On August 11, 2023, the FDA accelerated the approval of the fixed-dose combination of niraparib and abiraterone acetate (Akeega; Janssen Biotech), with prednisone, for the treatment of adults with deleterious or suspected deleterious BRCA-mutated, castration-resistant prostate cancer (CRPC), as determined by an FDA-approved test. The FDA granted this approval priority review.
This is the first oral tablet combining the dual mechanisms of action of the poly (ADP-ribose) polymerase inhibitor niraparib (Zejula; GlaxoSmithKline) and the CYP17 inhibitor abiraterone acetate (Zytiga; Janssen Biotech), taken together with prednisone (a steroid).
Niraparib monotherapy was previously approved as maintenance therapy for adults with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or a partial response to first-line platinum-based chemotherapy, and as maintenance therapy for adults with deleterious or suspected deleterious germline BRCA-mutated recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Abiraterone acetate was previously approved for use with prednisone for the treatment of patients with metastatic CRPC or metastatic high-risk castration-sensitive prostate cancer.
The approval of this novel combination was based on results from cohort 1 of the MAGNITUDE study, a randomized, double-blind, placebo-controlled, phase 3 clinical trial of 423 patients with homologous recombination repair (HRR) gene–mutated metastatic CRPC. Patients were randomized in a 1:1 ratio to niraparib 200 mg and abiraterone acetate 1000 mg plus prednisone 10 mg daily (n=212) or placebo and abiraterone acetate plus prednisone daily (n=211). Patients were required to have a previous orchiectomy or be receiving gonadotropin-releasing hormone (GnRH) analogues.
Patients with metastatic CRPC were eligible to participate in the study if they had not received previous systemic therapy in the metastatic setting, except for a short duration (up to 4 months) of previous abiraterone acetate plus prednisone, and ongoing androgen-deprivation therapy. Patients could have received previous therapy with docetaxel or targeted therapy with an androgen receptor in earlier disease settings.
Patients were stratified based on previous use of docetaxel, targeted therapy with an androgen receptor, or abiraterone acetate plus prednisone, as well as BRCA status. Of the 423 patients in the study, 225 (53%) had BRCA mutations.
The main end point was radiographic progression-free survival (PFS), per RECIST version 1.1 for soft-tissue and Prostate Cancer Working Group 3 criteria for bone, as assessed by blinded independent central review. An additional end point was overall survival (OS).
A statistically significant improvement in radiographic PFS with the combination of niraparib and abiraterone acetate plus prednisone versus placebo and abiraterone acetate plus prednisone was observed in patients with BRCA mutation (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.36-0.79; P=.0014), with a median duration of improvement of 16.6 months versus 10.9 months, respectively. An exploratory OS analysis in the patients with BRCA mutation demonstrated a median of 30.4 months in the investigational arm versus 28.6 months in the placebo arm (HR, 0.79; 95% CI, 0.55-1.12).
A statistically significant improvement in radiographic PFS was seen in the overall cohort 1 (N=423) intent-to-treat (ITT) HRR-mutated patient population (HR, 0.73; 95% CI, 0.56-0.96; P=.0217); however, in the subgroup of 198 (47%) patients with non-BRCA and -HRR mutations, the HR for radiographic PFS was 0.99 (95% CI, 0.67-1.44) and the HR for OS was 1.13 (95% CI, 0.77-1.64), indicating that the improvement in the ITT patient population of those with HRR mutations was attributed to the results seen in the subgroup of patients with BRCA mutation.
No clinical benefit was observed in patients with metastatic CRPC who did not have an HRR gene mutation (cohort 2), which met the study criterion for futility.
The most common (≥20%) adverse reactions, 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 the patients with metastatic CRPC who received the investigational combination agent plus prednisone in cohort 1 of MAGNITUDE (N=423), 27% required a blood transfusion, including 11% who required multiple transfusions.
The recommended dose for this new fixed-dose oral agent is 200 mg of niraparib and 1000 mg of abiraterone acetate, plus 10 mg of prednisone, taken daily until disease progression or unacceptable toxicity. It should be taken on an empty stomach (no food intake for at least 2 hours before and at least 1 hour after taking the drug). Patients receiving niraparib and abiraterone acetate plus prednisone should also receive a GnRH analog concurrently unless they have had a bilateral orchiectomy.