Genitourinary Cancer

Black men with newly diagnosed nonmetastatic prostate cancer had no significant difference in prostate cancer–specific mortality compared with white men when treated with a standardized approach and follow-up or at a health care system with standardized access, according to recent research published in JAMA Oncology.

Robert T. Dess, MD, from the department of radiation oncology at the University of Michigan, Ann Arbor, and colleagues examined data from 296,273 patients in the Surveillance, Epidemiology, and End Results (SEER) cohort, 3,972 patients from the Veterans Affairs (VA) health system, and 5,854 patients in four randomized controlled trials (RCTs) from the National Cancer Institute–sponsored Radiation Therapy Oncology Group between January 1992 and December 2013. Of these, 52,840 patients (17.8%) in the SEER cohort, 1,513 patients (38.1%) in the VA cohort, and 1,129 (19.3%) in the RCT cohort were black men. The mean age across all cohorts was 64.9 years, and the median follow-up was 75 months in the SEER cohort, 97 months in the VA cohort, and 104 months in the RCT cohort.

After adjustment for age in the SEER cohort, black men had a 30% increased risk of prostate cancer–specific mortality (PCSM) compared with white men (subdistribution hazard ratio, 1.30; 95% CI, 1.23-1.37; P less than .001). However, after the researchers performed inverse probability weighting (IPW) to adjust for race-based imbalances such as access to care and standardized treatment, there was a 0.5% increased risk over 10 years (sHR, 1.09; 95% CI, 1.04-1.15; P less than .001) after diagnosis.

In the VA cohort, IPW yielded no significant differences between black men and white men (sHR, 0.85; 95% CI, 0.56-1.30; P = .46), and there was a significantly lower risk for black men in the RCT cohort after IPW (sHR, 0.81; 95% CI, 0.66-0.99; P = .04). With regard to other outcomes, other-cause mortality was significantly higher for black men in the SEER cohort (sHR, 1.30; 95% CI, 1.27-1.34; P less than .001) and in the RCT cohort (sHR, 1.17; 95% CI, 1.06-1.29; P = .002) after IPW.

“Black race remains associated with many factors that negatively affect outcomes, and disparities persist at the population level,” Dr. Dess and colleagues wrote in their study. “Continued efforts are needed to address this clear racial health inequity driven by modifiable nonbiological risk factors.”

The researchers said some residual confounding may exist, but noted the strengths of the study included a diverse cohort with a large range of treatment approaches.

This study was funded in part by the Prostate Cancer Foundation, a grant from the Prostate Cancer National Institutes of Health Specialized Programs of Research Excellence, two grants from the Department of Defense, a grant from NIH, and a grant from the NIH Cancer Center. One or more of the authors reported relationships in the form of grants, personal fees, and consulting fees with numerous companies. The other authors report no relevant conflicts of interest.

SOURCE: Dess RT et al. JAMA Oncol. 2019 May 23. doi: 10.1001/jamaoncol.2019.0826.

Black men with newly diagnosed nonmetastatic prostate cancer had no significant difference in prostate cancer–specific mortality compared with white men when treated with a standardized approach and follow-up or at a health care system with standardized access, according to recent research published in JAMA Oncology.

Robert T. Dess, MD, from the department of radiation oncology at the University of Michigan, Ann Arbor, and colleagues examined data from 296,273 patients in the Surveillance, Epidemiology, and End Results (SEER) cohort, 3,972 patients from the Veterans Affairs (VA) health system, and 5,854 patients in four randomized controlled trials (RCTs) from the National Cancer Institute–sponsored Radiation Therapy Oncology Group between January 1992 and December 2013. Of these, 52,840 patients (17.8%) in the SEER cohort, 1,513 patients (38.1%) in the VA cohort, and 1,129 (19.3%) in the RCT cohort were black men. The mean age across all cohorts was 64.9 years, and the median follow-up was 75 months in the SEER cohort, 97 months in the VA cohort, and 104 months in the RCT cohort.

After adjustment for age in the SEER cohort, black men had a 30% increased risk of prostate cancer–specific mortality (PCSM) compared with white men (subdistribution hazard ratio, 1.30; 95% CI, 1.23-1.37; P less than .001). However, after the researchers performed inverse probability weighting (IPW) to adjust for race-based imbalances such as access to care and standardized treatment, there was a 0.5% increased risk over 10 years (sHR, 1.09; 95% CI, 1.04-1.15; P less than .001) after diagnosis.

In the VA cohort, IPW yielded no significant differences between black men and white men (sHR, 0.85; 95% CI, 0.56-1.30; P = .46), and there was a significantly lower risk for black men in the RCT cohort after IPW (sHR, 0.81; 95% CI, 0.66-0.99; P = .04). With regard to other outcomes, other-cause mortality was significantly higher for black men in the SEER cohort (sHR, 1.30; 95% CI, 1.27-1.34; P less than .001) and in the RCT cohort (sHR, 1.17; 95% CI, 1.06-1.29; P = .002) after IPW.

“Black race remains associated with many factors that negatively affect outcomes, and disparities persist at the population level,” Dr. Dess and colleagues wrote in their study. “Continued efforts are needed to address this clear racial health inequity driven by modifiable nonbiological risk factors.”

The researchers said some residual confounding may exist, but noted the strengths of the study included a diverse cohort with a large range of treatment approaches.

This study was funded in part by the Prostate Cancer Foundation, a grant from the Prostate Cancer National Institutes of Health Specialized Programs of Research Excellence, two grants from the Department of Defense, a grant from NIH, and a grant from the NIH Cancer Center. One or more of the authors reported relationships in the form of grants, personal fees, and consulting fees with numerous companies. The other authors report no relevant conflicts of interest.

SOURCE: Dess RT et al. JAMA Oncol. 2019 May 23. doi: 10.1001/jamaoncol.2019.0826.

Black men with newly diagnosed nonmetastatic prostate cancer had no significant difference in prostate cancer–specific mortality compared with white men when treated with a standardized approach and follow-up or at a health care system with standardized access, according to recent research published in JAMA Oncology.

Robert T. Dess, MD, from the department of radiation oncology at the University of Michigan, Ann Arbor, and colleagues examined data from 296,273 patients in the Surveillance, Epidemiology, and End Results (SEER) cohort, 3,972 patients from the Veterans Affairs (VA) health system, and 5,854 patients in four randomized controlled trials (RCTs) from the National Cancer Institute–sponsored Radiation Therapy Oncology Group between January 1992 and December 2013. Of these, 52,840 patients (17.8%) in the SEER cohort, 1,513 patients (38.1%) in the VA cohort, and 1,129 (19.3%) in the RCT cohort were black men. The mean age across all cohorts was 64.9 years, and the median follow-up was 75 months in the SEER cohort, 97 months in the VA cohort, and 104 months in the RCT cohort.

After adjustment for age in the SEER cohort, black men had a 30% increased risk of prostate cancer–specific mortality (PCSM) compared with white men (subdistribution hazard ratio, 1.30; 95% CI, 1.23-1.37; P less than .001). However, after the researchers performed inverse probability weighting (IPW) to adjust for race-based imbalances such as access to care and standardized treatment, there was a 0.5% increased risk over 10 years (sHR, 1.09; 95% CI, 1.04-1.15; P less than .001) after diagnosis.

In the VA cohort, IPW yielded no significant differences between black men and white men (sHR, 0.85; 95% CI, 0.56-1.30; P = .46), and there was a significantly lower risk for black men in the RCT cohort after IPW (sHR, 0.81; 95% CI, 0.66-0.99; P = .04). With regard to other outcomes, other-cause mortality was significantly higher for black men in the SEER cohort (sHR, 1.30; 95% CI, 1.27-1.34; P less than .001) and in the RCT cohort (sHR, 1.17; 95% CI, 1.06-1.29; P = .002) after IPW.

“Black race remains associated with many factors that negatively affect outcomes, and disparities persist at the population level,” Dr. Dess and colleagues wrote in their study. “Continued efforts are needed to address this clear racial health inequity driven by modifiable nonbiological risk factors.”

The researchers said some residual confounding may exist, but noted the strengths of the study included a diverse cohort with a large range of treatment approaches.

This study was funded in part by the Prostate Cancer Foundation, a grant from the Prostate Cancer National Institutes of Health Specialized Programs of Research Excellence, two grants from the Department of Defense, a grant from NIH, and a grant from the NIH Cancer Center. One or more of the authors reported relationships in the form of grants, personal fees, and consulting fees with numerous companies. The other authors report no relevant conflicts of interest.

SOURCE: Dess RT et al. JAMA Oncol. 2019 May 23. doi: 10.1001/jamaoncol.2019.0826.

In this edition of “How I will treat my next patient,” I take a look at two recent trials – a late-breaking abstract presented at the annual meeting of the American Urological Association on the value of enzalutamide in hormone-sensitive metastatic prostate cancer (mHSPC) patients and a recent publication in JAMA Oncology about the potential for circulating tumor DNA (ctDNA) testing to inform our management of early stage colorectal cancer (CRC).

ARCHES trial

The ARCHES trial was reported as a late-breaking abstract at AUA 2019. ARCHES was a double-blind, placebo-controlled trial in 1,150 men with mHSPC. Patients were required to have been free from radiographic disease progression or a rising prostate-specific antigen (PSA) level for at least 3 months on androgen deprivation therapy (ADT) or at least 6 months after prior docetaxel chemotherapy.

Patients were randomly assigned to receive either ADT plus enzalutamide (an androgen receptor signaling inhibitor) or ADT plus placebo. The coprimary endpoints of the trial were radiographic progression-free survival (rPFS) and death within 24 weeks.

ADT plus enzalutamide had dramatically better PSA-related endpoints (as expected) and produced significantly better rPFS (median PFS, not reached versus 19.5 months; 61% relative prolongation of rPFS) than placebo plus ADT.

Overall survival data were unreported and may be confounded by all patients being offered enzalutamide at progression. Despite the known adverse effects of enzalutamide from prior studies, enzalutamide-related adverse effects in ARCHES were no worse than placebo (about 85% in both study arms). Formal quality-of-life analyses are yet to be reported.
 

What this means in practice

It is no surprise that enzalutamide, a potent drug in castration-resistant prostate cancer, would beat placebo. It joins docetaxel and abiraterone in helping to delay the time until castration-resistant disease develops – a meaningful goal. The authors commented that baseline PSA level did not predict benefit from enzalutamide – again, no surprise given that other published trials have suggested that baseline PSA is more likely prognostic than predictive.

It is always prudent to wait for a formal manuscript, but this abstract suggests that men with mHSPC have yet another option for treatment with modest toxicity and broad applicability in practice.
 

ctDNA in early colorectal cancer

In JAMA Oncology, Yuxuan Wang, MD, PhD, and colleagues summarized their experience with 58 patients with stages I-III colorectal cancer (CRC) who had curative-intent surgical resection at four Swedish hospitals.

The patients had levels of ctDNA monitored every 3 months post operatively. Prediction of the development of metastatic disease using ctDNA was compared to conventional surveillance testing (carcinoembryonic antigen [CEA] blood tests and computed tomographic scanning) per guidelines from the National Comprehensive Cancer Network.

Among the 45 patients with no elevation of ctDNA, there were no recurrences at median follow-up of 49 months. In contrast, 10 of 13 patients (77%) with elevated ctDNA levels during follow-up developed metastatic disease. CEA levels were less sensitive, detecting just 63% of recurrences.

Among the three patients with false positive ctDNA levels, all three fell to undetectable levels with continued follow-up. One of the 18 patients who received adjuvant post-operative chemotherapy had the ctDNA levels fall to undetectable with chemotherapy and that patient remained relapse-free at 37 months.

What this means in practice

The results of this study are remarkably concordant with recently published work in the Journal of Clinical Oncology by Emil Christensen, PhD, and colleagues, that involved patients with localized bladder cancer and illustrate the predictive value of ctDNA over traditional risk factors and conventional surveillance monitoring.

Monitoring ctDNA remains a promising research tool that should not be used for clinical decision making at the present time. However, its potential to help us personalize treatment selection, surveillance intensity, and to select patients who may be spared costly, toxic, and anxiety-provoking treatment and monitoring could be practice changing in the near future.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I will treat my next patient,” I take a look at two recent trials – a late-breaking abstract presented at the annual meeting of the American Urological Association on the value of enzalutamide in hormone-sensitive metastatic prostate cancer (mHSPC) patients and a recent publication in JAMA Oncology about the potential for circulating tumor DNA (ctDNA) testing to inform our management of early stage colorectal cancer (CRC).

ARCHES trial

The ARCHES trial was reported as a late-breaking abstract at AUA 2019. ARCHES was a double-blind, placebo-controlled trial in 1,150 men with mHSPC. Patients were required to have been free from radiographic disease progression or a rising prostate-specific antigen (PSA) level for at least 3 months on androgen deprivation therapy (ADT) or at least 6 months after prior docetaxel chemotherapy.

Patients were randomly assigned to receive either ADT plus enzalutamide (an androgen receptor signaling inhibitor) or ADT plus placebo. The coprimary endpoints of the trial were radiographic progression-free survival (rPFS) and death within 24 weeks.

ADT plus enzalutamide had dramatically better PSA-related endpoints (as expected) and produced significantly better rPFS (median PFS, not reached versus 19.5 months; 61% relative prolongation of rPFS) than placebo plus ADT.

Overall survival data were unreported and may be confounded by all patients being offered enzalutamide at progression. Despite the known adverse effects of enzalutamide from prior studies, enzalutamide-related adverse effects in ARCHES were no worse than placebo (about 85% in both study arms). Formal quality-of-life analyses are yet to be reported.
 

What this means in practice

It is no surprise that enzalutamide, a potent drug in castration-resistant prostate cancer, would beat placebo. It joins docetaxel and abiraterone in helping to delay the time until castration-resistant disease develops – a meaningful goal. The authors commented that baseline PSA level did not predict benefit from enzalutamide – again, no surprise given that other published trials have suggested that baseline PSA is more likely prognostic than predictive.

It is always prudent to wait for a formal manuscript, but this abstract suggests that men with mHSPC have yet another option for treatment with modest toxicity and broad applicability in practice.
 

ctDNA in early colorectal cancer

In JAMA Oncology, Yuxuan Wang, MD, PhD, and colleagues summarized their experience with 58 patients with stages I-III colorectal cancer (CRC) who had curative-intent surgical resection at four Swedish hospitals.

The patients had levels of ctDNA monitored every 3 months post operatively. Prediction of the development of metastatic disease using ctDNA was compared to conventional surveillance testing (carcinoembryonic antigen [CEA] blood tests and computed tomographic scanning) per guidelines from the National Comprehensive Cancer Network.

Among the 45 patients with no elevation of ctDNA, there were no recurrences at median follow-up of 49 months. In contrast, 10 of 13 patients (77%) with elevated ctDNA levels during follow-up developed metastatic disease. CEA levels were less sensitive, detecting just 63% of recurrences.

Among the three patients with false positive ctDNA levels, all three fell to undetectable levels with continued follow-up. One of the 18 patients who received adjuvant post-operative chemotherapy had the ctDNA levels fall to undetectable with chemotherapy and that patient remained relapse-free at 37 months.

What this means in practice

The results of this study are remarkably concordant with recently published work in the Journal of Clinical Oncology by Emil Christensen, PhD, and colleagues, that involved patients with localized bladder cancer and illustrate the predictive value of ctDNA over traditional risk factors and conventional surveillance monitoring.

Monitoring ctDNA remains a promising research tool that should not be used for clinical decision making at the present time. However, its potential to help us personalize treatment selection, surveillance intensity, and to select patients who may be spared costly, toxic, and anxiety-provoking treatment and monitoring could be practice changing in the near future.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I will treat my next patient,” I take a look at two recent trials – a late-breaking abstract presented at the annual meeting of the American Urological Association on the value of enzalutamide in hormone-sensitive metastatic prostate cancer (mHSPC) patients and a recent publication in JAMA Oncology about the potential for circulating tumor DNA (ctDNA) testing to inform our management of early stage colorectal cancer (CRC).

ARCHES trial

The ARCHES trial was reported as a late-breaking abstract at AUA 2019. ARCHES was a double-blind, placebo-controlled trial in 1,150 men with mHSPC. Patients were required to have been free from radiographic disease progression or a rising prostate-specific antigen (PSA) level for at least 3 months on androgen deprivation therapy (ADT) or at least 6 months after prior docetaxel chemotherapy.

Patients were randomly assigned to receive either ADT plus enzalutamide (an androgen receptor signaling inhibitor) or ADT plus placebo. The coprimary endpoints of the trial were radiographic progression-free survival (rPFS) and death within 24 weeks.

ADT plus enzalutamide had dramatically better PSA-related endpoints (as expected) and produced significantly better rPFS (median PFS, not reached versus 19.5 months; 61% relative prolongation of rPFS) than placebo plus ADT.

Overall survival data were unreported and may be confounded by all patients being offered enzalutamide at progression. Despite the known adverse effects of enzalutamide from prior studies, enzalutamide-related adverse effects in ARCHES were no worse than placebo (about 85% in both study arms). Formal quality-of-life analyses are yet to be reported.
 

What this means in practice

It is no surprise that enzalutamide, a potent drug in castration-resistant prostate cancer, would beat placebo. It joins docetaxel and abiraterone in helping to delay the time until castration-resistant disease develops – a meaningful goal. The authors commented that baseline PSA level did not predict benefit from enzalutamide – again, no surprise given that other published trials have suggested that baseline PSA is more likely prognostic than predictive.

It is always prudent to wait for a formal manuscript, but this abstract suggests that men with mHSPC have yet another option for treatment with modest toxicity and broad applicability in practice.
 

ctDNA in early colorectal cancer

In JAMA Oncology, Yuxuan Wang, MD, PhD, and colleagues summarized their experience with 58 patients with stages I-III colorectal cancer (CRC) who had curative-intent surgical resection at four Swedish hospitals.

The patients had levels of ctDNA monitored every 3 months post operatively. Prediction of the development of metastatic disease using ctDNA was compared to conventional surveillance testing (carcinoembryonic antigen [CEA] blood tests and computed tomographic scanning) per guidelines from the National Comprehensive Cancer Network.

Among the 45 patients with no elevation of ctDNA, there were no recurrences at median follow-up of 49 months. In contrast, 10 of 13 patients (77%) with elevated ctDNA levels during follow-up developed metastatic disease. CEA levels were less sensitive, detecting just 63% of recurrences.

Among the three patients with false positive ctDNA levels, all three fell to undetectable levels with continued follow-up. One of the 18 patients who received adjuvant post-operative chemotherapy had the ctDNA levels fall to undetectable with chemotherapy and that patient remained relapse-free at 37 months.

What this means in practice

The results of this study are remarkably concordant with recently published work in the Journal of Clinical Oncology by Emil Christensen, PhD, and colleagues, that involved patients with localized bladder cancer and illustrate the predictive value of ctDNA over traditional risk factors and conventional surveillance monitoring.

Monitoring ctDNA remains a promising research tool that should not be used for clinical decision making at the present time. However, its potential to help us personalize treatment selection, surveillance intensity, and to select patients who may be spared costly, toxic, and anxiety-provoking treatment and monitoring could be practice changing in the near future.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

For men with metastatic hormone-sensitive prostate cancer (mHSPC), enzalutamide with androgen deprivation therapy (ADT) offers longer radiographic progression-free survival (rPFS) compared with placebo and ADT, regardless of baseline prostate-specific antigen level (PSA), based on results from the phase 3 ARCHES trial.

Although initial PSA level was not predictive of response, treatment with enzalutamide and ADT improved PSA-related efficacy measures, reported lead author Arnulf Stenzl, MD, of the University of Tübingen, Germany, and colleagues. The adverse effect profile of enzalutamide was similar to previous experiences with castrate-resistant patients, they noted in their abstract, which was presented at the annual meeting of the American Urological Association.

ARCHES was a double-blind, placebo-controlled trial involving 1,150 patients with mHSPC, divided approximately 1:1 to receive either enzalutamide with ADT (n = 574) or placebo with ADT (n = 576). Eligibility required that patients had not exhibited radiographic disease progression or rising PSA levels for up to 3 months of ADT, or up to 6 months with prior docetaxel. The primary endpoints were death within 24 weeks of stopping treatment and rPFS. Treatment was continued until unacceptable toxicity or disease progression. PSA levels were measured at baseline and at follow-up, which was an average of 14.4 months.

Median baseline PSA level across both cohorts was 5.21 ng/mL, with most patients having received prior ADT (91%). Baseline PSA was not predictive of response, “suggesting the limitation of baseline PSA as a predictive factor in this population in which most [patients] received prior ADT,” the investigators wrote. Although PSA levels were not predictive, enzalutamide did have a greater impact on PSA-related efficacy endpoints; compared with the placebo group, patients in the enzalutamide arm were significantly more likely to have PSA reductions from baseline of at least 50% (92.9% vs. 56.8%) and at least 90% (72.8% vs. 30.0%). In further support of the efficacy of enzalutamide, median rPFS in the enzalutamide group was significantly better than in the placebo group (not reached vs. 19.4 months). Adverse events were comparable between enzalutamide (85.1%) and placebo (85.9%) cohorts.

Astellas Pharma and Medivation funded the study. The investigators reported no conflicts of interest.
 

SOURCE: Stenzl et al. AUA 2019. Abstract LBA-10.

For men with metastatic hormone-sensitive prostate cancer (mHSPC), enzalutamide with androgen deprivation therapy (ADT) offers longer radiographic progression-free survival (rPFS) compared with placebo and ADT, regardless of baseline prostate-specific antigen level (PSA), based on results from the phase 3 ARCHES trial.

Although initial PSA level was not predictive of response, treatment with enzalutamide and ADT improved PSA-related efficacy measures, reported lead author Arnulf Stenzl, MD, of the University of Tübingen, Germany, and colleagues. The adverse effect profile of enzalutamide was similar to previous experiences with castrate-resistant patients, they noted in their abstract, which was presented at the annual meeting of the American Urological Association.

ARCHES was a double-blind, placebo-controlled trial involving 1,150 patients with mHSPC, divided approximately 1:1 to receive either enzalutamide with ADT (n = 574) or placebo with ADT (n = 576). Eligibility required that patients had not exhibited radiographic disease progression or rising PSA levels for up to 3 months of ADT, or up to 6 months with prior docetaxel. The primary endpoints were death within 24 weeks of stopping treatment and rPFS. Treatment was continued until unacceptable toxicity or disease progression. PSA levels were measured at baseline and at follow-up, which was an average of 14.4 months.

Median baseline PSA level across both cohorts was 5.21 ng/mL, with most patients having received prior ADT (91%). Baseline PSA was not predictive of response, “suggesting the limitation of baseline PSA as a predictive factor in this population in which most [patients] received prior ADT,” the investigators wrote. Although PSA levels were not predictive, enzalutamide did have a greater impact on PSA-related efficacy endpoints; compared with the placebo group, patients in the enzalutamide arm were significantly more likely to have PSA reductions from baseline of at least 50% (92.9% vs. 56.8%) and at least 90% (72.8% vs. 30.0%). In further support of the efficacy of enzalutamide, median rPFS in the enzalutamide group was significantly better than in the placebo group (not reached vs. 19.4 months). Adverse events were comparable between enzalutamide (85.1%) and placebo (85.9%) cohorts.

Astellas Pharma and Medivation funded the study. The investigators reported no conflicts of interest.
 

SOURCE: Stenzl et al. AUA 2019. Abstract LBA-10.

For men with metastatic hormone-sensitive prostate cancer (mHSPC), enzalutamide with androgen deprivation therapy (ADT) offers longer radiographic progression-free survival (rPFS) compared with placebo and ADT, regardless of baseline prostate-specific antigen level (PSA), based on results from the phase 3 ARCHES trial.

Although initial PSA level was not predictive of response, treatment with enzalutamide and ADT improved PSA-related efficacy measures, reported lead author Arnulf Stenzl, MD, of the University of Tübingen, Germany, and colleagues. The adverse effect profile of enzalutamide was similar to previous experiences with castrate-resistant patients, they noted in their abstract, which was presented at the annual meeting of the American Urological Association.

ARCHES was a double-blind, placebo-controlled trial involving 1,150 patients with mHSPC, divided approximately 1:1 to receive either enzalutamide with ADT (n = 574) or placebo with ADT (n = 576). Eligibility required that patients had not exhibited radiographic disease progression or rising PSA levels for up to 3 months of ADT, or up to 6 months with prior docetaxel. The primary endpoints were death within 24 weeks of stopping treatment and rPFS. Treatment was continued until unacceptable toxicity or disease progression. PSA levels were measured at baseline and at follow-up, which was an average of 14.4 months.

Median baseline PSA level across both cohorts was 5.21 ng/mL, with most patients having received prior ADT (91%). Baseline PSA was not predictive of response, “suggesting the limitation of baseline PSA as a predictive factor in this population in which most [patients] received prior ADT,” the investigators wrote. Although PSA levels were not predictive, enzalutamide did have a greater impact on PSA-related efficacy endpoints; compared with the placebo group, patients in the enzalutamide arm were significantly more likely to have PSA reductions from baseline of at least 50% (92.9% vs. 56.8%) and at least 90% (72.8% vs. 30.0%). In further support of the efficacy of enzalutamide, median rPFS in the enzalutamide group was significantly better than in the placebo group (not reached vs. 19.4 months). Adverse events were comparable between enzalutamide (85.1%) and placebo (85.9%) cohorts.

Astellas Pharma and Medivation funded the study. The investigators reported no conflicts of interest.
 

SOURCE: Stenzl et al. AUA 2019. Abstract LBA-10.

Prostate cancer is the most common malignancy in men, with an estimated 165,000 new prostate cancer diagnoses and 29,000 prostate cancer deaths occurring in the United States in 2018.¹ Due to the widespread use of screening prostate-specific antigen (PSA), prostate cancer has been mainly diagnosed when the tumor is confined to the prostate. Despite definitive treatment of localized prostate cancer, some men develop systemic disease, either biochemical failure, as defined by rising PSA level, or metastatic disease.¹ Several factors have been demonstrated to predict risk of relapse, including higher pretreatment PSA, higher Gleason score, and a greater anatomic extent of disease.² In addition, the incidence of de novo metastatic prostate cancer was recently noted to be increasing. This may be due to changes in the United States Preventive Services Task Force prostate cancer screening guidelines in 2012, which recommended against screening for prostate cancer in men of any age. The updated 2018 guidelines recommend a discussion of the risks versus benefits of screening for prostate cancer for all men aged 55 to 69 years,recommend against screening for men older than 70 years, and do not have recommendations for high-risk subgroups.³

Androgen deprivation therapy (ADT) has been the cornerstone of therapy since 1941 for men with hormone-sensitive systemic disease, both in biochemically relapsed and metastatic disease.^4,5 While more than 90% of patients respond to initial ADT, castration resistance is inevitable in some men.^6,7 Prostate cancer will become castration-resistant typically after 18 to 24 months of ADT, with the majority of patients developing castration-resistant prostate cancer (CRPC) within 5 years of initiation of ADT.⁸

Pathogenesis

CRPC (previously called androgen independent prostate cancer) is defined as progression of disease despite serum total testosterone levels less than 50 ng/dL. CRPC is characterized by a rising PSA level and/or radiographic progression. One mechanism of castration resistance is genetic modification of the androgen receptor (AR), including increased expression of the wild-type AR.⁹ Alternatively, mutations of the steroid-binding domain may play a role in the development of castration resistance by allowing the AR to become activated by non-androgen steroid hormones or even paradoxically by antiandrogens. Studies suggest, however, that AR mutations may be seen in only 10% of prostate cancers that have developed castration resistance.¹⁰ The AR-V7 splice variant of the AR lacks an androgen binding site altogether, and may play an important role in castration resistance. In one study, the presence of this splice variant in circulating prostate cancer tumor cells predicted resistance to enzalutamide and abiraterone as well as poor outcomes.¹¹ Intratumoral androgen synthesis also may play a role in the development of CRPC.^12,13

CRPC can be broadly categorized into 2 categories, metastatic (mCRPC) and nonmetastatic (nmCRPC; Figure). The exact proportion of patients entering CRPC at a nonmetastatic stage (M0) is largely unknown.¹⁴ In one study of patients at the time of diagnosis of CRPC, ≥ 84% of patients were shown to have metastases.⁸ In this article, we review key aspects of management of CRPC, including selection of first- and second-line therapy, and briefly discuss upcoming clinical trials.

 

 

Treatment of Nonmetastatic CRPC (M0 Disease)

Early identification of M0 CRPC is important because patients with nonmetastatic CRPC are at risk for metastasis, as demonstrated by Smith and colleagues.¹⁵ In this study that evaluated data from patients with nmCRPC in the placebo group (n = 331) of a randomized controlled trial, at 2 years 46% had developed ≥ 1 bone metastasis, 20% had died, and the median bone metastasis-free survival (MFS) was 25 months.¹⁵

Rapid PSA doubling time (PSADT) is linked to shorter time to metastasis in this group of patients. Patients with a PSADT of < 10 months had a risk for bone metastasis 12 times greater and a risk for death 4 times greater than patients with a PSADT of ≥ 10 months.¹⁶ Accordingly, observation should be reserved for those patients with a PSADT of ≥ 10 months.

Options for secondary hormonal therapy in those with a PSADT of ≤ 10 months include a first-generation antiandrogen (bicalutamide, flutamide, nilutamide), ketoconazole with hydrocortisone, and more recently second-generation antiandrogens (apalutamide or enzalutamide).

Bicalutamide competitively inhibits dihydrotestosterone and testosterone binding to the AR and is generally well-tolerated; it is given in conjunction with a GnRH agonist/castration.¹⁷ The use of other first-generation antiandrogens is limited mainly due to their toxicity profile. When compared to flutamide in a randomized, double-blinded control study, bicalutamide had significantly improved time to treatment failure.¹⁸ Due to promiscuous binding to AR, withdrawal of first-generation antiandrogen therapy has been associated with a biochemical response in a small proportion of patients, with response typically seen after 5 to 7 half-lives of the drug have elapsed.¹⁹

Although traditionally used as an antifungal agent, ketoconazole also inhibits androgen synthesis in the adrenal glands and acts as a direct cytotoxin to cancer cells.²⁰ Ketoconazole (with hydrocortisone) has been considered as a treatment option, typically at the time of antiandrogen withdrawal. However, ketoconazole offers no survival benefit, and with the approval of abiraterone in M1 CRPC, its use has declined significantly.²¹ Additionally, ketoconazole poses a risk for severe hepatotoxicity and QT prolongation, and has significant interactions with numerous drugs, thereby limiting its use. Given the typically short duration of response to first-generation antiandrogens, the second-generation antiandrogens were developed and are associated with a significantly greater progression-free survival (PFS) in M0 CRPC.^22,23

The second-generation antiandrogens enzalutamide and apalutamide not only competitively bind to the AR, inhibiting formation of the androgen/AR complex, but they also inhibit androgen/AR complex nuclear translocation and binding to nuclear DNA. In the PROSPER trial, enzalutamide significantly increased radiographic PFS and improved quality of life compared to placebo in chemotherapy-naive patients (Table 1).²⁴ Apalutamide significantly increased MFS as well as PFS and time to PSA progression compared to placebo in the phase 3 SPARTAN trial.²⁵ Apalutamide is generally well tolerated, with hypertension and rash being the most common severe adverse effects. Apalutamide also has less potential for central nervous system toxicities than enzalutamide. The recent approval of these agents is likely to change responses to subsequent treatments, especially in the metastatic setting.

 

 

Treatment of Metastatic CRPC (M1 Disease)

As with M0 CRPC, ADT should be continued in patients with mCRPC to maintain castration levels of testosterone while initiating additional treatments. Several drugs for the treatment of mCRPC have been approved by the US Food and Drug Administration (FDA) since 2010, including abiraterone with prednisone (or methylprednisolone), enzalutamide (but not apalutamide), radium-223, sipuleucel-T, and cabazitaxel (Table 2).

Given the availability of numerous treatment options for men with mCRPC, the sequencing of treatments should be based on careful consideration of the efficacy and adverse effect profiles of each drug as well as the anatomic and molecular characteristics of the cancer, comorbidities, and patient preference. If there is no evidence of visceral disease and the patient has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 with an estimated life expectancy of greater than 6 months and is minimally symptomatic, then treatment with either oral targeted agents or immunotherapy with sipuleucel-T is considered appropriate.

Sipuleucel-T is an autologous dendritic cell vaccination designed to enhance T-cell–mediated response to prostatic acid phosphatase (PAP). The treatments are prepared from leukapheresed host mononuclear cells that are then exposed to PAP fused to granulocyte-macrophage colony-stimulating factor. The activated dendritic cells are then infused back into the host once every 2 weeks for a total of 3 treatments. The main side effects of this treatment include chills, fever, and headache, but it is generally well-tolerated and has demonstrated a survival benefit.²⁶

Both enzalutamide and abiraterone (abiraterone given with physiologic-dose steroid replacement) confer a survival benefit in chemotherapy-naive patients with M1 CRPC. Per the PREVAIL study, enzalutamide (when compared to placebo) offers a median improvement in overall survival (OS) by about 2 months and in radiographic PFS by about 14.6 months.²⁴ Abiraterone blocks the synthesis of androgens via inhibition of CYP17 in the testes and adrenal glands. Abiraterone also confers an overall survival advantage for patients with M1 CRPC who are chemotherapy-naïve, with an estimated 25% decrease in the risk of death (hazard ratio, 0.75, P = 0.009) when compared to prednisone.²⁷

In patients with symptomatic M1 CRPC who have visceral disease or rapidly progressive disease and who are candidates for chemotherapy, docetaxel is frequently used and is given concurrently with steroids. Docetaxel has been given for up to 10 cycles in clinical trials (assuming no progression of disease or dose-limiting toxicities were observed), and at least 6 cycles of treatment are recommended. When compared to mitoxantrone plus prednisone in the TAX 327 phase 3 trial, docetaxel plus prednisone offered a significant OS benefit of about 3 months (19.2 months versus 16.3 months).²⁸ For patients who are not candidates for docetaxel (eg, due to preexisting peripheral neuropathy), cabazitaxel should be considered. OS is similar for mCRPC with docetaxel versus cabazitaxel when given in the first-line setting.²⁹ Additionally, cabazitaxel dosed at 20 mg/m² is noninferior to cabazitaxel dosed at 25 mg/m², and the lower dose is associated with lower rates of peripheral neuropathy.³⁰ Cabazitaxel should also be considered for mCRPC that has progressed following treatment with docetaxel, with improved OS and PFS when compared to treatment with mitoxantrone and prednisone in this setting, as shown in the TROPIC study.³¹ Mitoxantrone given with prednisone has been shown to improve quality of life, but it is associated with significant cardiac toxicity. Additionally, mitoxantrone does not improve disease-free survival or OS in chemotherapy-naive patients³² or in patients who have progressed on docetaxel, and therefore should not be given to patients prior to a taxane chemotherapy unless the patient absolutely cannot tolerate docetaxel or cabazitaxel.

Once a patient’s prostate cancer progresses following treatment with a taxane, the sequence in which to administer subsequent therapies should involve careful consideration of previous treatments and duration of response to each of these treatments. Both enzalutamide and abiraterone are FDA-approved for use following treatment with chemotherapy. Per the AFFIRM trial, heavily pre-treated patients (including those who have received docetaxel) have a median 5-month OS benefit with enzalutamide compared to placebo.³³ Another study of M1 CRPC patients who had previously received docetaxel demonstrated an OS benefit with abiraterone (versus placebo),³⁴ but this regimen has limited benefit in patients who have previously received both docetaxel and enzalutamide.³⁵ A rechallenge with docetaxel therapy also can be considered if the patient’s disease responded to docetaxel in the metastatic hormone-sensitive setting.

If the patient’s metastases are limited to bone (ie, no visceral disease), then radiotherapy with radium-223 should be considered. Radium-223 is an alpha-emitting calcium-mimetic radioactive compound that tracks to bone to delay the onset of symptoms from bone metastases.³⁶ Radium-223 also confers a median OS benefit of about 3 months.³⁷ However, this treatment is often limited by preexisting cytopenias.

Diethylstilbestrol (1 mg daily) competes with androgens for AR binding and is also cytotoxic to androgen-sensitive and insensitive prostate cancer cells. While its efficacy is similar to bicalutamide in terms of PSA response rate and median response duration, diethylstilbestrol is associated with significantly more cardiovascular toxicity, including stroke, pulmonary embolism, and heart failure, and its use is therefore limited.³⁸ The glucocorticoids—prednisone (5 mg orally twice daily), dexamethasone (0.5 mg daily), and hydrocortisone (40 mg daily)—inhibit pituitary synthesis of adrenocorticotropic hormone, resulting in decreased adrenal androgen synthesis. Data suggest that among the glucocorticoids, dexamethasone monotherapy may produce superior response rates compared to prednisone monotherapy.³⁹ While the glucocorticoids do produce a PSA response, prolong time to disease progression, and can provide symptomatic relief (eg, from bone pain), they have not been shown to confer a survival benefit and therefore are not commonly used as monotherapy.

Future of CRPC Treatment

Patients with CRPC should be considered for clinical trials when available. These patients’ tumors should be assessed with next-generation sequencing for analysis of microsatellite instability (MSI) or mismatch repair (MMR) as well as the presence of other potentially targetable mutations, as this information may bring into consideration additional investigational as well as FDA-approved treatment options. As of May 2017, immunotherapy with pembrolizumab is approved for patients whose prostate cancer is deficient in MMR or has a high MSI burden based on a study of 12 solid tumor types (including prostate cancer) with deficient MMR.⁴⁰ Additionally, for patients whose tumor has ≥ 1% programmed death ligand 1 (PD-L1) expression, pembrolizumab has a 17% overall response rate and confers stability of disease in 35%, with a median response duration of 13.5 months.⁴¹ Cabozantinib is a mesenchymal epithelial transition (MET) kinase and vascular endothelial growth factor receptor (VEGF-R) inhibitor. When used in heavily pre-treated patients with mCRPC, it showed a radiographic PFS benefit but no survival benefit over prednisone monotherapy.⁴² One study showed that for patients whose mCRPC had a homozygous deletion and/or a deleterious mutation in the homologous recombination repair genes BRCA1/2, ATM, and CHEK2 or the Fanconi anemia genes, the response rate to the poly ADP ribose polymerase (PARP) inhibitor olaparib was 88%, with a 100% response rate in those with BRCA2 mutations.⁴³ Furthermore, mutations in these DNA repair genes predict increased sensitivity to platinum-based chemotherapy.

No chemotherapy regimen has demonstrated a survival benefit following cabazitaxel, although other chemotherapy regimens (in addition to mitoxantrone) have been shown to confer a palliative and radiographic response in clinical trials. For example, carboplatin has properties similar to PARP inhibitors, and has been given with docetaxel or paclitaxel as a salvage regimen in clinical trials in an attempt to lengthen time to tumor progression.^44,45 Studies combining pembrolizumab with enzalutamide (NCT02787005), abiraterone with olaparib (NCT03012321), and cabozantinib with atezolizumab (NCT03170960) are ongoing, and preliminary data appears promising.

Supportive Care

Zoledronic acid or denosumab are FDA approved for men with CRPC and bone metastasis based on the ability of these agents to delay skeletal-related events, including pathologic fracture and spinal cord compression.⁴⁶ Bisphosphonates, however, do not decrease the incidence of bone metastases.⁴⁷ And while denosumab does delay the time to first bone metastasis in nmCRPC (particularly in patients with a PSADT of ≤ 6 months), it does not improve OS.⁴⁸ Other supportive measures include exercise and nutrition. Moderate aerobic exercise for 150 minutes in addition to 2 or 3 strength training sessions per week is recommended by the American College of Sport Medicine to combat cancer-related fatigue.⁴⁹ There are currently no dietary changes that are routinely recommended to improve the outcome of prostate cancer, but a study noted a shorter biochemical failure–free survival in men with prostate cancer who were obese and consumed a diet high in saturated fat.⁵⁰

Conclusion

Prostate cancer affects more men in the United States than any other cancer. Once a patient is started on hormone therapy, in all likelihood their prostate cancer will become castration-resistant. Once prostate cancer has developed hormone resistance, there are a host of further treatment options available, including further hormone therapy, chemotherapy, immunotherapy, radiation therapy, bone-targeting agents, and clinical trials. Determining the appropriate sequence in which to use these therapies requires knowledge of the natural history of CRPC, the indications for changing therapies, the mechanism of action and adverse event profile of each treatment, and the optimal time to enroll in a clinical trial.

Prostate cancer is the most common malignancy in men, with an estimated 165,000 new prostate cancer diagnoses and 29,000 prostate cancer deaths occurring in the United States in 2018.¹ Due to the widespread use of screening prostate-specific antigen (PSA), prostate cancer has been mainly diagnosed when the tumor is confined to the prostate. Despite definitive treatment of localized prostate cancer, some men develop systemic disease, either biochemical failure, as defined by rising PSA level, or metastatic disease.¹ Several factors have been demonstrated to predict risk of relapse, including higher pretreatment PSA, higher Gleason score, and a greater anatomic extent of disease.² In addition, the incidence of de novo metastatic prostate cancer was recently noted to be increasing. This may be due to changes in the United States Preventive Services Task Force prostate cancer screening guidelines in 2012, which recommended against screening for prostate cancer in men of any age. The updated 2018 guidelines recommend a discussion of the risks versus benefits of screening for prostate cancer for all men aged 55 to 69 years,recommend against screening for men older than 70 years, and do not have recommendations for high-risk subgroups.³

Androgen deprivation therapy (ADT) has been the cornerstone of therapy since 1941 for men with hormone-sensitive systemic disease, both in biochemically relapsed and metastatic disease.^4,5 While more than 90% of patients respond to initial ADT, castration resistance is inevitable in some men.^6,7 Prostate cancer will become castration-resistant typically after 18 to 24 months of ADT, with the majority of patients developing castration-resistant prostate cancer (CRPC) within 5 years of initiation of ADT.⁸

Pathogenesis

CRPC (previously called androgen independent prostate cancer) is defined as progression of disease despite serum total testosterone levels less than 50 ng/dL. CRPC is characterized by a rising PSA level and/or radiographic progression. One mechanism of castration resistance is genetic modification of the androgen receptor (AR), including increased expression of the wild-type AR.⁹ Alternatively, mutations of the steroid-binding domain may play a role in the development of castration resistance by allowing the AR to become activated by non-androgen steroid hormones or even paradoxically by antiandrogens. Studies suggest, however, that AR mutations may be seen in only 10% of prostate cancers that have developed castration resistance.¹⁰ The AR-V7 splice variant of the AR lacks an androgen binding site altogether, and may play an important role in castration resistance. In one study, the presence of this splice variant in circulating prostate cancer tumor cells predicted resistance to enzalutamide and abiraterone as well as poor outcomes.¹¹ Intratumoral androgen synthesis also may play a role in the development of CRPC.^12,13

CRPC can be broadly categorized into 2 categories, metastatic (mCRPC) and nonmetastatic (nmCRPC; Figure). The exact proportion of patients entering CRPC at a nonmetastatic stage (M0) is largely unknown.¹⁴ In one study of patients at the time of diagnosis of CRPC, ≥ 84% of patients were shown to have metastases.⁸ In this article, we review key aspects of management of CRPC, including selection of first- and second-line therapy, and briefly discuss upcoming clinical trials.

 

 

Treatment of Nonmetastatic CRPC (M0 Disease)

Early identification of M0 CRPC is important because patients with nonmetastatic CRPC are at risk for metastasis, as demonstrated by Smith and colleagues.¹⁵ In this study that evaluated data from patients with nmCRPC in the placebo group (n = 331) of a randomized controlled trial, at 2 years 46% had developed ≥ 1 bone metastasis, 20% had died, and the median bone metastasis-free survival (MFS) was 25 months.¹⁵

Rapid PSA doubling time (PSADT) is linked to shorter time to metastasis in this group of patients. Patients with a PSADT of < 10 months had a risk for bone metastasis 12 times greater and a risk for death 4 times greater than patients with a PSADT of ≥ 10 months.¹⁶ Accordingly, observation should be reserved for those patients with a PSADT of ≥ 10 months.

Options for secondary hormonal therapy in those with a PSADT of ≤ 10 months include a first-generation antiandrogen (bicalutamide, flutamide, nilutamide), ketoconazole with hydrocortisone, and more recently second-generation antiandrogens (apalutamide or enzalutamide).

Bicalutamide competitively inhibits dihydrotestosterone and testosterone binding to the AR and is generally well-tolerated; it is given in conjunction with a GnRH agonist/castration.¹⁷ The use of other first-generation antiandrogens is limited mainly due to their toxicity profile. When compared to flutamide in a randomized, double-blinded control study, bicalutamide had significantly improved time to treatment failure.¹⁸ Due to promiscuous binding to AR, withdrawal of first-generation antiandrogen therapy has been associated with a biochemical response in a small proportion of patients, with response typically seen after 5 to 7 half-lives of the drug have elapsed.¹⁹

Although traditionally used as an antifungal agent, ketoconazole also inhibits androgen synthesis in the adrenal glands and acts as a direct cytotoxin to cancer cells.²⁰ Ketoconazole (with hydrocortisone) has been considered as a treatment option, typically at the time of antiandrogen withdrawal. However, ketoconazole offers no survival benefit, and with the approval of abiraterone in M1 CRPC, its use has declined significantly.²¹ Additionally, ketoconazole poses a risk for severe hepatotoxicity and QT prolongation, and has significant interactions with numerous drugs, thereby limiting its use. Given the typically short duration of response to first-generation antiandrogens, the second-generation antiandrogens were developed and are associated with a significantly greater progression-free survival (PFS) in M0 CRPC.^22,23

The second-generation antiandrogens enzalutamide and apalutamide not only competitively bind to the AR, inhibiting formation of the androgen/AR complex, but they also inhibit androgen/AR complex nuclear translocation and binding to nuclear DNA. In the PROSPER trial, enzalutamide significantly increased radiographic PFS and improved quality of life compared to placebo in chemotherapy-naive patients (Table 1).²⁴ Apalutamide significantly increased MFS as well as PFS and time to PSA progression compared to placebo in the phase 3 SPARTAN trial.²⁵ Apalutamide is generally well tolerated, with hypertension and rash being the most common severe adverse effects. Apalutamide also has less potential for central nervous system toxicities than enzalutamide. The recent approval of these agents is likely to change responses to subsequent treatments, especially in the metastatic setting.

 

 

Treatment of Metastatic CRPC (M1 Disease)

As with M0 CRPC, ADT should be continued in patients with mCRPC to maintain castration levels of testosterone while initiating additional treatments. Several drugs for the treatment of mCRPC have been approved by the US Food and Drug Administration (FDA) since 2010, including abiraterone with prednisone (or methylprednisolone), enzalutamide (but not apalutamide), radium-223, sipuleucel-T, and cabazitaxel (Table 2).

Given the availability of numerous treatment options for men with mCRPC, the sequencing of treatments should be based on careful consideration of the efficacy and adverse effect profiles of each drug as well as the anatomic and molecular characteristics of the cancer, comorbidities, and patient preference. If there is no evidence of visceral disease and the patient has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 with an estimated life expectancy of greater than 6 months and is minimally symptomatic, then treatment with either oral targeted agents or immunotherapy with sipuleucel-T is considered appropriate.

Sipuleucel-T is an autologous dendritic cell vaccination designed to enhance T-cell–mediated response to prostatic acid phosphatase (PAP). The treatments are prepared from leukapheresed host mononuclear cells that are then exposed to PAP fused to granulocyte-macrophage colony-stimulating factor. The activated dendritic cells are then infused back into the host once every 2 weeks for a total of 3 treatments. The main side effects of this treatment include chills, fever, and headache, but it is generally well-tolerated and has demonstrated a survival benefit.²⁶

Both enzalutamide and abiraterone (abiraterone given with physiologic-dose steroid replacement) confer a survival benefit in chemotherapy-naive patients with M1 CRPC. Per the PREVAIL study, enzalutamide (when compared to placebo) offers a median improvement in overall survival (OS) by about 2 months and in radiographic PFS by about 14.6 months.²⁴ Abiraterone blocks the synthesis of androgens via inhibition of CYP17 in the testes and adrenal glands. Abiraterone also confers an overall survival advantage for patients with M1 CRPC who are chemotherapy-naïve, with an estimated 25% decrease in the risk of death (hazard ratio, 0.75, P = 0.009) when compared to prednisone.²⁷

In patients with symptomatic M1 CRPC who have visceral disease or rapidly progressive disease and who are candidates for chemotherapy, docetaxel is frequently used and is given concurrently with steroids. Docetaxel has been given for up to 10 cycles in clinical trials (assuming no progression of disease or dose-limiting toxicities were observed), and at least 6 cycles of treatment are recommended. When compared to mitoxantrone plus prednisone in the TAX 327 phase 3 trial, docetaxel plus prednisone offered a significant OS benefit of about 3 months (19.2 months versus 16.3 months).²⁸ For patients who are not candidates for docetaxel (eg, due to preexisting peripheral neuropathy), cabazitaxel should be considered. OS is similar for mCRPC with docetaxel versus cabazitaxel when given in the first-line setting.²⁹ Additionally, cabazitaxel dosed at 20 mg/m² is noninferior to cabazitaxel dosed at 25 mg/m², and the lower dose is associated with lower rates of peripheral neuropathy.³⁰ Cabazitaxel should also be considered for mCRPC that has progressed following treatment with docetaxel, with improved OS and PFS when compared to treatment with mitoxantrone and prednisone in this setting, as shown in the TROPIC study.³¹ Mitoxantrone given with prednisone has been shown to improve quality of life, but it is associated with significant cardiac toxicity. Additionally, mitoxantrone does not improve disease-free survival or OS in chemotherapy-naive patients³² or in patients who have progressed on docetaxel, and therefore should not be given to patients prior to a taxane chemotherapy unless the patient absolutely cannot tolerate docetaxel or cabazitaxel.

Once a patient’s prostate cancer progresses following treatment with a taxane, the sequence in which to administer subsequent therapies should involve careful consideration of previous treatments and duration of response to each of these treatments. Both enzalutamide and abiraterone are FDA-approved for use following treatment with chemotherapy. Per the AFFIRM trial, heavily pre-treated patients (including those who have received docetaxel) have a median 5-month OS benefit with enzalutamide compared to placebo.³³ Another study of M1 CRPC patients who had previously received docetaxel demonstrated an OS benefit with abiraterone (versus placebo),³⁴ but this regimen has limited benefit in patients who have previously received both docetaxel and enzalutamide.³⁵ A rechallenge with docetaxel therapy also can be considered if the patient’s disease responded to docetaxel in the metastatic hormone-sensitive setting.

If the patient’s metastases are limited to bone (ie, no visceral disease), then radiotherapy with radium-223 should be considered. Radium-223 is an alpha-emitting calcium-mimetic radioactive compound that tracks to bone to delay the onset of symptoms from bone metastases.³⁶ Radium-223 also confers a median OS benefit of about 3 months.³⁷ However, this treatment is often limited by preexisting cytopenias.

Diethylstilbestrol (1 mg daily) competes with androgens for AR binding and is also cytotoxic to androgen-sensitive and insensitive prostate cancer cells. While its efficacy is similar to bicalutamide in terms of PSA response rate and median response duration, diethylstilbestrol is associated with significantly more cardiovascular toxicity, including stroke, pulmonary embolism, and heart failure, and its use is therefore limited.³⁸ The glucocorticoids—prednisone (5 mg orally twice daily), dexamethasone (0.5 mg daily), and hydrocortisone (40 mg daily)—inhibit pituitary synthesis of adrenocorticotropic hormone, resulting in decreased adrenal androgen synthesis. Data suggest that among the glucocorticoids, dexamethasone monotherapy may produce superior response rates compared to prednisone monotherapy.³⁹ While the glucocorticoids do produce a PSA response, prolong time to disease progression, and can provide symptomatic relief (eg, from bone pain), they have not been shown to confer a survival benefit and therefore are not commonly used as monotherapy.

Future of CRPC Treatment

Patients with CRPC should be considered for clinical trials when available. These patients’ tumors should be assessed with next-generation sequencing for analysis of microsatellite instability (MSI) or mismatch repair (MMR) as well as the presence of other potentially targetable mutations, as this information may bring into consideration additional investigational as well as FDA-approved treatment options. As of May 2017, immunotherapy with pembrolizumab is approved for patients whose prostate cancer is deficient in MMR or has a high MSI burden based on a study of 12 solid tumor types (including prostate cancer) with deficient MMR.⁴⁰ Additionally, for patients whose tumor has ≥ 1% programmed death ligand 1 (PD-L1) expression, pembrolizumab has a 17% overall response rate and confers stability of disease in 35%, with a median response duration of 13.5 months.⁴¹ Cabozantinib is a mesenchymal epithelial transition (MET) kinase and vascular endothelial growth factor receptor (VEGF-R) inhibitor. When used in heavily pre-treated patients with mCRPC, it showed a radiographic PFS benefit but no survival benefit over prednisone monotherapy.⁴² One study showed that for patients whose mCRPC had a homozygous deletion and/or a deleterious mutation in the homologous recombination repair genes BRCA1/2, ATM, and CHEK2 or the Fanconi anemia genes, the response rate to the poly ADP ribose polymerase (PARP) inhibitor olaparib was 88%, with a 100% response rate in those with BRCA2 mutations.⁴³ Furthermore, mutations in these DNA repair genes predict increased sensitivity to platinum-based chemotherapy.

No chemotherapy regimen has demonstrated a survival benefit following cabazitaxel, although other chemotherapy regimens (in addition to mitoxantrone) have been shown to confer a palliative and radiographic response in clinical trials. For example, carboplatin has properties similar to PARP inhibitors, and has been given with docetaxel or paclitaxel as a salvage regimen in clinical trials in an attempt to lengthen time to tumor progression.^44,45 Studies combining pembrolizumab with enzalutamide (NCT02787005), abiraterone with olaparib (NCT03012321), and cabozantinib with atezolizumab (NCT03170960) are ongoing, and preliminary data appears promising.

Supportive Care

Zoledronic acid or denosumab are FDA approved for men with CRPC and bone metastasis based on the ability of these agents to delay skeletal-related events, including pathologic fracture and spinal cord compression.⁴⁶ Bisphosphonates, however, do not decrease the incidence of bone metastases.⁴⁷ And while denosumab does delay the time to first bone metastasis in nmCRPC (particularly in patients with a PSADT of ≤ 6 months), it does not improve OS.⁴⁸ Other supportive measures include exercise and nutrition. Moderate aerobic exercise for 150 minutes in addition to 2 or 3 strength training sessions per week is recommended by the American College of Sport Medicine to combat cancer-related fatigue.⁴⁹ There are currently no dietary changes that are routinely recommended to improve the outcome of prostate cancer, but a study noted a shorter biochemical failure–free survival in men with prostate cancer who were obese and consumed a diet high in saturated fat.⁵⁰

Conclusion

Prostate cancer affects more men in the United States than any other cancer. Once a patient is started on hormone therapy, in all likelihood their prostate cancer will become castration-resistant. Once prostate cancer has developed hormone resistance, there are a host of further treatment options available, including further hormone therapy, chemotherapy, immunotherapy, radiation therapy, bone-targeting agents, and clinical trials. Determining the appropriate sequence in which to use these therapies requires knowledge of the natural history of CRPC, the indications for changing therapies, the mechanism of action and adverse event profile of each treatment, and the optimal time to enroll in a clinical trial.

Prostate cancer is the most common malignancy in men, with an estimated 165,000 new prostate cancer diagnoses and 29,000 prostate cancer deaths occurring in the United States in 2018.¹ Due to the widespread use of screening prostate-specific antigen (PSA), prostate cancer has been mainly diagnosed when the tumor is confined to the prostate. Despite definitive treatment of localized prostate cancer, some men develop systemic disease, either biochemical failure, as defined by rising PSA level, or metastatic disease.¹ Several factors have been demonstrated to predict risk of relapse, including higher pretreatment PSA, higher Gleason score, and a greater anatomic extent of disease.² In addition, the incidence of de novo metastatic prostate cancer was recently noted to be increasing. This may be due to changes in the United States Preventive Services Task Force prostate cancer screening guidelines in 2012, which recommended against screening for prostate cancer in men of any age. The updated 2018 guidelines recommend a discussion of the risks versus benefits of screening for prostate cancer for all men aged 55 to 69 years,recommend against screening for men older than 70 years, and do not have recommendations for high-risk subgroups.³

Androgen deprivation therapy (ADT) has been the cornerstone of therapy since 1941 for men with hormone-sensitive systemic disease, both in biochemically relapsed and metastatic disease.^4,5 While more than 90% of patients respond to initial ADT, castration resistance is inevitable in some men.^6,7 Prostate cancer will become castration-resistant typically after 18 to 24 months of ADT, with the majority of patients developing castration-resistant prostate cancer (CRPC) within 5 years of initiation of ADT.⁸

Pathogenesis

CRPC (previously called androgen independent prostate cancer) is defined as progression of disease despite serum total testosterone levels less than 50 ng/dL. CRPC is characterized by a rising PSA level and/or radiographic progression. One mechanism of castration resistance is genetic modification of the androgen receptor (AR), including increased expression of the wild-type AR.⁹ Alternatively, mutations of the steroid-binding domain may play a role in the development of castration resistance by allowing the AR to become activated by non-androgen steroid hormones or even paradoxically by antiandrogens. Studies suggest, however, that AR mutations may be seen in only 10% of prostate cancers that have developed castration resistance.¹⁰ The AR-V7 splice variant of the AR lacks an androgen binding site altogether, and may play an important role in castration resistance. In one study, the presence of this splice variant in circulating prostate cancer tumor cells predicted resistance to enzalutamide and abiraterone as well as poor outcomes.¹¹ Intratumoral androgen synthesis also may play a role in the development of CRPC.^12,13

CRPC can be broadly categorized into 2 categories, metastatic (mCRPC) and nonmetastatic (nmCRPC; Figure). The exact proportion of patients entering CRPC at a nonmetastatic stage (M0) is largely unknown.¹⁴ In one study of patients at the time of diagnosis of CRPC, ≥ 84% of patients were shown to have metastases.⁸ In this article, we review key aspects of management of CRPC, including selection of first- and second-line therapy, and briefly discuss upcoming clinical trials.

 

 

Treatment of Nonmetastatic CRPC (M0 Disease)

Early identification of M0 CRPC is important because patients with nonmetastatic CRPC are at risk for metastasis, as demonstrated by Smith and colleagues.¹⁵ In this study that evaluated data from patients with nmCRPC in the placebo group (n = 331) of a randomized controlled trial, at 2 years 46% had developed ≥ 1 bone metastasis, 20% had died, and the median bone metastasis-free survival (MFS) was 25 months.¹⁵

Rapid PSA doubling time (PSADT) is linked to shorter time to metastasis in this group of patients. Patients with a PSADT of < 10 months had a risk for bone metastasis 12 times greater and a risk for death 4 times greater than patients with a PSADT of ≥ 10 months.¹⁶ Accordingly, observation should be reserved for those patients with a PSADT of ≥ 10 months.

Options for secondary hormonal therapy in those with a PSADT of ≤ 10 months include a first-generation antiandrogen (bicalutamide, flutamide, nilutamide), ketoconazole with hydrocortisone, and more recently second-generation antiandrogens (apalutamide or enzalutamide).

Bicalutamide competitively inhibits dihydrotestosterone and testosterone binding to the AR and is generally well-tolerated; it is given in conjunction with a GnRH agonist/castration.¹⁷ The use of other first-generation antiandrogens is limited mainly due to their toxicity profile. When compared to flutamide in a randomized, double-blinded control study, bicalutamide had significantly improved time to treatment failure.¹⁸ Due to promiscuous binding to AR, withdrawal of first-generation antiandrogen therapy has been associated with a biochemical response in a small proportion of patients, with response typically seen after 5 to 7 half-lives of the drug have elapsed.¹⁹

Although traditionally used as an antifungal agent, ketoconazole also inhibits androgen synthesis in the adrenal glands and acts as a direct cytotoxin to cancer cells.²⁰ Ketoconazole (with hydrocortisone) has been considered as a treatment option, typically at the time of antiandrogen withdrawal. However, ketoconazole offers no survival benefit, and with the approval of abiraterone in M1 CRPC, its use has declined significantly.²¹ Additionally, ketoconazole poses a risk for severe hepatotoxicity and QT prolongation, and has significant interactions with numerous drugs, thereby limiting its use. Given the typically short duration of response to first-generation antiandrogens, the second-generation antiandrogens were developed and are associated with a significantly greater progression-free survival (PFS) in M0 CRPC.^22,23

The second-generation antiandrogens enzalutamide and apalutamide not only competitively bind to the AR, inhibiting formation of the androgen/AR complex, but they also inhibit androgen/AR complex nuclear translocation and binding to nuclear DNA. In the PROSPER trial, enzalutamide significantly increased radiographic PFS and improved quality of life compared to placebo in chemotherapy-naive patients (Table 1).²⁴ Apalutamide significantly increased MFS as well as PFS and time to PSA progression compared to placebo in the phase 3 SPARTAN trial.²⁵ Apalutamide is generally well tolerated, with hypertension and rash being the most common severe adverse effects. Apalutamide also has less potential for central nervous system toxicities than enzalutamide. The recent approval of these agents is likely to change responses to subsequent treatments, especially in the metastatic setting.

 

 

Treatment of Metastatic CRPC (M1 Disease)

As with M0 CRPC, ADT should be continued in patients with mCRPC to maintain castration levels of testosterone while initiating additional treatments. Several drugs for the treatment of mCRPC have been approved by the US Food and Drug Administration (FDA) since 2010, including abiraterone with prednisone (or methylprednisolone), enzalutamide (but not apalutamide), radium-223, sipuleucel-T, and cabazitaxel (Table 2).

Given the availability of numerous treatment options for men with mCRPC, the sequencing of treatments should be based on careful consideration of the efficacy and adverse effect profiles of each drug as well as the anatomic and molecular characteristics of the cancer, comorbidities, and patient preference. If there is no evidence of visceral disease and the patient has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 with an estimated life expectancy of greater than 6 months and is minimally symptomatic, then treatment with either oral targeted agents or immunotherapy with sipuleucel-T is considered appropriate.

Sipuleucel-T is an autologous dendritic cell vaccination designed to enhance T-cell–mediated response to prostatic acid phosphatase (PAP). The treatments are prepared from leukapheresed host mononuclear cells that are then exposed to PAP fused to granulocyte-macrophage colony-stimulating factor. The activated dendritic cells are then infused back into the host once every 2 weeks for a total of 3 treatments. The main side effects of this treatment include chills, fever, and headache, but it is generally well-tolerated and has demonstrated a survival benefit.²⁶

Both enzalutamide and abiraterone (abiraterone given with physiologic-dose steroid replacement) confer a survival benefit in chemotherapy-naive patients with M1 CRPC. Per the PREVAIL study, enzalutamide (when compared to placebo) offers a median improvement in overall survival (OS) by about 2 months and in radiographic PFS by about 14.6 months.²⁴ Abiraterone blocks the synthesis of androgens via inhibition of CYP17 in the testes and adrenal glands. Abiraterone also confers an overall survival advantage for patients with M1 CRPC who are chemotherapy-naïve, with an estimated 25% decrease in the risk of death (hazard ratio, 0.75, P = 0.009) when compared to prednisone.²⁷

In patients with symptomatic M1 CRPC who have visceral disease or rapidly progressive disease and who are candidates for chemotherapy, docetaxel is frequently used and is given concurrently with steroids. Docetaxel has been given for up to 10 cycles in clinical trials (assuming no progression of disease or dose-limiting toxicities were observed), and at least 6 cycles of treatment are recommended. When compared to mitoxantrone plus prednisone in the TAX 327 phase 3 trial, docetaxel plus prednisone offered a significant OS benefit of about 3 months (19.2 months versus 16.3 months).²⁸ For patients who are not candidates for docetaxel (eg, due to preexisting peripheral neuropathy), cabazitaxel should be considered. OS is similar for mCRPC with docetaxel versus cabazitaxel when given in the first-line setting.²⁹ Additionally, cabazitaxel dosed at 20 mg/m² is noninferior to cabazitaxel dosed at 25 mg/m², and the lower dose is associated with lower rates of peripheral neuropathy.³⁰ Cabazitaxel should also be considered for mCRPC that has progressed following treatment with docetaxel, with improved OS and PFS when compared to treatment with mitoxantrone and prednisone in this setting, as shown in the TROPIC study.³¹ Mitoxantrone given with prednisone has been shown to improve quality of life, but it is associated with significant cardiac toxicity. Additionally, mitoxantrone does not improve disease-free survival or OS in chemotherapy-naive patients³² or in patients who have progressed on docetaxel, and therefore should not be given to patients prior to a taxane chemotherapy unless the patient absolutely cannot tolerate docetaxel or cabazitaxel.

Once a patient’s prostate cancer progresses following treatment with a taxane, the sequence in which to administer subsequent therapies should involve careful consideration of previous treatments and duration of response to each of these treatments. Both enzalutamide and abiraterone are FDA-approved for use following treatment with chemotherapy. Per the AFFIRM trial, heavily pre-treated patients (including those who have received docetaxel) have a median 5-month OS benefit with enzalutamide compared to placebo.³³ Another study of M1 CRPC patients who had previously received docetaxel demonstrated an OS benefit with abiraterone (versus placebo),³⁴ but this regimen has limited benefit in patients who have previously received both docetaxel and enzalutamide.³⁵ A rechallenge with docetaxel therapy also can be considered if the patient’s disease responded to docetaxel in the metastatic hormone-sensitive setting.

If the patient’s metastases are limited to bone (ie, no visceral disease), then radiotherapy with radium-223 should be considered. Radium-223 is an alpha-emitting calcium-mimetic radioactive compound that tracks to bone to delay the onset of symptoms from bone metastases.³⁶ Radium-223 also confers a median OS benefit of about 3 months.³⁷ However, this treatment is often limited by preexisting cytopenias.

Diethylstilbestrol (1 mg daily) competes with androgens for AR binding and is also cytotoxic to androgen-sensitive and insensitive prostate cancer cells. While its efficacy is similar to bicalutamide in terms of PSA response rate and median response duration, diethylstilbestrol is associated with significantly more cardiovascular toxicity, including stroke, pulmonary embolism, and heart failure, and its use is therefore limited.³⁸ The glucocorticoids—prednisone (5 mg orally twice daily), dexamethasone (0.5 mg daily), and hydrocortisone (40 mg daily)—inhibit pituitary synthesis of adrenocorticotropic hormone, resulting in decreased adrenal androgen synthesis. Data suggest that among the glucocorticoids, dexamethasone monotherapy may produce superior response rates compared to prednisone monotherapy.³⁹ While the glucocorticoids do produce a PSA response, prolong time to disease progression, and can provide symptomatic relief (eg, from bone pain), they have not been shown to confer a survival benefit and therefore are not commonly used as monotherapy.

Future of CRPC Treatment

Patients with CRPC should be considered for clinical trials when available. These patients’ tumors should be assessed with next-generation sequencing for analysis of microsatellite instability (MSI) or mismatch repair (MMR) as well as the presence of other potentially targetable mutations, as this information may bring into consideration additional investigational as well as FDA-approved treatment options. As of May 2017, immunotherapy with pembrolizumab is approved for patients whose prostate cancer is deficient in MMR or has a high MSI burden based on a study of 12 solid tumor types (including prostate cancer) with deficient MMR.⁴⁰ Additionally, for patients whose tumor has ≥ 1% programmed death ligand 1 (PD-L1) expression, pembrolizumab has a 17% overall response rate and confers stability of disease in 35%, with a median response duration of 13.5 months.⁴¹ Cabozantinib is a mesenchymal epithelial transition (MET) kinase and vascular endothelial growth factor receptor (VEGF-R) inhibitor. When used in heavily pre-treated patients with mCRPC, it showed a radiographic PFS benefit but no survival benefit over prednisone monotherapy.⁴² One study showed that for patients whose mCRPC had a homozygous deletion and/or a deleterious mutation in the homologous recombination repair genes BRCA1/2, ATM, and CHEK2 or the Fanconi anemia genes, the response rate to the poly ADP ribose polymerase (PARP) inhibitor olaparib was 88%, with a 100% response rate in those with BRCA2 mutations.⁴³ Furthermore, mutations in these DNA repair genes predict increased sensitivity to platinum-based chemotherapy.

No chemotherapy regimen has demonstrated a survival benefit following cabazitaxel, although other chemotherapy regimens (in addition to mitoxantrone) have been shown to confer a palliative and radiographic response in clinical trials. For example, carboplatin has properties similar to PARP inhibitors, and has been given with docetaxel or paclitaxel as a salvage regimen in clinical trials in an attempt to lengthen time to tumor progression.^44,45 Studies combining pembrolizumab with enzalutamide (NCT02787005), abiraterone with olaparib (NCT03012321), and cabozantinib with atezolizumab (NCT03170960) are ongoing, and preliminary data appears promising.

Supportive Care

Zoledronic acid or denosumab are FDA approved for men with CRPC and bone metastasis based on the ability of these agents to delay skeletal-related events, including pathologic fracture and spinal cord compression.⁴⁶ Bisphosphonates, however, do not decrease the incidence of bone metastases.⁴⁷ And while denosumab does delay the time to first bone metastasis in nmCRPC (particularly in patients with a PSADT of ≤ 6 months), it does not improve OS.⁴⁸ Other supportive measures include exercise and nutrition. Moderate aerobic exercise for 150 minutes in addition to 2 or 3 strength training sessions per week is recommended by the American College of Sport Medicine to combat cancer-related fatigue.⁴⁹ There are currently no dietary changes that are routinely recommended to improve the outcome of prostate cancer, but a study noted a shorter biochemical failure–free survival in men with prostate cancer who were obese and consumed a diet high in saturated fat.⁵⁰

Conclusion

Prostate cancer affects more men in the United States than any other cancer. Once a patient is started on hormone therapy, in all likelihood their prostate cancer will become castration-resistant. Once prostate cancer has developed hormone resistance, there are a host of further treatment options available, including further hormone therapy, chemotherapy, immunotherapy, radiation therapy, bone-targeting agents, and clinical trials. Determining the appropriate sequence in which to use these therapies requires knowledge of the natural history of CRPC, the indications for changing therapies, the mechanism of action and adverse event profile of each treatment, and the optimal time to enroll in a clinical trial.

SAN FRANCISCO – A combination of a targeted therapy and an immune checkpoint inhibitor showed promising activity against advanced urothelial cancer in early data from a phase 1b/2 study.

In a cohort of 20 patients with urothelial carcinoma who were enrolled in a larger clinical trial testing the combination of the tyrosine kinase inhibitor (TKI) lenvatinib (Lenvima) and the checkpoint inhibitor pembrolizumab (Keytruda) against urinary tract and other solid malignancies, 5 had an objective response to the combination, including one complete and four partial responses, for an objective response rate of 25%, reported Nicholas J. Vogelzang, MD, from Comprehensive Cancers Centers of Nevada in Las Vegas.

“This response rate warrants further investigation. The lenvatinib plus pembrolizumab combination will be studied in a phase 3 trial in urothelial carcinoma,” he said at the American Society of Clinical Oncology (ASCO) - Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

Dr. Vogelzang noted that urothelial carcinomas account for more than 90% of all bladder cancers. Pembrolizumab monotherapy is approved for treatment of patients with urothelial carcinoma who are ineligible for cisplatin and whose tumors have a combined positive score (CPS) for programmed death-ligand 1 (PD-L1) of 10 or greater or who are ineligible for platinum-based chemotherapy regimens and, in the second line, for advanced or metastatic urothelial carcinoma.

Lenvatinib, a multikinase inhibitor, is approved as monotherapy for radioiodine-refractory differentiated thyroid cancer, unresectable hepatocellular carcinoma, and in combination with everolimus for advanced renal cell carcinoma (RCC) after one year of antiangiogenic therapy.

Dr. Vogelzang reported results of the urothelial cancer cohort from a multicohort study testing the combination.

Twenty patients with histologically confirmed metastatic urothelial cancer were enrolled. The patients all had no more than two prior systemic regimens, good performance status, and a life expectancy of at least 12 weeks. The patients received oral lenvatinib 20 mg daily and pembrolizumab 200 mg intravenously every 21 days. The median patient age was 72 years. The cohort included 14 men and six women.

The objective response rate (ORR) at 24 weeks, the primary endpoint, was 25%, comprising one complete and four partial responses. Nine patients had stable disease, two had disease progression, and four were not evaluable for efficacy. The results were identical according to immune-related Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and modified RECIST version 1.1. Of the 16 evaluable patients, 12 experienced tumor-size reductions from baseline.

“Although there were five objective responses, there were an additional seven patients or more who had minor regressions of disease – clearly an active regimen,” Dr. Vogelzang said. Four of the patients, including one with a PD-L1–positive tumor and three with PD-L1–negative tumors were still alive, with the longest survival past 80 weeks since the start of therapy. The majority of patients, however, had no objective response or disease progression within about 20 weeks.

After a median follow-up of 11.7 months, the median progression-free survival (PFS) was 5.4 months, and the 12-month PFS rate was 26%.

In all, 18 of the 20 patients (90%) experienced a treatment-related adverse event of any grade, 10 had grade 3 or 4 events, and 6 had serious adverse events including one death from gastrointestinal hemorrhage that Dr. Vogelzang said appeared to be related to lenvatinib. A total of four patients (20%) had a treatment-related event leading to withdrawal or discontinuation, seven had a dose reduction, and 12 had an interruption in therapy, primarily of lenvatinib. The most common toxicities were proteinuria, diarrhea, hypertension, fatigue, hypothyroidism, decreased appetite with nausea, pancreatitis with increased lipase, skin rash, vomiting, and dry mouth.

In addition to the planned phase 3 trial of the combination in urothelial carcinoma, lenvatinib/pembrolizumab is also being studied for the treatment of RCC.

The study was supported by Eisai and Merck Sharp & Dohme. Dr. Vogelzang disclosed financial relationships with Caris Life Sciences, Pfizer, Up to Date, AstraZeneca, MedImmune, and other companies. Five coauthors are employees of Merck or Esai.

SOURCE: Vogelzang NJ et al. ASCO-SITC, Abstract 11.

SAN FRANCISCO – A combination of a targeted therapy and an immune checkpoint inhibitor showed promising activity against advanced urothelial cancer in early data from a phase 1b/2 study.

In a cohort of 20 patients with urothelial carcinoma who were enrolled in a larger clinical trial testing the combination of the tyrosine kinase inhibitor (TKI) lenvatinib (Lenvima) and the checkpoint inhibitor pembrolizumab (Keytruda) against urinary tract and other solid malignancies, 5 had an objective response to the combination, including one complete and four partial responses, for an objective response rate of 25%, reported Nicholas J. Vogelzang, MD, from Comprehensive Cancers Centers of Nevada in Las Vegas.

“This response rate warrants further investigation. The lenvatinib plus pembrolizumab combination will be studied in a phase 3 trial in urothelial carcinoma,” he said at the American Society of Clinical Oncology (ASCO) - Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

Dr. Vogelzang noted that urothelial carcinomas account for more than 90% of all bladder cancers. Pembrolizumab monotherapy is approved for treatment of patients with urothelial carcinoma who are ineligible for cisplatin and whose tumors have a combined positive score (CPS) for programmed death-ligand 1 (PD-L1) of 10 or greater or who are ineligible for platinum-based chemotherapy regimens and, in the second line, for advanced or metastatic urothelial carcinoma.

Lenvatinib, a multikinase inhibitor, is approved as monotherapy for radioiodine-refractory differentiated thyroid cancer, unresectable hepatocellular carcinoma, and in combination with everolimus for advanced renal cell carcinoma (RCC) after one year of antiangiogenic therapy.

Dr. Vogelzang reported results of the urothelial cancer cohort from a multicohort study testing the combination.

Twenty patients with histologically confirmed metastatic urothelial cancer were enrolled. The patients all had no more than two prior systemic regimens, good performance status, and a life expectancy of at least 12 weeks. The patients received oral lenvatinib 20 mg daily and pembrolizumab 200 mg intravenously every 21 days. The median patient age was 72 years. The cohort included 14 men and six women.

The objective response rate (ORR) at 24 weeks, the primary endpoint, was 25%, comprising one complete and four partial responses. Nine patients had stable disease, two had disease progression, and four were not evaluable for efficacy. The results were identical according to immune-related Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and modified RECIST version 1.1. Of the 16 evaluable patients, 12 experienced tumor-size reductions from baseline.

“Although there were five objective responses, there were an additional seven patients or more who had minor regressions of disease – clearly an active regimen,” Dr. Vogelzang said. Four of the patients, including one with a PD-L1–positive tumor and three with PD-L1–negative tumors were still alive, with the longest survival past 80 weeks since the start of therapy. The majority of patients, however, had no objective response or disease progression within about 20 weeks.

After a median follow-up of 11.7 months, the median progression-free survival (PFS) was 5.4 months, and the 12-month PFS rate was 26%.

In all, 18 of the 20 patients (90%) experienced a treatment-related adverse event of any grade, 10 had grade 3 or 4 events, and 6 had serious adverse events including one death from gastrointestinal hemorrhage that Dr. Vogelzang said appeared to be related to lenvatinib. A total of four patients (20%) had a treatment-related event leading to withdrawal or discontinuation, seven had a dose reduction, and 12 had an interruption in therapy, primarily of lenvatinib. The most common toxicities were proteinuria, diarrhea, hypertension, fatigue, hypothyroidism, decreased appetite with nausea, pancreatitis with increased lipase, skin rash, vomiting, and dry mouth.

In addition to the planned phase 3 trial of the combination in urothelial carcinoma, lenvatinib/pembrolizumab is also being studied for the treatment of RCC.

The study was supported by Eisai and Merck Sharp & Dohme. Dr. Vogelzang disclosed financial relationships with Caris Life Sciences, Pfizer, Up to Date, AstraZeneca, MedImmune, and other companies. Five coauthors are employees of Merck or Esai.

SOURCE: Vogelzang NJ et al. ASCO-SITC, Abstract 11.

SAN FRANCISCO – A combination of a targeted therapy and an immune checkpoint inhibitor showed promising activity against advanced urothelial cancer in early data from a phase 1b/2 study.

In a cohort of 20 patients with urothelial carcinoma who were enrolled in a larger clinical trial testing the combination of the tyrosine kinase inhibitor (TKI) lenvatinib (Lenvima) and the checkpoint inhibitor pembrolizumab (Keytruda) against urinary tract and other solid malignancies, 5 had an objective response to the combination, including one complete and four partial responses, for an objective response rate of 25%, reported Nicholas J. Vogelzang, MD, from Comprehensive Cancers Centers of Nevada in Las Vegas.

“This response rate warrants further investigation. The lenvatinib plus pembrolizumab combination will be studied in a phase 3 trial in urothelial carcinoma,” he said at the American Society of Clinical Oncology (ASCO) - Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

Dr. Vogelzang noted that urothelial carcinomas account for more than 90% of all bladder cancers. Pembrolizumab monotherapy is approved for treatment of patients with urothelial carcinoma who are ineligible for cisplatin and whose tumors have a combined positive score (CPS) for programmed death-ligand 1 (PD-L1) of 10 or greater or who are ineligible for platinum-based chemotherapy regimens and, in the second line, for advanced or metastatic urothelial carcinoma.

Lenvatinib, a multikinase inhibitor, is approved as monotherapy for radioiodine-refractory differentiated thyroid cancer, unresectable hepatocellular carcinoma, and in combination with everolimus for advanced renal cell carcinoma (RCC) after one year of antiangiogenic therapy.

Dr. Vogelzang reported results of the urothelial cancer cohort from a multicohort study testing the combination.

Twenty patients with histologically confirmed metastatic urothelial cancer were enrolled. The patients all had no more than two prior systemic regimens, good performance status, and a life expectancy of at least 12 weeks. The patients received oral lenvatinib 20 mg daily and pembrolizumab 200 mg intravenously every 21 days. The median patient age was 72 years. The cohort included 14 men and six women.

The objective response rate (ORR) at 24 weeks, the primary endpoint, was 25%, comprising one complete and four partial responses. Nine patients had stable disease, two had disease progression, and four were not evaluable for efficacy. The results were identical according to immune-related Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and modified RECIST version 1.1. Of the 16 evaluable patients, 12 experienced tumor-size reductions from baseline.

“Although there were five objective responses, there were an additional seven patients or more who had minor regressions of disease – clearly an active regimen,” Dr. Vogelzang said. Four of the patients, including one with a PD-L1–positive tumor and three with PD-L1–negative tumors were still alive, with the longest survival past 80 weeks since the start of therapy. The majority of patients, however, had no objective response or disease progression within about 20 weeks.

After a median follow-up of 11.7 months, the median progression-free survival (PFS) was 5.4 months, and the 12-month PFS rate was 26%.

In all, 18 of the 20 patients (90%) experienced a treatment-related adverse event of any grade, 10 had grade 3 or 4 events, and 6 had serious adverse events including one death from gastrointestinal hemorrhage that Dr. Vogelzang said appeared to be related to lenvatinib. A total of four patients (20%) had a treatment-related event leading to withdrawal or discontinuation, seven had a dose reduction, and 12 had an interruption in therapy, primarily of lenvatinib. The most common toxicities were proteinuria, diarrhea, hypertension, fatigue, hypothyroidism, decreased appetite with nausea, pancreatitis with increased lipase, skin rash, vomiting, and dry mouth.

In addition to the planned phase 3 trial of the combination in urothelial carcinoma, lenvatinib/pembrolizumab is also being studied for the treatment of RCC.

The study was supported by Eisai and Merck Sharp & Dohme. Dr. Vogelzang disclosed financial relationships with Caris Life Sciences, Pfizer, Up to Date, AstraZeneca, MedImmune, and other companies. Five coauthors are employees of Merck or Esai.

SOURCE: Vogelzang NJ et al. ASCO-SITC, Abstract 11.

Prostate cancer patients with cardiovascular disease (CVD) who are treated with abiraterone acetate (Zytiga) have an increased risk of death within 6 months of starting therapy, compared with those without preexisting CVD, according to an analysis of Surveillance, Epidemiology, and End Results (SEER)–Medicare linked data.

Of 2,845 patients diagnosed with prostate cancer between 1991 and 2013 and treated with abiraterone acetate (AA) between 2011 and 2014, 1,924 (67.6%) had at least one serious preexisting CVD condition. Mortality within 6 months of treatment initiation in those with preexisting CVD ranged from 21.4% to 25.6%, depending on the type of condition, compared with 15.8% among those with no preexisting CVD, Grace Lu-Yao, PhD, reported during a press conference highlighting data to be presented at the upcoming American Association for Cancer Research annual meeting in Atlanta.

An additional analysis of health care utilization showed that AA treatment was associated with risks for all patients, regardless of CVD; among patients without chemotherapy and without CVD, the hospitalization rate increased by 53%, and in those with preexisting CVD the rate increased from 34% to 55%, depending on the cardiovascular condition, said Dr. Lu-Yao, associate director for population science at the Sidney Kimmel Cancer Center at Jefferson, Philadelphia.


Since patients with preexisting CVD are frequently excluded from clinical trials of AA, its effects in this population are uncertain. However, these data – though limited by the retrospective nature of the study – provide evidence that a significant proportion of patients treated in the real world differ from those in clinical trials, and therefore that the trial findings may not apply to patients who are excluded, said Dr. Lu-Yao, professor and vice chair in the department of medical Oncology at the Sidney Kimmel Medical College.

AA, which was initially approved in 2011 for use in combination with prednisone in patients with metastatic castration-resistant prostate cancer who were previously treated with docetaxel, received additional approval in 2018 for use in combination with prednisone for metastatic high-risk castration-sensitive prostate cancer.

The potential for expanded use of AA further underscores the need for improved understanding of its effects in the real-world setting, she noted.

This study was funded by a Pennsylvania CURE Program award and the National Cancer Institute. Dr. Lu-Yao has no direct conflicts to declare except that her spouse, who has no involvement with this study, is an officer of Sun Pharmaceutical Industries Inc.

SOURCE: Lu-Yao G et al. AACR 2019, Abstract preview.

Prostate cancer patients with cardiovascular disease (CVD) who are treated with abiraterone acetate (Zytiga) have an increased risk of death within 6 months of starting therapy, compared with those without preexisting CVD, according to an analysis of Surveillance, Epidemiology, and End Results (SEER)–Medicare linked data.

Of 2,845 patients diagnosed with prostate cancer between 1991 and 2013 and treated with abiraterone acetate (AA) between 2011 and 2014, 1,924 (67.6%) had at least one serious preexisting CVD condition. Mortality within 6 months of treatment initiation in those with preexisting CVD ranged from 21.4% to 25.6%, depending on the type of condition, compared with 15.8% among those with no preexisting CVD, Grace Lu-Yao, PhD, reported during a press conference highlighting data to be presented at the upcoming American Association for Cancer Research annual meeting in Atlanta.

An additional analysis of health care utilization showed that AA treatment was associated with risks for all patients, regardless of CVD; among patients without chemotherapy and without CVD, the hospitalization rate increased by 53%, and in those with preexisting CVD the rate increased from 34% to 55%, depending on the cardiovascular condition, said Dr. Lu-Yao, associate director for population science at the Sidney Kimmel Cancer Center at Jefferson, Philadelphia.


Since patients with preexisting CVD are frequently excluded from clinical trials of AA, its effects in this population are uncertain. However, these data – though limited by the retrospective nature of the study – provide evidence that a significant proportion of patients treated in the real world differ from those in clinical trials, and therefore that the trial findings may not apply to patients who are excluded, said Dr. Lu-Yao, professor and vice chair in the department of medical Oncology at the Sidney Kimmel Medical College.

AA, which was initially approved in 2011 for use in combination with prednisone in patients with metastatic castration-resistant prostate cancer who were previously treated with docetaxel, received additional approval in 2018 for use in combination with prednisone for metastatic high-risk castration-sensitive prostate cancer.

The potential for expanded use of AA further underscores the need for improved understanding of its effects in the real-world setting, she noted.

This study was funded by a Pennsylvania CURE Program award and the National Cancer Institute. Dr. Lu-Yao has no direct conflicts to declare except that her spouse, who has no involvement with this study, is an officer of Sun Pharmaceutical Industries Inc.

SOURCE: Lu-Yao G et al. AACR 2019, Abstract preview.

Prostate cancer patients with cardiovascular disease (CVD) who are treated with abiraterone acetate (Zytiga) have an increased risk of death within 6 months of starting therapy, compared with those without preexisting CVD, according to an analysis of Surveillance, Epidemiology, and End Results (SEER)–Medicare linked data.

Of 2,845 patients diagnosed with prostate cancer between 1991 and 2013 and treated with abiraterone acetate (AA) between 2011 and 2014, 1,924 (67.6%) had at least one serious preexisting CVD condition. Mortality within 6 months of treatment initiation in those with preexisting CVD ranged from 21.4% to 25.6%, depending on the type of condition, compared with 15.8% among those with no preexisting CVD, Grace Lu-Yao, PhD, reported during a press conference highlighting data to be presented at the upcoming American Association for Cancer Research annual meeting in Atlanta.

An additional analysis of health care utilization showed that AA treatment was associated with risks for all patients, regardless of CVD; among patients without chemotherapy and without CVD, the hospitalization rate increased by 53%, and in those with preexisting CVD the rate increased from 34% to 55%, depending on the cardiovascular condition, said Dr. Lu-Yao, associate director for population science at the Sidney Kimmel Cancer Center at Jefferson, Philadelphia.


Since patients with preexisting CVD are frequently excluded from clinical trials of AA, its effects in this population are uncertain. However, these data – though limited by the retrospective nature of the study – provide evidence that a significant proportion of patients treated in the real world differ from those in clinical trials, and therefore that the trial findings may not apply to patients who are excluded, said Dr. Lu-Yao, professor and vice chair in the department of medical Oncology at the Sidney Kimmel Medical College.

AA, which was initially approved in 2011 for use in combination with prednisone in patients with metastatic castration-resistant prostate cancer who were previously treated with docetaxel, received additional approval in 2018 for use in combination with prednisone for metastatic high-risk castration-sensitive prostate cancer.

The potential for expanded use of AA further underscores the need for improved understanding of its effects in the real-world setting, she noted.

This study was funded by a Pennsylvania CURE Program award and the National Cancer Institute. Dr. Lu-Yao has no direct conflicts to declare except that her spouse, who has no involvement with this study, is an officer of Sun Pharmaceutical Industries Inc.

SOURCE: Lu-Yao G et al. AACR 2019, Abstract preview.

Adjuvant treatments appear to have no significant detrimental long-term effects on sperm count in men being treated for clinical stage I testicular cancer, results of a recent investigation suggest.

Sperm number and concentration were largely stable over time in patients who received a round of chemotherapy or radiation to lymph nodes following orchiectomy, according to results of the 182-patient study.

Investigators said they still offer sperm banking before orchiectomy, since some patients will have low sperm counts prior to orchiectomy that persist after the procedure.
Moreover, the type of testicular cancer and the potential need for other postorchiectomy treatments are often “unknown factors” that underscore the importance of sperm banking, said the researchers, led by Kristina Weibring, MD, of Karolinska University Hospital, Stockholm.

“Assisted reproductive measures may be necessary for these patients regardless of any treatment given,” the researchers noted. The report is in Annals of Oncology.

The lack of effect on sperm counts in this study stands in contrast to previous studies, which clearly show the detrimental effects of multiple chemotherapy cycles on sperm recovery, the investigators said.

Their study comprised 182 patients 18-50 years of age with clinical stage I testicular cancer who underwent unilateral orchiectomy. Depending on tumor characteristics, the patients then received one cycle of adjuvant carboplatin, one cycle of a bleomycin, etoposide, and cisplatin (BEP) regimen, surveillance, or adjuvant radiotherapy to the infradiaphragmal para-aortic and ipsilateral iliac lymph nodes. Sperm samples were obtained at 6, 12, 24, 36, and 60 months after the completion of treatment.

While there was a transient drop in the radiation-treated patients at the 6-month evaluation, mean total sperm number otherwise increased over time in all groups, according to the investigators’ report.

Similarly, mean sperm concentration significantly increased from baseline to 12 months post treatment in the surveillance, BEP, and carboplatin groups, with a nonsignificant decrease in the radiotherapy group, they said in the report.

There were generally no significant differences in sperm count or concentration for the treatments, compared with surveillance, beyond a significant decrease in mean sperm count for radiation versus surveillance, they added.

There were likewise no significant changes in sperm measures for seminoma and nonseminoma patients at any point over the 5 years of evaluation, reported data show.

“With the results of this study, we can now inform our patients that adjuvant chemotherapy does not seem to affect the testicular function,” Dr. Weibring and her colleagues concluded.

The authors reported that they had no conflicts of interest related to the study, which was supported by the Swedish Cancer Society, among other sources.

SOURCE: Weibring K et al. Ann Oncol. 2019 Feb 25. doi: 10.1093/annonc/mdz017/5348526.

Adjuvant treatments appear to have no significant detrimental long-term effects on sperm count in men being treated for clinical stage I testicular cancer, results of a recent investigation suggest.

Sperm number and concentration were largely stable over time in patients who received a round of chemotherapy or radiation to lymph nodes following orchiectomy, according to results of the 182-patient study.

Investigators said they still offer sperm banking before orchiectomy, since some patients will have low sperm counts prior to orchiectomy that persist after the procedure.
Moreover, the type of testicular cancer and the potential need for other postorchiectomy treatments are often “unknown factors” that underscore the importance of sperm banking, said the researchers, led by Kristina Weibring, MD, of Karolinska University Hospital, Stockholm.

“Assisted reproductive measures may be necessary for these patients regardless of any treatment given,” the researchers noted. The report is in Annals of Oncology.

The lack of effect on sperm counts in this study stands in contrast to previous studies, which clearly show the detrimental effects of multiple chemotherapy cycles on sperm recovery, the investigators said.

Their study comprised 182 patients 18-50 years of age with clinical stage I testicular cancer who underwent unilateral orchiectomy. Depending on tumor characteristics, the patients then received one cycle of adjuvant carboplatin, one cycle of a bleomycin, etoposide, and cisplatin (BEP) regimen, surveillance, or adjuvant radiotherapy to the infradiaphragmal para-aortic and ipsilateral iliac lymph nodes. Sperm samples were obtained at 6, 12, 24, 36, and 60 months after the completion of treatment.

While there was a transient drop in the radiation-treated patients at the 6-month evaluation, mean total sperm number otherwise increased over time in all groups, according to the investigators’ report.

Similarly, mean sperm concentration significantly increased from baseline to 12 months post treatment in the surveillance, BEP, and carboplatin groups, with a nonsignificant decrease in the radiotherapy group, they said in the report.

There were generally no significant differences in sperm count or concentration for the treatments, compared with surveillance, beyond a significant decrease in mean sperm count for radiation versus surveillance, they added.

There were likewise no significant changes in sperm measures for seminoma and nonseminoma patients at any point over the 5 years of evaluation, reported data show.

“With the results of this study, we can now inform our patients that adjuvant chemotherapy does not seem to affect the testicular function,” Dr. Weibring and her colleagues concluded.

The authors reported that they had no conflicts of interest related to the study, which was supported by the Swedish Cancer Society, among other sources.

SOURCE: Weibring K et al. Ann Oncol. 2019 Feb 25. doi: 10.1093/annonc/mdz017/5348526.

Adjuvant treatments appear to have no significant detrimental long-term effects on sperm count in men being treated for clinical stage I testicular cancer, results of a recent investigation suggest.

Sperm number and concentration were largely stable over time in patients who received a round of chemotherapy or radiation to lymph nodes following orchiectomy, according to results of the 182-patient study.

Investigators said they still offer sperm banking before orchiectomy, since some patients will have low sperm counts prior to orchiectomy that persist after the procedure.
Moreover, the type of testicular cancer and the potential need for other postorchiectomy treatments are often “unknown factors” that underscore the importance of sperm banking, said the researchers, led by Kristina Weibring, MD, of Karolinska University Hospital, Stockholm.

“Assisted reproductive measures may be necessary for these patients regardless of any treatment given,” the researchers noted. The report is in Annals of Oncology.

The lack of effect on sperm counts in this study stands in contrast to previous studies, which clearly show the detrimental effects of multiple chemotherapy cycles on sperm recovery, the investigators said.

Their study comprised 182 patients 18-50 years of age with clinical stage I testicular cancer who underwent unilateral orchiectomy. Depending on tumor characteristics, the patients then received one cycle of adjuvant carboplatin, one cycle of a bleomycin, etoposide, and cisplatin (BEP) regimen, surveillance, or adjuvant radiotherapy to the infradiaphragmal para-aortic and ipsilateral iliac lymph nodes. Sperm samples were obtained at 6, 12, 24, 36, and 60 months after the completion of treatment.

While there was a transient drop in the radiation-treated patients at the 6-month evaluation, mean total sperm number otherwise increased over time in all groups, according to the investigators’ report.

Similarly, mean sperm concentration significantly increased from baseline to 12 months post treatment in the surveillance, BEP, and carboplatin groups, with a nonsignificant decrease in the radiotherapy group, they said in the report.

There were generally no significant differences in sperm count or concentration for the treatments, compared with surveillance, beyond a significant decrease in mean sperm count for radiation versus surveillance, they added.

There were likewise no significant changes in sperm measures for seminoma and nonseminoma patients at any point over the 5 years of evaluation, reported data show.

“With the results of this study, we can now inform our patients that adjuvant chemotherapy does not seem to affect the testicular function,” Dr. Weibring and her colleagues concluded.

The authors reported that they had no conflicts of interest related to the study, which was supported by the Swedish Cancer Society, among other sources.

SOURCE: Weibring K et al. Ann Oncol. 2019 Feb 25. doi: 10.1093/annonc/mdz017/5348526.

SAN FRANCISCO – Dual targeting of the androgen signaling axis in metastatic hormone-sensitive prostate cancer improves outcomes and is well tolerated, according to results of the phase 3 ARCHES trial reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

“Androgen-deprivation therapy [ADT] has been the mainstay of therapy for men who present with metastatic disease for many years. But generally, progression to castration-resistant diseases is observed within approximately 3 years,” said lead investigator Andrew J. Armstrong, MD, a professor of medicine in medical oncology at Duke University, Durham, N.C.

“Thus the advent of improving outcomes with the [additional] use of early docetaxel, abiraterone, and now radiation to the primary in the face of oligometastatic disease has been shown to improve survival,” he added. “However, the most recent studies have really not studied the sequential use of docetaxel and have largely excluded patients who had had prior docetaxel chemotherapy in the hormone-sensitive setting.”

The investigators in the ARCHES trial (NCT02677896) randomized 1,150 men with metastatic hormone-sensitive prostate cancer to enzalutamide (Xtandi) plus ADT or placebo plus ADT.

With a median follow-up of 14.4 months, radiographic progression-free survival – the trial’s primary endpoint – was prolonged in the enzalutamide arm. Risk of progression or death was reduced by a relative 61% with enzalutamide versus placebo. There were also significant relative reductions in risks of other important outcomes such as time to prostate-specific antigen (PSA) progression (81% reduction), time to new antineoplastic therapy (72% reduction), and time to castration resistance (72% reduction).

Meanwhile, the enzalutamide group had somewhat more fatigue, hot flashes, and hypertension, but most of these events were grade 1 or 2. Rates of adverse events leading to treatment withdrawal were similar and low.

“Following the success of this study, all patients in the placebo group will be offered participation in an open-label extension protocol where they’ll be offered enzalutamide and the opportunity to receive a clinically beneficial treatment,” Dr. Armstrong reported.
 

Ready for prime time?

The ARCHES findings are probably not yet sufficient to be implemented in real-world practice, according to invited discussant Ian D. Davis, MBBS, PhD, a professor at Monash University, Melbourne.

The condition studied in the trial – metastatic hormone-sensitive prostate cancer – certainly needs treatment, but it is unclear whether radiographic progression-free survival is a meaningful endpoint, he said. “We know in the CRPC [castration-resistant prostate cancer] setting for enzalutamide in the PREVAIL study, radiographic progression-free survival was correlated with overall survival, but we haven’t actually proven that yet in the CSPC [castration-sensitive prostate cancer] setting.”

Toxicity was acceptable, but information about the efficacy of subsequent treatment is lacking. “This is where progression-free survival 2 [PFS2] information would be useful if we had it,” Dr. Davis noted. Cost-effectiveness in terms of overall survival is likewise still unknown.

“Cautiously, and I’m conscious of my conflict of interest here because I’m doing a similar trial, I’d say that the ARCHES trial should probably not yet change practice,” he said. However, he qualified that statement by pointing to recently announced results from the phase 3 TITAN trial (NCT02489318) of apalutamide (Erleada), showing significant radiographic progression-free survival and overall survival benefit in this patient population. “So we await those data with interest.”

The first interim analysis of the enzalutamide trial he is cochairing, ANZUP ENZAMET (NCT02446405), is imminent, according to Dr. Davis. “The differences here are the primary endpoint of ENZAMET is overall survival and there was an early amendment to allow concurrent docetaxel, so a significant proportion of patients on this study will have received concurrent docetaxel with enzalutamide or ADT,” he noted.

Men enrolled in ARCHES were allowed to have received prior ADT for up to 3 months or, if they had received docetaxel, for up to 6 months, Dr. Armstrong noted at the symposium.

About two-thirds each had high disease volume and had distant metastasis at their initial diagnosis. Overall, median duration of prior ADT was 1.6 months.

Radiographic progression-free survival was not reached with enzalutamide versus 19.45 months with placebo (hazard ratio, 0.39; P less than .0001). Corresponding 12-month rates were 84% and 64%. Findings were essentially the same across diverse subgroups, including among the 18% of patients who had received prior docetaxel (HR, 0.53).

Median time to PSA progression – typically one of the first indications of castration resistance – was not reached in either group, but the 12-month rate was 91% with enzalutamide versus 63% with placebo (HR, 0.19; P less than .0001), Dr. Armstrong reported. Median time to castration resistance was not reached with enzalutamide versus 13.9 months with placebo (HR, 0.28; P less than .0001).

There also were significant differences in favor of enzalutamide on the rate of achievement of undetectable PSA (68.1% vs. 17.6%; P less than .0001), the objective response rate (83.1% vs. 63.7%; P less than .0001), and the time to initiation of new antineoplastic therapy (not reached vs. 30.19 months; HR, 0.28; P less than .0001).

Quality of life was very high in both groups at study baseline and remained similarly so during follow-up. An interim analysis showed overall survival had not been reached in either group, although there was a nonsignificant trend favoring enzalutamide.

Safety was much the same, with the enzalutamide and placebo groups having similar rates of grade 3 or worse adverse events (24.3% vs. 25.6%), as well as similar rates of adverse events leading to treatment withdrawal (7.2% vs. 5.2%) and death (2.4% vs. 1.7%).

In terms of adverse events of special interest, the groups were comparable on rates of grade 3 or 4 convulsion, ischemic heart disease, falls, and fractures.

Dr. Armstrong disclosed that he has a consulting or advisory role with, receives research funding (institutional) from, and receives travel, accommodations, and/or expenses from Astellas – among other disclosures. The trial was sponsored by Astellas.

SOURCE: Armstrong AJ et al. GUCS 2019, Abstract 687.

SAN FRANCISCO – Dual targeting of the androgen signaling axis in metastatic hormone-sensitive prostate cancer improves outcomes and is well tolerated, according to results of the phase 3 ARCHES trial reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

“Androgen-deprivation therapy [ADT] has been the mainstay of therapy for men who present with metastatic disease for many years. But generally, progression to castration-resistant diseases is observed within approximately 3 years,” said lead investigator Andrew J. Armstrong, MD, a professor of medicine in medical oncology at Duke University, Durham, N.C.

“Thus the advent of improving outcomes with the [additional] use of early docetaxel, abiraterone, and now radiation to the primary in the face of oligometastatic disease has been shown to improve survival,” he added. “However, the most recent studies have really not studied the sequential use of docetaxel and have largely excluded patients who had had prior docetaxel chemotherapy in the hormone-sensitive setting.”

The investigators in the ARCHES trial (NCT02677896) randomized 1,150 men with metastatic hormone-sensitive prostate cancer to enzalutamide (Xtandi) plus ADT or placebo plus ADT.

With a median follow-up of 14.4 months, radiographic progression-free survival – the trial’s primary endpoint – was prolonged in the enzalutamide arm. Risk of progression or death was reduced by a relative 61% with enzalutamide versus placebo. There were also significant relative reductions in risks of other important outcomes such as time to prostate-specific antigen (PSA) progression (81% reduction), time to new antineoplastic therapy (72% reduction), and time to castration resistance (72% reduction).

Meanwhile, the enzalutamide group had somewhat more fatigue, hot flashes, and hypertension, but most of these events were grade 1 or 2. Rates of adverse events leading to treatment withdrawal were similar and low.

“Following the success of this study, all patients in the placebo group will be offered participation in an open-label extension protocol where they’ll be offered enzalutamide and the opportunity to receive a clinically beneficial treatment,” Dr. Armstrong reported.
 

Ready for prime time?

The ARCHES findings are probably not yet sufficient to be implemented in real-world practice, according to invited discussant Ian D. Davis, MBBS, PhD, a professor at Monash University, Melbourne.

The condition studied in the trial – metastatic hormone-sensitive prostate cancer – certainly needs treatment, but it is unclear whether radiographic progression-free survival is a meaningful endpoint, he said. “We know in the CRPC [castration-resistant prostate cancer] setting for enzalutamide in the PREVAIL study, radiographic progression-free survival was correlated with overall survival, but we haven’t actually proven that yet in the CSPC [castration-sensitive prostate cancer] setting.”

Toxicity was acceptable, but information about the efficacy of subsequent treatment is lacking. “This is where progression-free survival 2 [PFS2] information would be useful if we had it,” Dr. Davis noted. Cost-effectiveness in terms of overall survival is likewise still unknown.

“Cautiously, and I’m conscious of my conflict of interest here because I’m doing a similar trial, I’d say that the ARCHES trial should probably not yet change practice,” he said. However, he qualified that statement by pointing to recently announced results from the phase 3 TITAN trial (NCT02489318) of apalutamide (Erleada), showing significant radiographic progression-free survival and overall survival benefit in this patient population. “So we await those data with interest.”

The first interim analysis of the enzalutamide trial he is cochairing, ANZUP ENZAMET (NCT02446405), is imminent, according to Dr. Davis. “The differences here are the primary endpoint of ENZAMET is overall survival and there was an early amendment to allow concurrent docetaxel, so a significant proportion of patients on this study will have received concurrent docetaxel with enzalutamide or ADT,” he noted.

Men enrolled in ARCHES were allowed to have received prior ADT for up to 3 months or, if they had received docetaxel, for up to 6 months, Dr. Armstrong noted at the symposium.

About two-thirds each had high disease volume and had distant metastasis at their initial diagnosis. Overall, median duration of prior ADT was 1.6 months.

Radiographic progression-free survival was not reached with enzalutamide versus 19.45 months with placebo (hazard ratio, 0.39; P less than .0001). Corresponding 12-month rates were 84% and 64%. Findings were essentially the same across diverse subgroups, including among the 18% of patients who had received prior docetaxel (HR, 0.53).

Median time to PSA progression – typically one of the first indications of castration resistance – was not reached in either group, but the 12-month rate was 91% with enzalutamide versus 63% with placebo (HR, 0.19; P less than .0001), Dr. Armstrong reported. Median time to castration resistance was not reached with enzalutamide versus 13.9 months with placebo (HR, 0.28; P less than .0001).

There also were significant differences in favor of enzalutamide on the rate of achievement of undetectable PSA (68.1% vs. 17.6%; P less than .0001), the objective response rate (83.1% vs. 63.7%; P less than .0001), and the time to initiation of new antineoplastic therapy (not reached vs. 30.19 months; HR, 0.28; P less than .0001).

Quality of life was very high in both groups at study baseline and remained similarly so during follow-up. An interim analysis showed overall survival had not been reached in either group, although there was a nonsignificant trend favoring enzalutamide.

Safety was much the same, with the enzalutamide and placebo groups having similar rates of grade 3 or worse adverse events (24.3% vs. 25.6%), as well as similar rates of adverse events leading to treatment withdrawal (7.2% vs. 5.2%) and death (2.4% vs. 1.7%).

In terms of adverse events of special interest, the groups were comparable on rates of grade 3 or 4 convulsion, ischemic heart disease, falls, and fractures.

Dr. Armstrong disclosed that he has a consulting or advisory role with, receives research funding (institutional) from, and receives travel, accommodations, and/or expenses from Astellas – among other disclosures. The trial was sponsored by Astellas.

SOURCE: Armstrong AJ et al. GUCS 2019, Abstract 687.

SAN FRANCISCO – Dual targeting of the androgen signaling axis in metastatic hormone-sensitive prostate cancer improves outcomes and is well tolerated, according to results of the phase 3 ARCHES trial reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

“Androgen-deprivation therapy [ADT] has been the mainstay of therapy for men who present with metastatic disease for many years. But generally, progression to castration-resistant diseases is observed within approximately 3 years,” said lead investigator Andrew J. Armstrong, MD, a professor of medicine in medical oncology at Duke University, Durham, N.C.

“Thus the advent of improving outcomes with the [additional] use of early docetaxel, abiraterone, and now radiation to the primary in the face of oligometastatic disease has been shown to improve survival,” he added. “However, the most recent studies have really not studied the sequential use of docetaxel and have largely excluded patients who had had prior docetaxel chemotherapy in the hormone-sensitive setting.”

The investigators in the ARCHES trial (NCT02677896) randomized 1,150 men with metastatic hormone-sensitive prostate cancer to enzalutamide (Xtandi) plus ADT or placebo plus ADT.

With a median follow-up of 14.4 months, radiographic progression-free survival – the trial’s primary endpoint – was prolonged in the enzalutamide arm. Risk of progression or death was reduced by a relative 61% with enzalutamide versus placebo. There were also significant relative reductions in risks of other important outcomes such as time to prostate-specific antigen (PSA) progression (81% reduction), time to new antineoplastic therapy (72% reduction), and time to castration resistance (72% reduction).

Meanwhile, the enzalutamide group had somewhat more fatigue, hot flashes, and hypertension, but most of these events were grade 1 or 2. Rates of adverse events leading to treatment withdrawal were similar and low.

“Following the success of this study, all patients in the placebo group will be offered participation in an open-label extension protocol where they’ll be offered enzalutamide and the opportunity to receive a clinically beneficial treatment,” Dr. Armstrong reported.
 

Ready for prime time?

The ARCHES findings are probably not yet sufficient to be implemented in real-world practice, according to invited discussant Ian D. Davis, MBBS, PhD, a professor at Monash University, Melbourne.

The condition studied in the trial – metastatic hormone-sensitive prostate cancer – certainly needs treatment, but it is unclear whether radiographic progression-free survival is a meaningful endpoint, he said. “We know in the CRPC [castration-resistant prostate cancer] setting for enzalutamide in the PREVAIL study, radiographic progression-free survival was correlated with overall survival, but we haven’t actually proven that yet in the CSPC [castration-sensitive prostate cancer] setting.”

Toxicity was acceptable, but information about the efficacy of subsequent treatment is lacking. “This is where progression-free survival 2 [PFS2] information would be useful if we had it,” Dr. Davis noted. Cost-effectiveness in terms of overall survival is likewise still unknown.

“Cautiously, and I’m conscious of my conflict of interest here because I’m doing a similar trial, I’d say that the ARCHES trial should probably not yet change practice,” he said. However, he qualified that statement by pointing to recently announced results from the phase 3 TITAN trial (NCT02489318) of apalutamide (Erleada), showing significant radiographic progression-free survival and overall survival benefit in this patient population. “So we await those data with interest.”

The first interim analysis of the enzalutamide trial he is cochairing, ANZUP ENZAMET (NCT02446405), is imminent, according to Dr. Davis. “The differences here are the primary endpoint of ENZAMET is overall survival and there was an early amendment to allow concurrent docetaxel, so a significant proportion of patients on this study will have received concurrent docetaxel with enzalutamide or ADT,” he noted.

Men enrolled in ARCHES were allowed to have received prior ADT for up to 3 months or, if they had received docetaxel, for up to 6 months, Dr. Armstrong noted at the symposium.

About two-thirds each had high disease volume and had distant metastasis at their initial diagnosis. Overall, median duration of prior ADT was 1.6 months.

Radiographic progression-free survival was not reached with enzalutamide versus 19.45 months with placebo (hazard ratio, 0.39; P less than .0001). Corresponding 12-month rates were 84% and 64%. Findings were essentially the same across diverse subgroups, including among the 18% of patients who had received prior docetaxel (HR, 0.53).

Median time to PSA progression – typically one of the first indications of castration resistance – was not reached in either group, but the 12-month rate was 91% with enzalutamide versus 63% with placebo (HR, 0.19; P less than .0001), Dr. Armstrong reported. Median time to castration resistance was not reached with enzalutamide versus 13.9 months with placebo (HR, 0.28; P less than .0001).

There also were significant differences in favor of enzalutamide on the rate of achievement of undetectable PSA (68.1% vs. 17.6%; P less than .0001), the objective response rate (83.1% vs. 63.7%; P less than .0001), and the time to initiation of new antineoplastic therapy (not reached vs. 30.19 months; HR, 0.28; P less than .0001).

Quality of life was very high in both groups at study baseline and remained similarly so during follow-up. An interim analysis showed overall survival had not been reached in either group, although there was a nonsignificant trend favoring enzalutamide.

Safety was much the same, with the enzalutamide and placebo groups having similar rates of grade 3 or worse adverse events (24.3% vs. 25.6%), as well as similar rates of adverse events leading to treatment withdrawal (7.2% vs. 5.2%) and death (2.4% vs. 1.7%).

In terms of adverse events of special interest, the groups were comparable on rates of grade 3 or 4 convulsion, ischemic heart disease, falls, and fractures.

Dr. Armstrong disclosed that he has a consulting or advisory role with, receives research funding (institutional) from, and receives travel, accommodations, and/or expenses from Astellas – among other disclosures. The trial was sponsored by Astellas.

SOURCE: Armstrong AJ et al. GUCS 2019, Abstract 687.

First-line treatment with nivolumab plus ipilimumab may be cost effective when compared with sunitinib for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC), according to a cost-effectiveness analysis.

“A Markov model was developed to estimate the costs and effectiveness of treatment of mRCC,” XiaoMin Wan, PhD, of the Capital Medical University in Beijing and his colleagues wrote in JAMA Oncology.

The researchers used data from an economic model that extrapolated findings from a phase 3 randomized study of 1,096 patients with intermediate- and poor-risk mRCC treated with first-line sunitinib or nivolumab plus ipilimumab.

“We assumed that the first-line treatments continued until disease progression or unacceptable toxic effects,” the team wrote.

Several measures were estimated using the model, including quality-adjusted life-years (QALYs), lifetime costs, and life-years. The team set a willingness-to-pay threshold of $100,000-$150,000 per QALY. In addition, Dr. Wan and his colleagues completed a sensitivity analysis to investigate how the results changed across different ranges of drug cost.

After analysis, the researchers found that first-line therapy with nivolumab plus ipilimumab was estimated to cost $108,363 per QALY gained. The incremental QALYs added using the combination was 0.96 years versus sunitinib, at the same cost per QALY.

With respect to the sensitivity analysis, the likelihood of the combination being cost effective, compared with sunitinib, was calculated to be 42.5% and 80.2% at the minimum and maximum of the willingness-to-pay threshold, respectively.

“The results of subgroup analyses showed that nivolumab plus ipilimumab was most cost effective for patients with 1% or greater programmed cell death 1 ligand 1 (PD-L1) expression,” they added.

The researchers acknowledged a key limitation of the study was that the analysis used data from only a single randomized trial. Consequently, Dr. Wan and his colleagues reported that any bias contained within that trial will also be present in this analysis.

The study was supported by funding from the National Natural Science Foundation of China and the Health and Family Planning Commission of Hunan province. The authors reported no conflicts of interest.

SOURCE: Wan X et al. JAMA Oncol. 2019 Feb 21. doi: 10.1001/jamaoncol.2018.7086.

First-line treatment with nivolumab plus ipilimumab may be cost effective when compared with sunitinib for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC), according to a cost-effectiveness analysis.

“A Markov model was developed to estimate the costs and effectiveness of treatment of mRCC,” XiaoMin Wan, PhD, of the Capital Medical University in Beijing and his colleagues wrote in JAMA Oncology.

The researchers used data from an economic model that extrapolated findings from a phase 3 randomized study of 1,096 patients with intermediate- and poor-risk mRCC treated with first-line sunitinib or nivolumab plus ipilimumab.

“We assumed that the first-line treatments continued until disease progression or unacceptable toxic effects,” the team wrote.

Several measures were estimated using the model, including quality-adjusted life-years (QALYs), lifetime costs, and life-years. The team set a willingness-to-pay threshold of $100,000-$150,000 per QALY. In addition, Dr. Wan and his colleagues completed a sensitivity analysis to investigate how the results changed across different ranges of drug cost.

After analysis, the researchers found that first-line therapy with nivolumab plus ipilimumab was estimated to cost $108,363 per QALY gained. The incremental QALYs added using the combination was 0.96 years versus sunitinib, at the same cost per QALY.

With respect to the sensitivity analysis, the likelihood of the combination being cost effective, compared with sunitinib, was calculated to be 42.5% and 80.2% at the minimum and maximum of the willingness-to-pay threshold, respectively.

“The results of subgroup analyses showed that nivolumab plus ipilimumab was most cost effective for patients with 1% or greater programmed cell death 1 ligand 1 (PD-L1) expression,” they added.

The researchers acknowledged a key limitation of the study was that the analysis used data from only a single randomized trial. Consequently, Dr. Wan and his colleagues reported that any bias contained within that trial will also be present in this analysis.

The study was supported by funding from the National Natural Science Foundation of China and the Health and Family Planning Commission of Hunan province. The authors reported no conflicts of interest.

SOURCE: Wan X et al. JAMA Oncol. 2019 Feb 21. doi: 10.1001/jamaoncol.2018.7086.

First-line treatment with nivolumab plus ipilimumab may be cost effective when compared with sunitinib for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC), according to a cost-effectiveness analysis.

“A Markov model was developed to estimate the costs and effectiveness of treatment of mRCC,” XiaoMin Wan, PhD, of the Capital Medical University in Beijing and his colleagues wrote in JAMA Oncology.

The researchers used data from an economic model that extrapolated findings from a phase 3 randomized study of 1,096 patients with intermediate- and poor-risk mRCC treated with first-line sunitinib or nivolumab plus ipilimumab.

“We assumed that the first-line treatments continued until disease progression or unacceptable toxic effects,” the team wrote.

Several measures were estimated using the model, including quality-adjusted life-years (QALYs), lifetime costs, and life-years. The team set a willingness-to-pay threshold of $100,000-$150,000 per QALY. In addition, Dr. Wan and his colleagues completed a sensitivity analysis to investigate how the results changed across different ranges of drug cost.

After analysis, the researchers found that first-line therapy with nivolumab plus ipilimumab was estimated to cost $108,363 per QALY gained. The incremental QALYs added using the combination was 0.96 years versus sunitinib, at the same cost per QALY.

With respect to the sensitivity analysis, the likelihood of the combination being cost effective, compared with sunitinib, was calculated to be 42.5% and 80.2% at the minimum and maximum of the willingness-to-pay threshold, respectively.

“The results of subgroup analyses showed that nivolumab plus ipilimumab was most cost effective for patients with 1% or greater programmed cell death 1 ligand 1 (PD-L1) expression,” they added.

The researchers acknowledged a key limitation of the study was that the analysis used data from only a single randomized trial. Consequently, Dr. Wan and his colleagues reported that any bias contained within that trial will also be present in this analysis.

The study was supported by funding from the National Natural Science Foundation of China and the Health and Family Planning Commission of Hunan province. The authors reported no conflicts of interest.

SOURCE: Wan X et al. JAMA Oncol. 2019 Feb 21. doi: 10.1001/jamaoncol.2018.7086.

SAN FRANCISCO – When used as first-line therapy for renal cell carcinoma (RCC), the combination of avelumab and axitinib has better efficacy than does single-agent sunitinib, which is the current standard of care, across a wide range of patients, subgroup analyses of the JAVELIN Renal 101 trial have shown. Results were reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Previous research had shown that avelumab (Bavencio), an immune checkpoint inhibitor targeting programmed death-ligand 1 (PD-L1), is active when used alone for advanced RCC, noted lead investigator Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston. And axitinib (Inlyta), a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, is approved for use in the second line. In an early-phase trial among patients being treated in the first line, a combination of the two drugs led to an impressive 58% objective response rate (ORR) and had a favorable safety profile (Lancet Oncol. 2018 Apr;19(4):451-60).

JAVELIN Renal 101 (NCT02684006), a phase 3 randomized, controlled trial, enrolled 886 patients with treatment-naive advanced RCC having a clear cell component regardless of their tumor’s PD-L1 status. They were randomized to the combination of avelumab/axitinib or to the VEGF tyrosine kinase inhibitor sunitinib (Sutent) alone.

Full trial results, published during the symposium in the New England Journal of Medicine (2019 Feb 16. doi: 10.1056/NEJMoa1816047), showed significant progression-free and overall survival benefits of avelumab/axitinib over sunitinib in the 63.2% of patients with PD-L1–positive tumors – the trial’s primary endpoints – as well as a progression-free survival benefit in the entire trial population.

In the subgroup analyses reported at the symposium, the combination reduced risk of progression or death by roughly 20%-50% across patients having different statuses in regard to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group, Memorial Sloan Kettering Cancer Center (MSKCC) risk group, and tumor PD-L1, as well as other characteristics. Findings were similar for ORR, with the combination roughly doubling to quadrupling the odds of response, irrespective of patient and disease characteristics.

“The progression-free survival and response rate benefit was observed in all patients, regardless of PD-L1 status, regardless of prognostic risk group. At this time, the study continues to follow up for overall survival,” Dr. Choueiri commented. Taken together, “the results do support avelumab plus axitinib as a new first-line standard of care for patients with advanced RCC.”

When it comes to selecting among the three combinations above, “I don’t think PD-L1 expression is going to help us at all,” she said. In contrast, IMDC risk category is likely still helpful because, in CheckMate 214, there was no progression-free or overall survival benefit of ipilimumab/nivolumab in patients with favorable-risk disease.

Differences in rates of discontinuation of all treatment because of treatment-related adverse events are hard to assess because CheckMate 214 had restrictions on allowing patients in the combination group to receive single-agent nivolumab, according to Dr. Wood. Financial costs are a major consideration, but so are time and staffing costs: Compared with single-agent sunitinib, the combinations as much as triple physician visits, nurse visits, infusions, and unscheduled visits.

SOURCE: Choueiri TK et al. GUCS 2019, Abstract 544.

SAN FRANCISCO – When used as first-line therapy for renal cell carcinoma (RCC), the combination of avelumab and axitinib has better efficacy than does single-agent sunitinib, which is the current standard of care, across a wide range of patients, subgroup analyses of the JAVELIN Renal 101 trial have shown. Results were reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Previous research had shown that avelumab (Bavencio), an immune checkpoint inhibitor targeting programmed death-ligand 1 (PD-L1), is active when used alone for advanced RCC, noted lead investigator Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston. And axitinib (Inlyta), a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, is approved for use in the second line. In an early-phase trial among patients being treated in the first line, a combination of the two drugs led to an impressive 58% objective response rate (ORR) and had a favorable safety profile (Lancet Oncol. 2018 Apr;19(4):451-60).

JAVELIN Renal 101 (NCT02684006), a phase 3 randomized, controlled trial, enrolled 886 patients with treatment-naive advanced RCC having a clear cell component regardless of their tumor’s PD-L1 status. They were randomized to the combination of avelumab/axitinib or to the VEGF tyrosine kinase inhibitor sunitinib (Sutent) alone.

Full trial results, published during the symposium in the New England Journal of Medicine (2019 Feb 16. doi: 10.1056/NEJMoa1816047), showed significant progression-free and overall survival benefits of avelumab/axitinib over sunitinib in the 63.2% of patients with PD-L1–positive tumors – the trial’s primary endpoints – as well as a progression-free survival benefit in the entire trial population.

In the subgroup analyses reported at the symposium, the combination reduced risk of progression or death by roughly 20%-50% across patients having different statuses in regard to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group, Memorial Sloan Kettering Cancer Center (MSKCC) risk group, and tumor PD-L1, as well as other characteristics. Findings were similar for ORR, with the combination roughly doubling to quadrupling the odds of response, irrespective of patient and disease characteristics.

“The progression-free survival and response rate benefit was observed in all patients, regardless of PD-L1 status, regardless of prognostic risk group. At this time, the study continues to follow up for overall survival,” Dr. Choueiri commented. Taken together, “the results do support avelumab plus axitinib as a new first-line standard of care for patients with advanced RCC.”

When it comes to selecting among the three combinations above, “I don’t think PD-L1 expression is going to help us at all,” she said. In contrast, IMDC risk category is likely still helpful because, in CheckMate 214, there was no progression-free or overall survival benefit of ipilimumab/nivolumab in patients with favorable-risk disease.

Differences in rates of discontinuation of all treatment because of treatment-related adverse events are hard to assess because CheckMate 214 had restrictions on allowing patients in the combination group to receive single-agent nivolumab, according to Dr. Wood. Financial costs are a major consideration, but so are time and staffing costs: Compared with single-agent sunitinib, the combinations as much as triple physician visits, nurse visits, infusions, and unscheduled visits.

SOURCE: Choueiri TK et al. GUCS 2019, Abstract 544.

SAN FRANCISCO – When used as first-line therapy for renal cell carcinoma (RCC), the combination of avelumab and axitinib has better efficacy than does single-agent sunitinib, which is the current standard of care, across a wide range of patients, subgroup analyses of the JAVELIN Renal 101 trial have shown. Results were reported at the 2019 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Previous research had shown that avelumab (Bavencio), an immune checkpoint inhibitor targeting programmed death-ligand 1 (PD-L1), is active when used alone for advanced RCC, noted lead investigator Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston. And axitinib (Inlyta), a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor, is approved for use in the second line. In an early-phase trial among patients being treated in the first line, a combination of the two drugs led to an impressive 58% objective response rate (ORR) and had a favorable safety profile (Lancet Oncol. 2018 Apr;19(4):451-60).

JAVELIN Renal 101 (NCT02684006), a phase 3 randomized, controlled trial, enrolled 886 patients with treatment-naive advanced RCC having a clear cell component regardless of their tumor’s PD-L1 status. They were randomized to the combination of avelumab/axitinib or to the VEGF tyrosine kinase inhibitor sunitinib (Sutent) alone.

Full trial results, published during the symposium in the New England Journal of Medicine (2019 Feb 16. doi: 10.1056/NEJMoa1816047), showed significant progression-free and overall survival benefits of avelumab/axitinib over sunitinib in the 63.2% of patients with PD-L1–positive tumors – the trial’s primary endpoints – as well as a progression-free survival benefit in the entire trial population.

In the subgroup analyses reported at the symposium, the combination reduced risk of progression or death by roughly 20%-50% across patients having different statuses in regard to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group, Memorial Sloan Kettering Cancer Center (MSKCC) risk group, and tumor PD-L1, as well as other characteristics. Findings were similar for ORR, with the combination roughly doubling to quadrupling the odds of response, irrespective of patient and disease characteristics.

“The progression-free survival and response rate benefit was observed in all patients, regardless of PD-L1 status, regardless of prognostic risk group. At this time, the study continues to follow up for overall survival,” Dr. Choueiri commented. Taken together, “the results do support avelumab plus axitinib as a new first-line standard of care for patients with advanced RCC.”

When it comes to selecting among the three combinations above, “I don’t think PD-L1 expression is going to help us at all,” she said. In contrast, IMDC risk category is likely still helpful because, in CheckMate 214, there was no progression-free or overall survival benefit of ipilimumab/nivolumab in patients with favorable-risk disease.

Differences in rates of discontinuation of all treatment because of treatment-related adverse events are hard to assess because CheckMate 214 had restrictions on allowing patients in the combination group to receive single-agent nivolumab, according to Dr. Wood. Financial costs are a major consideration, but so are time and staffing costs: Compared with single-agent sunitinib, the combinations as much as triple physician visits, nurse visits, infusions, and unscheduled visits.

SOURCE: Choueiri TK et al. GUCS 2019, Abstract 544.