PROSPER: Enzalutamide Benefit in Nonmetastatic CRPC?

An updated analysis from the phase III PROSPER trial presented at the American Urological Association (AUA) 2018 annual meeting, held in San Francisco from May 18–21, suggests treatment with the androgen receptor inhibitor enzalutamide (Xtandi) plus androgen deprivation therapy (ADT) may be highly advantageous compared with ADT alone in men with nonmetastatic castration-resistant prostate cancer (CRPC).

Researchers found that for men with nonmetastatic CRPC and rapidly rising prostate-specific antigen (PSA) levels, enzalutamide resulted in a clinically meaningful and statistically significant reduction in developing metastatic CRPC. This agent also resulted in an increase in median time to first use of new antineoplastic therapy, including chemotherapy. Benefits were also demonstrated for chemotherapy-free disease-specific survival (CFDS) and chemotherapy-free survival (CFS).

“This is an opportunity heretofore to meet an unmet therapeutic need,” said study investigator Neal Shore, MD, director of the Carolina Urologic Research Center, Myrtle Beach, South Carolina.

Dr. Shore, who presented the study findings at the meeting, said the goal when treating nonmetastatic disease is to delay both progression and the need for additional antineoplastic therapies. Enzalutamide is already approved for the treatment of metastatic disease. The PROSPER trial was a randomized, double-blind, placebo-controlled, phase III multinational study (NCT02003924) in men with asymptomatic nonmetastatic CRPC. All patients in this trial had PSA doubling times ≤ 10 months and a PSA level ≥ 2 ng/mL at screening.

Included in the study were 1,402 men who were randomized 2:1 to enzalutamide 160 mg or placebo. The primary endpoint was metastasis-free survival (MFS). Dr. Shore said the secondary endpoints included time to PSA progression; time to first use of new antineoplastic therapy; time to first use of cytotoxic chemotherapy; CFDS and CFS; and safety.

The researchers found that the addition of enzalutamide significantly increased MFS (hazard ratio [HR], 0.29), time to PSA progression (HR, 0.07), and time to first use of new antineoplastic therapy (HR, 0.21) vs placebo. The study also demonstrated that this agent significantly delayed the time to first use of cytotoxic chemotherapy (HR, 0.38), while increasing CFDS (HR, 0.40) and CFS (HR, 0.50).

“This is clinically relevant,” Dr. Shore said in an interview with Cancer Network. “There is opportunity to delay the need for neoplastic therapies.” Adverse events (AEs) were higher with the treatment arm vs the placebo arm (any grade: 87% vs 77%). For grade ≥ 3, the same was true (31% vs 23%). In this cohort, 10% of the patients in the treatment arm discontinued treatment due to AEs, vs 8% of men in the placebo arm.

The most common AEs in two previous placebo-controlled clinical trials of enzalutamide were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, decreased weight, headache, hypertension, and dizziness/vertigo.

“You can see some increase in fatigue in these patients, and you can see a small change in hypertension and some mild GI [gastrointestinal] effects,” said Dr. Shore. “We see an established safety profile.”