Enzalutamide Succeeds in Phase III Nonmetastatic CRPC Trial

Mace Rothenberg, MD

Adding enzalutamide (Xtandi) to androgen deprivation therapy (ADT) significantly improved metastasis-free survival (MFS) versus ADT alone in patients with nonmetastatic castration-resistant prostate cancer (CRPC), according to findings from the phase III PROSPER trial.

No data have been released yet, with Pfizer and Astellas, the codevelopers of the androgen receptor inhibitor, planning to share the results at an upcoming medical meeting.

“Many prostate cancer patients who initiate ADT will experience disease progression illustrated by a rising prostate-specific antigen (PSA) level, and currently, there are no FDA-approved treatment options for patients with nonmetastatic CRPC until they develop confirmed radiographic metastatic disease,” Neal Shore, MD, director, CPI, Carolina Urologic Research Center, said in a statement.

PROSPER is a multinational, randomized, double-blind, placebo controlled trial evaluating the efficacy and safety of enzalutamide. The study was initiated in December 2013 at 287 locations and is scheduled to end in May 2020. Patients in the experimental arm are assigned to 160 mg daily of oral enzalutamide. The primary endpoint is MFS and secondary endpoints include overall survival (OS), time to prostate-specific antigen progression, and time to chemotherapy-free survival.

On June 9, 2017, Pfizer and Astellas announced an amendment to the PROSPER protocol that accelerated the clinical trial completion date by 2 years. The companies reported today that there have been no new safety signals thus far for enzalutamide in PROSPER.

“We are delighted with the significant results seen in the PROSPER study, showing that Xtandi plus ADT delayed clinically detectable metastases compared to ADT alone in patients with nonmetastatic CRPC whose only sign of underlying disease was a rapidly rising PSA level. We look forward to discussing the data with regulatory authorities,” Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development, said in a statement.

“Xtandi is already established as a standard of care for men with metastatic CRPC based on the results of prior studies, such as AFFIRM and PREVAIL, which demonstrated that Xtandi delayed disease progression and improved OS in men with clinically detectable metastatic disease.”

Enzalutamide has been FDA-approved to treat late-stage CRPC for men previously treated with docetaxel since 2012. The agency approved the drug for first-line therapy in 2014 based on results from the phase III PREVAIL trial which showed that enzalutamide improved OS by 29% and radiographic progression-free survival (rPFS) by 81% compared with placebo.

In PREVAIL, 1717 men with a median age of 71 years received treatment with enzalutamide (n = 872) or placebo (n = 845). Enzalutamide was administered at 160 mg daily. An interim analysis was conducted following 540 deaths, which demonstrated a statistically significant advantage for enzalutamide for both OS and rPFS. At that point, the study was halted and men in the placebo arm were allowed to crossover to enzalutamide.

The agency expanded the drug’s label again last year based on results from the phase II TERRAIN trial. Those results showed that enzalutamide reduced the risk of radiographic progression or death by 40% compared with bicalutamide, and improved median rPFS by 6.1 months in patients with metastatic CRPC.

In TERRAIN, chemotherapy-naïve patients with metastatic CRPC (N = 375) were randomized to enzalutamide at 160 mg orally once daily or 50 mg of once-daily bicalutamide at 50 mg. Median rPFS was 19.5 months with enzalutamide compared with 13.4 months with bicalutamide (HR, 0.60; 95% CI, 0.43-0.83).

The safety data for enzalutamide was comparable to results reported from previous enzalutamide studies. The most common all-grade adverse events (AEs) with enzalutamide included asthenic conditions, back pain, musculoskeletal pain, hot flush, hypertension, diarrhea, upper respiratory tract infection, and weight loss.

Grade 3/4 AEs occurred in 38.8% and 37.6% of the enzalutamide and bicalutamide arms, respectively. Although most grade ≥3 AEs occurred at similar rates between the arms, there were a few exceptions: hypertension (7.1% in the enzalutamide arm vs 4.4% in the bicalutamide arm), diarrhea (0% vs 1.1%), and back pain (2.7% vs 1.6%). Seizures occurred in 2 patients in the enzalutamide group and 1 patient in the bicalutamide group.