The following article is part of conference coverage from the 2018 Genitourinary Cancers Symposium in San Francisco. Renal and Urology News’ staff will be reporting live on medical studies conducted by urologists and other specialists who are tops in their field in kidney stones, prostate cancer, kidney cancer, bladder cancer, enlarged prostate, and more. Check back for the latest news from GU 2018.

SAN FRANCISCO—Treatment of non-metastatic castration-resistant prostate cancer (CRPC) with apalutamide or enzalutamide, both orally administered androgen receptor inhibitors, prolongs metastasis-free survival (MFS), according to the findings of separate studies presented at the 2018 Genitourinary Cancers Symposium.

Apalutamide is a next-generation medication that received FDA approval in February for use in men with non-metastatic CRPC. Enzalutamide received FDA approval for treating metastatic CRPC in August 2012, but is not yet approved for use in men with non-metastatic CRPC.

In the phase 3, randomized, double-blind, placebo-controlled SPARTAN trial, men with non-metastatic CRPC treated with apalutamide had a significant 72% lower risk of metastasis or death compared with placebo recipients (HR = 0.28; 95% CI, 0.23-0.35; P < .0001), with a median 2-year improvement in metastasis-free survival (MFS), said lead investigator Eric Jay Small, MD, of the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, who presented study findings. The investigators observed a non-significant trend toward improved overall survival.

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Dr Small pointed out that although subsequent FDA-approved treatment was administered to 80% of the patients in the placebo group, the apalutamide arm still had an improvement in time to symptomatic progression as well as a 51% improvement in second progression-free survival (time from randomization to investigator-assessed disease progression during the first subsequent therapy for metastatic castration-resistant disease or death from any cause).

“Treatment with apalutamide was generally well tolerated, with no impact on quality of life scores and with low rates of discontinuation due to treatment-related adverse events,” Dr Small said. “Overall, these data suggest that apalutamide should now be considered a new standard of care for men with high-risk non-metastatic castration-resistant prostate cancer.”

The study, which was published online ahead of print in the New England Journal of Medicine, included 1207 patients whose cancer no longer responded to androgen-deprivation therapy (ADT) and were at high risk of metastasis based on PSA doubling time (PSADT) of 10 months or less. The median PSADT at study entry was about 4.5 months. Investigators randomly assigned 806 patients to receive apalutamide 240 mg once daily and 401 to receive placebo. The primary end point was MSF, defined as the time from randomization to first radiographic distant metastasis or death.

The median MFS was 40.5 months in the apalutamide group compared with 16.2 months in the placebo arm. At a median follow-up of 20.3 months, 61% of apalutamide-treated patients and 30% of placebo recipients remained on treatment. Rates of discontinuation due to adverse events were 10.7% and 6.3% in apalutamide and placebo groups, respectively.

Dr Small’s team concluded that their results support the addition of apalutamide to ADT for men with nmCRPC.

Sumanta K. Pal, MD, who moderated a pre-symposium press conference at which Dr Small presented study findings, observed, “Until the results of studies presented at this meeting, there’s really been no obvious standard of care for these patients.” He called the 72% decrease in the risk of metastasis or death associated with apalutamide treatment “a very clinically meaningful finding.” Moreover, he said the drug appears to be very well tolerated.

In the randomized, double-blind phase 3 PROSPER trial, men with non-metastatic CRPC who received enzalutamide in addition to ADT had a prolonged median MFS—the study’s primary end point, which was defined as the time from randomization to radiographic progression or death within 112 days of treatment discontinuation—compared with those who received ADT plus placebo (36.6 vs 14.7 months; P< .0001), reported lead investigator Maha Hussain, MD, of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago. In men with non-metastatic CRPC and rapid PSA doubling time, “enzalutamide resulted in a clinically meaningful and statistically significant 71% reduction in the relative risk of developing metastatic castration-resistant prostate cancer,” Dr Hussain told attendees.

In addition, enzalutamide treatment was associated with prolonged time to first use of a new antineoplastic agent (median 39.6 vs 17.7 months; P< .0001) and time to PSA progression (median 37.2 vs 3.9 months; P< .0001) compared with placebo. Compared with placebo, enzalutamide was associated with a statistically significant 79% decreased risk of requiring a new antineoplastic agent (HR = 0.21; 95% CI 0.17-0.26) and 93% decreased risk of PSA progression (HR = 0.07; 95% CI 0.05-0.08). Median duration of treatment was 18.4 months in the enzalutamide group compared with 11.1 months in the placebo arm.

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As of June 2017 (cutoff date), median duration of treatment was 18.4 months in the enzalutamide group compared with 11.1 months in the placebo arm. As of February 5, 61% of patients randomly assigned to enzalutamide were active on treatment compared with 28% in the placebo arm. At first interim analysis with a median follow-up time of about 22 months, there was a 20% reduction in the relative risk of death with enzalutamide vs placebo.

The study included 1401 men with a PSA doubling time of 10 months or less and a PSA level of 2 ng/mL or higher. All men continued receiving ADT. Investigators randomly assigned 933 patients to receive enzalutamide 160 mg and 468 to receive placebo. The enzalutamide and placebo arms had median ages of 74 and 73 years, respectively.

Adverse events were generally consistent with those reported in prior enzalutamide clinical trials in patients with metastatic CRPC. Grade 3 or higher adverse events were reported in 31% of men treated with enzalutamide plus ADT compared with 23% of those who received ADT alone.

The Genitourinary Cancer Symposium is sponsored by the American Society of Clinical Oncology, American Society for Radiation Oncology, and the Society of Urologic Oncology.

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Small EJ, Saad F, Chowdhury S, et al. SPARTAN, a phase 3 double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC). Data presented at the 2018 Genitourinary Cancers Symposium, held in in San Francisco Feb. 8–10. Abstract 161.

Hussain M, Fizazi K, Saad F, et al. PROSPER: A phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalultamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC). Data presented at the 2018 Genitourinary Cancers Symposium, held in San Francisco February 8–10. Abstract 3.