On August 11, the U.S. Food and Drug Administration (FDA) approved the fixed-dose combination of niraparib and abiraterone acetate (Akeega), with prednisone, for adult patients with deleterious or suspected deleterious BRCA-mutated metastatic castration-resistant prostate cancer, as determined by an FDA-approved test.
MAGNITUDE Trial
Efficacy was evaluated in cohort 1 of MAGNITUDE (ClinicalTrials.gov identifier NCT03748641), a randomized, double-blind, placebo-controlled trial that enrolled 423 patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer. Patients were randomly assigned 1:1 to receive niraparib at 200 mg and abiraterone acetate at 1,000 mg plus prednisone at 10 mg daily, or placebo and abiraterone acetate plus prednisone daily.
Patients were required to have undergone a prior orchiectomy or be receiving gonadotropin-releasing hormone (GnRH) analogs. Patients with metastatic castration-resistant prostate cancer were eligible if they had not received prior systemic therapy in the metastatic castration-resistant prostate cancer setting except for a short duration of prior abiraterone acetate plus prednisone (up to 4 months) and ongoing androgen-deprivation therapy. Patients could have received prior docetaxel or androgen receptor–targeted therapies in earlier disease settings.
Random assignment was stratified by prior receipt of docetaxel, prior receipt of androgen receptor–targeted therapy, prior receipt of abiraterone acetate plus prednisone, and BRCA status. Of the 423 patients enrolled, 225 (53%) had prospectively determined BRCA gene mutations. No benefit was observed in patients with metastatic castration-resistant prostate cancer without an HRR gene mutation (cohort 2 of MAGNITUDE) as the criterion for futility was met. The major efficacy outcome measure was radiographic progression–free survival per Response Evaluation Criteria in Solid Tumors version 1.1 for soft tissue and Prostate Cancer Working Group 3 criteria for bone, assessed by blinded independent central review. Overall survival was an additional endpoint.
A statistically significant improvement in radiographic progression–free survival for niraparib and abiraterone acetate plus prednisone compared to placebo and abiraterone acetate plus prednisone was observed in patients with a BRCA mutation, with a median of 16.6 months vs 10.9 months (hazard ratio [HR] = 0.53, 95% confidence interval [CI] = 0.36–0.79, P = .0014). An exploratory overall survival analysis in patients with a BRCA mutation demonstrated a median of 30.4 vs 28.6 months (HR = 0.79, 95% CI = 0.55–1.12) favoring the investigational arm.
A statistically significant improvement in radiographic progression–free survival was seen in the overall cohort 1 intention-to-treat (ITT) HRR population (HR = 0.73, 95% CI = 0.56–0.96, P = .0217). However, in the subgroup of 198 (47%) patients with non-BRCA HRR mutations, the radiographic progression–free survival hazard ratio was 0.99 (95% CI = 0.67–1.44) and the overall survival hazard ratio was 1.13 (95% CI = 0.77–1.64), indicating that the improvement in the ITT HRR gene–mutated population was primarily attributed to the results seen in the subgroup of patients with a BRCA mutation.
The most common adverse reactions (≥ 20%), including laboratory abnormalities, 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. Among all patients with metastatic castration-resistant prostate cancer treated with niraparib and abiraterone acetate plus prednisone in cohort 1 of MAGNITUDE (n = 423), 27% required a blood transfusion, including 11% who required multiple transfusions.
The recommended dose of the agent is 200 mg of niraparib and 1,000 mg of abiraterone acetate taken orally once daily in combination with 10 mg of prednisone daily until disease progression or unacceptable toxicity. Patients receiving niraparib and abiraterone acetate plus prednisone should also receive a GnRH analog concurrently or should have had bilateral orchiectomy.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. This application was granted Priority Review.
