FDA Approves Fixed-Dose Prostate Cancer Combination Treatment

The FDA approved the first fixed-dose combination of the PARP inhibitor niraparib and the androgen biosynthesis inhibitor abiraterone (Akeega) for metastatic BRCA-mutant castration-resistant prostate cancer (CRPC).

The approval stipulates use of the dual-action tablet with prednisone in patients with metastatic BRCA-mutant CRPC confirmed by an FDA-approved diagnostic test. Eligible patients must have had prior bilateral orchiectomy or current treatment with a gonadotropin releasing hormone analog.

Support for the approval came from the randomized, double-blind, placebo-controlled multicenter phase III MAGNITUDE trial.

"As a physician, identifying patients with a worse prognosis is a priority, especially those whose cancers have a BRCA mutation," said MAGNITUDE principal investigator Kim Chi, MD, of BC Cancer in Vancouver, in a statement from drugmaker Janssen. "We prospectively designed the MAGNITUDE study to identify the subset of patients most likely to benefit from targeted treatment with Akeega and to help us understand how we can potentially achieve better health outcomes for patients."

MAGNITUDE involved 423 patients with metastatic CRPC, 53% with BRCA1/2 mutations. Patients were randomized to the fixed-dose combination or placebo and abiraterone acetate, each in combination with prednisone. The primary endpoint was radiographic progression-free survival (rPFS).

After a median follow-up of 18.6 months, the BRCA+ subgroup had a median rPFS of 16.6 months with the fixed-dose combination versus 10.9 months for the placebo group, representing a 47% reduction in the hazard ratio (P=0.001). A second analysis after 24.8 months of follow-up showed a median rPFS of 19.5 months in the niraparib/abiraterone group and 10.9 months in the placebo group.

All patients were prospectively tested for nine types of homologous recombination repair alterations (HRR+), including BRCA1/2. Among all HRR+ patients, the combination therapy resulted in a median rPFS of 16.5 months versus 13.7 months with placebo, a 27% reduction in the hazard ratio (P=0.022). An analysis limited to patients with non-BRCA alterations, as well as an analysis of HRR- patients, showed no significant difference between treatment groups.

The most common adverse events (≥20% of patients) were decreased hemoglobin, decreased lymphocytes, decreased white blood cells, musculoskeletal pain, fatigue, decreased platelets, increased alkaline phosphatase, constipation, hypertension, nausea, decreased neutrophils, increased creatinine, increased potassium, decreased potassium, and increased aspartate aminotransferase. Additionally, 27% of patients treated with niraparib/abiraterone and prednisone required one or more blood transfusions.

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