Enzalutamide (XTANDI) with androgen deprivation therapy delays the development of metastatic disease in men with M0 castration-resistant prostate cancer compared with ADT alone, according to results from the randomized phase III PROSPER study.
Enzalutamide (XTANDI) with androgen deprivation therapy (ADT) delays the development of metastatic disease in men with M0 castration-resistant prostate cancer (CRPC) compared with ADT alone, according to results from the randomized phase III PROSPER study.
Further, early data suggest a potential improvement in overall survival (OS) in enzalutamide-treated men relative to placebo, said Maha Hussain, MD, at the Genitourinary Cancers Symposium in San Francisco.
Nonmetastatic (M0) castration-resistant prostate cancer is an area of unmet need with no currently approved therapies.
“The development of metastases is very predictable in this group of patients and is associated with increasing baseline PSA and PSA doubling time of less than 10 months,” said Dr. Hussain, of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University, Chicago. “Delaying time to all metastases, which is a very clinically relevant endpoint because that is the terminal phase of the disease, is important, with the potential to delay cancer-related morbidity, improve survivorship, and also prolong OS.”
Enzalutamide gained approval by the FDA because it significantly improved OS and radiographic progression-free survival (PFS) in men with chemotherapy-naÃ¯ve metastatic CRPC in the PREVAIL study. Enzalutamide also was superior to bicalutamide (Casodex) in improving radiographic PFS in a subgroup of patients with chemotherapy-naÃ¯ve M0 CRPC.
PROSPER included 1,401 patients with PSA doubling time ≤10 months who were randomly assigned 2:1 to receive enzalutamide, 160 mg/day, with ADT or placebo plus ADT. The median age was 74 years in the enzalutamide group and 73 years in the placebo arm. The median PSA doubling time was 3.8 and 3.6 months, respectively, in the two arms.
The primary outcome was metastases-free survival (MFS), defined as time from randomization to radiographic progression or death within 112 days of treatment discontinuation.
At the data cut-off of June 28, 2017, the median duration of therapy of therapy was 18.4 months for enzalutamide and 11.1 months for placebo.
“As of early February of this year, we had still 61% of patients on the enzalutamide arm and 28% are active on the placebo arm,” Dr. Hussain said.
The median MFS was 36.6 months in the enzalutamide arm compared with 14.7 months in the placebo arm, corresponding to a 71% relative reduction in the risk of developing M1 CRPC (HR 0.29; p<.0001). This advantage to enzalutamide was apparent across all subgroups analyzed, including patients with longer and shorter PSA doubling times, and those with Eastern Cooperative Oncology Group ECOG performance status of 0 or 1 at baseline.
The proportion of progression events was >50% less in the enzalutamide arm compared with placebo (23% vs. 49%). Some 187 of the 219 (85%) progression events in the enzalutamide group were radiographic compared with 98% in the placebo arm. Fifteen percent of progression events in the enzalutamide arm were death without documented radiographic progression compared with 2% in the placebo arm.
The time to PSA progression was significantly longer with enzalutamide at 37.2 months, compared with 3.9 months with placebo, for a 93% relative risk reduction (HR 0.07; p<.0001). The time to first use of new antineoplastic therapy was also substantially longer with enzalutamide versus placebo (39.6 vs. 17.7 months; HR 0.21; p<.0001).
At first interim analysis, median OS was not reached in either arm, but Dr. Hussain emphasized that the median follow-up time was only 22 months in each arm.
“The interesting part is that there is a 20% reduction in the relative risk of enzalutamide compared to placebo,” said Dr. Hussain.
Therapy was well tolerated; adverse events were generally consistent with those reported in prior clinical trials of enzalutamide in men with CRPC. Hypertension of any grade occurred in 12% of the enzalutamide group and 5% of the placebo group. The rate of grade 3 or higher hypertension with enzalutamide was 5%.
Several of Dr. Hussain’s co-authors have served as consultant/advisers to, received honoraria from, and/or have received institutional funding from Astellas Pharma, Pfizer, and/or other pharmaceutical companies. One co-author is an employee of Astellas Pharma and two other co-authors are employees of Pfizer. For a full list of disclosures, click here.
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