On February 14, 2018, the Food and Drug Administration (FDA) approved the next-generation AR antagonist apalutamide (Erleada™, Janssen Biotech, Inc.) for patients with non-metastatic castration-resistant prostate cancer (NM-CRPC). The FDA granted this application a priority review.

This latest approval for advanced prostate cancer was based on results from the phase III SPARTAN trial (NCT01946204), a multicenter, double-blind, study randomizing 1207 patients with NM-CRPC (2:1) to receive either apalutamide, 240 mg orally once daily in combination with androgen deprivation therapy (ADT; medical castration or surgical castration) (n=806), or placebo once daily with ADT (n=401).

The primary outcome measure was metastasis-free survival (MFS) defined as the time from randomization to the time of first evidence of distant metastasis (new bone or soft tissue lesions or enlarged lymph nodes outside the pelvis), or death due to any cause, whichever occurred first. The estimated median MFS was 40.5 months for patients receiving apalutamide and 16.2 months for those receiving placebo (hazard ratio 0.28; 95% CI: 0.23, 0.35; p<0.0001). Full details of the study were published in the New England Journal of Medicine.

The Prostate Cancer Clinical Trials Consortium (PCCTC) led the early clinical development of apalutamide with a first-in-human phase I trial (NCT01171898) led by Dr. Dana Rathkopf of Memorial Sloan Kettering Cancer Center which showed dose-proportional inhibition of tracer uptake at the 120 mg daily dose level and above, consistent with the plasma levels that produced optimal inhibition of tumor growth pre-clinically.

With a recommended dose in hand, the issue was to determine the efficacy of apalutamide in specific cohorts of men so that a registrational path could be defined. Simply comparing the drug to enzalutamide was unlikely to show sufficient differences to enable approval. Accordingly, apalutamide was evaluated in a follow-up study led by Dr. Rathkopf, the phase II multicenter trial (NCT01171898) treating men who had 1) non-metastatic treatment-naïve CRPC; 2) treatment-naïve metastatic CRPC; and 3) metastatic CRPC pre-treated with abiraterone acetate. The primary endpoint was PSA response rate at 12 weeks according to PCWG2 criteria in each of the treatment groups. At 12 weeks, PSA response (≥50% decline from baseline) was 91% (non-metastatic), 88% (treatment-naïve), and 29% (post-abiraterone), respectively. Based on these results, a proposal to conduct an all-comers registration trial in the post-chemotherapy setting was abandoned in favor of a phase III trial in the NM-CRPC setting (i.e., SPARTAN).

The recommended apalutamide dose is 240 mg (four 60 mg tablets) administered orally once daily. Full prescribing information is available at ERLEADA™.