According to results from ENZAMET, a global phase III trial, adding enzalutamide to standard treatment for men with metastatic hormone-sensitive prostate cancer is superior in prolonging survival compared with older nonsteroidal antiandrogen drugs.

Interim findings from the global phase III ENZAMET trial indicate that adding enzalutamide (Xtandi; Astellas Pharma) to standard treatment for men with metastatic hormone-sensitive prostate cancer (mHSPC) is superior in prolonging survival compared with older nonsteroidal antiandrogen (NSAA) drugs. The newly published study data were presented by Christopher Sweeney, MBBS, of Dana-Farber Cancer Institute in Boston, MA, during the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL, May 31–June 4.

The treatment landscape for mHSPC has altered considerably in the last few years. Until recently, “testosterone suppression with or without a first-generation NSAA was the only option,” Sweeney said. Then in 2014 and 2017, respectively, docetaxel and the androgen biosynthesis inhibitor abiraterone acetate (Zytiga; Janssen)—the latter combined with prednisone—were approved to supplement androgen deprivation therapy (ADT) in these patients.

Now, the results from ENZAMET point toward older NSAAs, such as bicalutamide, being replaced with enzalutamide. Unlike its first-generation counterparts, which block only the cell-surface portion of the androgen receptor (AR), enzalutamide is a more potent inhibitor that “can enter cells and prevent the AR from continuously self-triggering within, which is thought to be a mechanism of resistance to ADT,” explained David Graham, MD, of Levine Cancer Institute in Charlotte, NC.

ENZAMET randomly assigned 1,125 men with mHSPC to receive enzalutamide or one of three standard NSAAs—bicalutamide, flutamide, or nilutamide—along with testosterone suppression. Nearly half of the patients were also given concurrent docetaxel, Sweeney noted, “recognizing that the standard of care can include chemotherapy, depending on the volume of disease and prognosis.” An interim analysis yielded data that were strong enough to warrant early reporting at ASCO, he added: Enzalutamide reduced the risk of disease progression or death by 33% compared with the control arm. Overall survival (OS) at 3 years was 80% for patients given enzalutamide versus 72% for those who received an older NSAA.

Interestingly, a subanalysis of the enzalutamide cohort showed that concurrent docetaxel did not significantly influence OS. On the other hand, the risk of disease progression or death was reduced by 47% in patients who had not also received chemotherapy. Because most of the former had a high disease burden, “the setting in which docetaxel is known to be most effective, this might have clouded some of the benefit from enzalutamide,” Graham observed. “Whereas for patients who didn't need docetaxel, enzalutamide's true benefit was allowed to be seen.”

Enzalutamide was largely well tolerated, Sweeney said, but associated with greater hypertension, fatigue, and frailty (risk of falls) compared with older NSAAs. It also augmented docetaxel-related adverse events, including sensory neuropathy, nail discoloration, and watery eyes.

In all, although approved for treating only castration-resistant prostate cancer (CRPC), enzalutamide “is certainly an appropriate option” that should be added to the therapeutic backbone of ADT for men with mHSPC, Sweeney concluded. Graham agreed, noting that “we've always thought of enzalutamide as a second-line therapy, but these data strongly suggest starting patients on it up front.”

Another next-generation NSAA expected to merit consideration as a first-line agent for mHSPC is apalutamide (Erleada; Janssen), currently also approved only for CRPC. According to the phase III TITAN trial—presented at ASCO and recently published—compared with placebo, adding apalutamide to ADT improved both radiographic progression-free survival and OS in patients with mHSPC. These findings are similar to the ARCHES study of enzalutamide that was reported at the 2019 Genitourinary Cancers Symposium in San Francisco, CA.

Should the indications for both enzalutamide and apalutamide expand in due course, “I expect it will be a Pepsi versus Coca-Cola world,” Sweeney quipped, in terms of which NSAA clinicians select to supplement ADT when treating mHSPC. With the availability of abiraterone–prednisone and docetaxel regimens, and given the different side-effect profiles across all these agents, “patients and physicians will need to have a discussion based on financial concerns, comorbidities, and other treatment preferences,” he added. “All options should be on the table.” –Alissa Poh