On June 20, 2023, the FDA approved a new indication for talazoparib (Talzenna; Pfizer), a poly (ADP-ribose) polymerase (PARP) inhibitor, in combination with enzalutamide (Xtandi; Astellas) for homologous recombination repair (HRR) gene mutation–positive, metastatic castration-resistant prostate cancer (mCRPC). The FDA granted this application priority review.
This is the first PARP inhibitor approved for use with a current standard of care (enzalutamide) for adults with mCRPC and HRR gene mutation.
Talazoparib was initially approved as monotherapy for locally advanced or metastatic HER2-negative breast cancer with deleterious or suspected deleterious germline BRCA mutation.
The new approval was based on the results of the phase 3 TALAPRO-2 study, a randomized, double-blind, placebo-controlled, multicohort clinical trial of patients with mCRPC and HRR gene mutation. Patients were randomized 1:1 to enzalutamide 160 mg daily plus talazoparib 0.5 mg or placebo daily.
The eligibility criteria included having a previous orchiectomy or receiving gonadotropin-releasing hormone analogs. Patients were excluded if they had previous systemic therapy for mCRPC, but previous treatment with cytochrome (CY) P17 inhibitors or docetaxel for metastatic castration-sensitive prostate cancer was permitted. The trial stratified randomization by previous treatment with a CYP17 inhibitor or docetaxel.
The study investigators prospectively assessed multiple HRR genes using circulating tumor DNA–based next-generation sequencing assays and/or tumor tissue.
There was a significant improvement in radiographic progression-free survival (PFS), which was the major efficacy measure, for talazoparib plus enzalutamide compared with placebo plus enzalutamide in patients with the HRR mutation (median, not reached vs 13.8 months; hazard ratio, 0.45; 95% confidence interval [CI], 0.33-0.61; P<.0001). According to the results of an exploratory analysis by BRCA mutation status, the hazard ratio for radiographic PFS was 0.20 (95% CI, 0.11-0.36) in patients with mCRPC and the BRCA mutation (n=155) and 0.72 (95% CI, 0.49-1.07) in patients who had HRR-positive mCRPC without the BRCA mutation.
The most common (≥10%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin, decreased neutrophils, decreased lymphocytes, fatigue, decreased platelets, decreased calcium, nausea, decreased appetite, decreased sodium, decreased phosphate, fractures, decreased magnesium, dizziness, increased bilirubin, decreased potassium, and dysgeusia. In TALAPRO-2, 39% (199/511) of the total patients with mCRPC who received talazoparib plus enzalutamide needed a blood transfusion, including 22% who needed multiple transfusions, and 2 patients were diagnosed with myelodysplastic syndrome or acute myeloid leukemia.
