FDA Accelerated the Approval of Akeega, First and Only Dual-Action Tablet for Metastatic Prostate Cancer With BRCA Mutation

JHOP - October 2023 Vol 13, No 5 - FDA Oncology Update
NEW COMBINATION

On August 11, 2023, the FDA accelerated the approval of niraparib and abiraterone acetate as a fixed-dose combination (Akeega; Janssen Biotech), plus prednisone, for the treatment of adults with castration-resistant prostate cancer (CRPC) and deleterious or suspected deleterious BRCA mutation, as determined by an FDA-approved test. This approval was granted priority review.

This is the first and only 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 for the maintenance treatment of adults with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who have had a partial or complete response to first-line platinum-based chemotherapy, and for the maintenance treatment of adults with recurrent deleterious or suspected deleterious germline BRCA mutation–positive epithelial ovarian, fallopian tube, or primary peritoneal cancer who have had 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 high-risk, metastatic castration-sensitive prostate cancer.

The approval of this novel combination was based on the results in cohort 1 (N=423) of the MAGNITUDE study (NCT03748641), a randomized, double-blind, placebo-controlled phase 3 clinical trial that included patients with metastatic CRPC and homologous recombination repair (HRR) gene mutation. The patients were randomized (1:1) to niraparib 200 mg and abiraterone acetate 1000 mg plus prednisone 10 mg daily (n=212), or to placebo and abiraterone acetate plus prednisone daily (n=211).

All patients had to have undergone orchiectomy or be taking gonadotropin-releasing hormone (GnRH) analogs. Patients with metastatic CRPC were eligible to participate in the study if they had not received systemic therapy in the metastatic setting, except for a short duration (up to 4 months) of treatment with abiraterone acetate plus prednisone, and ongoing androgen-deprivation therapy. Patients could have received 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 this phase 3 study, 225 (53%) had BRCA mutations.

The study’s major 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).

“As a physician, identifying patients with a worse prognosis is a priority, especially those whose cancers have a BRCA mutation,” said Kim Chi, MD, Medical Oncologist at BC Cancer in Vancouver, Canada, and principal investigator of the MAGNITUDE study, in a press release. “We prospectively designed the MAGNITUDE study to identify the subset of patients most likely to benefit from targeted treatment with Akeega,” Dr Chi added.

A significant improvement in radiographic PFS was observed in the patients who received niraparib and abiraterone acetate plus prednisone versus placebo and abiraterone acetate plus prednisone in those 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 significant improvement in radiographic PFS was seen in the overall cohort 1 (N=423) intention-to-treat (ITT) patient population with HRR mutation (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 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 patients with HRR mutation was attributed to the results in the subgroup of patients with BRCA mutation.

No clinical treatment benefit was seen in patients with metastatic CRPC who did not have an HRR gene mutation (cohort 2), which met the study criterion for futility (ie, this combination treatment has no benefit in patients without HRR mutation).

“The approval of Akeega brings an important treatment option to patients with prostate cancer as they consider their road ahead, and it also highlights the importance of genetic testing and precision medicine for this disease,” said Shelby Moneer, MS, CHES, Vice President of Patient Programs and Education of ZERO Prostate Cancer, in a press release. “All individuals diagnosed with prostate cancer should consider genetic testing, especially those from racial and ethnic minority groups who tend to have worse cancer outcomes. This is imperative to close the racial and ethnic disparities in prostate cancer health outcomes,” she said.

The most common (≥20%) adverse events, 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 niraparib and abiraterone acetate plus prednisone (n=212), 27% required a blood transfusion, including 11% who required multiple blood 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 adverse events. This novel combination should be taken on an empty stomach (2 hours before and 1 hour after any food intake).

Patients receiving niraparib and abiraterone acetate plus prednisone should also receive a concurrent GnRH analog, unless they have had bilateral orchiectomy.

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