But excess cardiovascular events were an issue, according to PROSPER results

In a study of men with nonmetastatic, castration-resistant prostate cancer characterized by rapidly increasing PSA levels, treatment with enzalutamide, an oral androgen-receptor inhibitor, increased median overall survival by 10 months compared to placebo, Cora N. Sternberg, MD, of the Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, and co-investigators with the PROSPER study reported.

The researchers enrolled 1,401 patients over a course of 3.5 years and randomized 933 to enzalutamide 160 mg daily and 468 to placebo. Androgen-deprivation therapy was continued in both arms. The median age of men in the enzalutamide arm was 74 versus 73 in the control group. PSA doubling time was similar: 3.8 months in the enzalutamide arm and 3.6 months in the placebo group.

“Enzalutamide plus androgen-deprivation therapy was associated with a significant 27% lower risk of death than placebo plus androgen-deprivation therapy (hazard ratio, 0.73; 95% CI, 0.61 to 0.89; P = 0.001),” Sternberg et al reported in The New England Journal of Medicine. The PROSPER results were also reported at the American Society of Clinical Oncology 2020 virtual meeting.

Overall, 31% of the enzalutamide patients (n=288) died versus 38% of controls (n=138), with the enzalutamide benefit driven by a significant reduction in prostate cancer related deaths: just 19% of patients assigned to enzalutamide died from prostate cancer, while prostate cancer claimed the lives of 29% of the men in the placebo arm. But 110 of the 953 patients randomized to enzalutamide died of other causes — usually cardiovascular complications — versus 42 non-prostate cancer-related deaths in the placebo arm.

“Median overall survival was 67.0 months (95% CI, 64.0 to not reached) in the enzalutamide group and 56.3 months (95% CI, 54.4-63.0) in the placebo group… In an unplanned analysis, the percentage of patients alive at 3 years was 80% (95% CI, 77-83) in the enzalutamide group and 73% (95% CI, 69-77) in the placebo group,” they wrote.

In an editorial that accompanied the PROSPER results, Celestia S. Higano, M.D., University of Washington, Seattle, pointed to the non-prostate cancer deaths as a cause for concern.

“Although metastasis-free and overall survival were improved in the enzalutamide group of the PROSPER trial, an increased risk of adverse events was observed, including falls, fatigue, hypertension, and death from cardiovascular causes. In men with risk factors for cardiovascular disease (such as hypertension, obesity, diabetes, and hyperlipidemia) who do not have a PSA doubling time of 10 months or less, the risk–benefit ratio of treating with enzalutamide should be considered in these asymptomatic men who may have a more indolent course of disease than those with a PSA doubling time of 10 months or less,” Higano wrote. “Given the findings of the PROSPER trial and the many years of post marketing data that also point to increased cardiovascular risk, the importance of coexisting conditions and the necessity for close monitoring should be factored into the choice of agent, if any, for men with non-metastatic, castration-resistant prostate cancer.”

Sternberg and colleagues acknowledged the concern about adverse events and offered some explanation.

“Although adverse events leading to death were more common in the enzalutamide group than in the placebo group, it is important to consider the significantly longer median treatment duration in the enzalutamide group (33.9 months versus 14.2 months),” they wrote. “The most frequently reported adverse events leading to death in the enzalutamide group were cardiovascular events. Most men who died from a cardiovascular event had a clinically significant history of cardiovascular disease. The World Health Organization reports that the leading cause of death among men older than 70 years of age in 2016 was ischemic heart disease. The longer follow-up interval, history of cardiovascular risk factors, and advanced age in patients treated with enzalutamide may explain this finding in our trial.”

The PROSPER investigators did not attribute any of the cardiovascular events to enzalutamide, but they too agreed that “physicians should be aware of the increased risk when determining whether a patient with preexisting cardiovascular disease should receive enzalutamide, and patients receiving this treatment should be followed closely.”

Among the limitations cited by Sternberg and colleagues was use of conventional imaging to obtain diagnoses and monitor patients’ conditions which may affect the classification of patients as having nonmetastatic disease. Additionally, “[D]ata on the time to progression while receiving the next subsequent therapy were not collected, so we cannot evaluate whether treatment with enzalutamide also translated into differences in treatment effects of subsequent therapies.”

  1. Be aware that results from a phase III, placebo-controlled study found that treatment with enzalutamide extended overall survival in men with nonmetastatic, castration-resistant prostate cancer.

  2. Note that patients with known cardiovascular risk factors should be carefully monitored if treated with enzalutamide.

Peggy Peck, Editor-in-Chief, BreakingMED™

The PROSPER trial was funded by Pfizer and Astellas Pharma.

Sternberg reported personal fees from MSD, personal fees from Pfizer, personal fees from Roche/Genentech, personal fees from Incyte, personal fees from AstraZeneca, personal fees from Sanofi-Genzyme, personal fees from Medscape, personal fees from UroToday, personal fees from Astellas Pharma, personal fees from Clovis, outside the submitted work.

Higano reported grants from Aragon, grants and personal fees from Astellas, grants from AstraZeneca, grants and personal fees from Clovis, grants from Dendreon, grants from eFFECTOR Therapeutics, grants from Emergent, grants and personal fees from Ferring, grants and personal fees from Genentech, grants from Hoffman-Laroche, grants from Medivation, grants and personal fees from Pfizer, grants and personal fees from Bayer, personal fees from Blue Earth Diagnositics, personal fees from Dendreon, personal fees from Hinova, personal fees from Janssen, personal fees from Merck, personal fees from Orion, personal fees from Tolmar, personal fees from Carrick Therapeutics, personal fees from Novartis, grants from Memorial Sloan Kettering/Bayer, outside the submitted work.

Cat ID: 25

Topic ID: 78,25,730,25,935,192,73,172