Men with nonmetastatic, castration (hormone)-resistant prostate cancer (CRPC) and a rapidly rising prostate-specific antigen (PSA) level are at high risk for metastasis. Currently, only one recently approved treatment, Erleada® (apalutamide), is available to these patients. Xtandi®, an androgen receptor inhibitor, is an approved treatment for metastatic CRPC patients. It has been shown to delay disease progression and prolong these patients’ overall survival. In a recent article published in the June 28th, 2018 issue of the New England Journal of Medicine, researchers hypothesized that enzalutamide (Xtandi®), which prolongs overall survival among patients with metastatic, hormone-resistant prostate cancer, could also delay metastasis in men with nonmetastatic, hormone-resistant prostate cancer and a rapidly rising PSA level. In this double-blind, phase 3 PROSPER trial, asymptomatic men with nonmetastatic, hormone-resistant prostate cancer and a PSA doubling time of 10 months or less and who were continuing androgen-deprivation (hormone) therapy received enzalutamide (at a dose of 160 mg) while men receiving only placebo and standard hormone therapy were randomized in a 2:1 ratio. The primary end point of the study was metastasis-free survival, the length of time a patient lives without cancer spreading or until death from any cause. Secondary goals included extension of the time to PSA progression and to the first use of a subsequent anticancer chemotherapy, patients’ overall survival, and safety.
A total of 1401 patients (median PSA doubling time, 3.7 months) were enrolled. As of June 28, 2017, a total of 219 of 933 patients (23%) in the enzalutamide group had metastasis or had died, as compared with 228 of 468 (49%) in the placebo group. The median metastasis-free survival was 36.6 months in the enzalutamide group versus 14.7 months in the placebo group. The time to the first use of subsequent chemotherapy was longer with enzalutamide treatment than with placebo (such therapy was used in 15% vs. 48% of patients) as was the time to PSA progression (37.2 vs. 3.9 months.) At the first interim analysis of overall survival, 103 patients (11%) receiving enzalutamide and 62 (13%) receiving placebo had died. So median overall survival had not been reached. However, the researchers noted that more patients receiving the combination therapy died without detectable development of metastasis than was seen in the placebo group. In these patients, no trend regarding the cause of death was found, and only two deaths were considered to be related to Xtandi treatment. The researchers noted that these patients were elderly, with a median age of 80 years in the Xtandi group and 81 years in the placebo group, and they had a high burden of other coexisting conditions. Subsequent follow-up and additional interim analysis are expected to clarify the benefits of Xtandi® in patients’ overall survival in the PROSPER study.
Conclusions from this PROSPER clinical trial indicated that in men receiving the combination therapy the time a patient remained alive and metastasis-free was significantly extended by nearly two years (21.9 months), the time to PSA progression by almost three years (33.3 months), and the time to the first use of chemotherapy by nearly two years (21.9 months), compared to single standard therapy. In men with nonmetastatic, hormone-resistant prostate cancer with a rapidly rising PSA level, enzalutamide treatment led to a clinically meaningful and significant 71% lower risk of metastasis or death than placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, (NCT02003924).
As mentioned above, these findings were recently published (“Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer”) in the New England Journal of Medicine and also summarized in the July 5th Prostate Cancer News Today. (I strongly encourage readers to subscribe to this valuable email resource.)