum. A version of this article originally appeared on Medscape.com.
“Don’t close the barn door after the horse is gone,” the old proverb goes. In other words, there’s no sense in trying to prevent something when it’s already too late.
In many ways and for many years, this saying has applied to providing local therapies to treat cancers that have metastasized to distant sites. I learned this lesson early on from my mentors and have relayed it to countless patients with advanced cancer over the past several decades.
But a growing body of evidence, alongside promising new therapies, highlights more and more exceptions to this long-held belief.
This concept was outlined decades ago for oligometastatic disease and has since been studied in greater depth, and is even being applied in practice. Local therapy for colorectal cancer with limited liver-only metastases is now established as a path to potentially excellent long-term survival. And prospective randomized trials of local therapies for oligometastatic lung cancer or prostate cancer have also demonstrated improvements in clinical outcomes that should lead us to strongly consider integrating local therapy for appropriately selected patients.
In addition, early retrospective studies have provided a proof of principle that patients with solitary brain or adrenal metastases from non–small cell lung cancer (NSCLC) can do exceptionally well and even remain disease-free for many years after definitive local therapy to the primary tumor and oligometastatic disease. For example, a recent press release on the LUNAR trial reported an improvement in overall survival with tumor-treating fields (TTFs), a local therapy, compared with docetaxel as second-line therapy for patients with advanced NSCLC.
That said, the selection process for who receives local therapy remains subjective. In practice, I see patients who fall well outside of conventional oligometastatic parameters but who are directed to local therapy, commonly when systemic therapy is considered futile or prohibitively toxic.
At the same time, however, I also see many patients who would be appropriate candidates for local therapy for oligometastatic disease for whom this strategy is not pursued, perhaps because some oncologists remain dubious about the value of local therapy in this setting. And although we await the full data from the LUNAR trial, I would expect TTFs to face challenges in broad adoption because it is a novel platform with cumbersome practical application, particularly outside of larger centers.
But beyond the potential for TTFs to change management of previously treated advanced NSCLC, I think the findings are more significant because they represent a step, perhaps even a quantum leap, in the role that local therapy could play in improving survival in a broad, unselected population with advanced disease. That is a far more meaningful prospect than conferring benefits in well-selected patients with a narrow subtype of lung cancer. It will be important to determine whether certain subgroups from the LUNAR trial are driving this overall survival benefit.
Local therapy may even have value in the advanced cancer setting beyond oligometastatic disease. That potential is being explored in the SABR-COMET-10 trial, which randomly assigned 159 patients with 4-10 metastatic lesions from various cancers to stereotactic ablative body radiation with standard systemic therapy or the latter alone. With overall survival as the primary endpoint, this study could further revise our understanding of the use of local therapy for treating patients whose cancer biology does not fit the definition of oligometastatic disease.
Does this evolving landscape mean that we were wrong to minimize the role of local therapy?
I don’t think so. The risk/benefit of local therapy today is predicated on two key factors that were absent a few decades ago. First, local therapies such as stereotactic ablative body radiation, minimally invasive surgery, and TTFs now offer disease control with far less attendant toxicity than conventional external beam radiation therapy or open surgery. Second, newer systemic therapies that include targeted therapies and immunotherapy confer remarkably greater disease control for far more patients than does conventional chemotherapy alone.
It is this combination of local therapy’s excellent therapeutic index applied against a background of far better systemic disease control that makes the interplay of local and systemic treatments a newly relevant, open question.
We have yet to see the details of several pivotal trials, but I feel that we should be prepared to question some of the historic dogma in our field to achieve better outcomes not just for selected, narrow subgroups but for a broader population with different types of metastatic cancer.
Dr. West is clinical associate professor, department of medical oncology, City of Hope Comprehensive Cancer Care, Duarte, Calif. He disclosed ties with Ariad/Takeda, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech/Roche, Merck, Pfizer, and Spectrum. A version of this article originally appeared on Medscape.com.