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Talzenna Received a New Indication, With Enzalutamide, for Metastatic Castration-Resistant Prostate Cancer With HRR Gene Mutation

Web Exclusives - FDA Approvals

On June 20, 2023, the FDA approved a new indication for talazoparib (Talzenna; Pfizer), an oral poly (ADP-ribose) polymerase (PARP) inhibitor, in combination with enzalutamide for homologous recombination repair (HRR) gene mutation–positive, metastatic castration-resistant prostate cancer (CRPC). 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 metastatic CRPC 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 current approval was based on the results of the phase 3 TALAPRO-2 (NCT03395197) study, a randomized, double-blind, placebo-controlled, multicohort clinical trial of patients with metastatic CRPC and HRR gene mutation. These 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 (GnRH) analogs. Patients were excluded if they had previous systemic therapy for metastatic CRPC, 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 with 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 metastatic CRPC and the BRCA mutation (n=155) and 0.72 (95% CI, 0.49-1.07) in patients who had HRR-positive metastatic CRPC 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% of the total patients with metastatic CRPC who received talazoparib plus enzalutamide (199/511) needed a blood transfusion, including 22% who needed multiple transfusions, and 2 patients were diagnosed with myelodysplastic syndrome or acute myeloid leukemia.

“Despite treatment advancement in metastatic castration-resistant prostate cancer, the disease can progress quickly, and many patients may only receive one line of therapy….For patients with [metastatic] CRPC harboring HRR genetic alterations, outcomes are even worse,” said Neeraj Agarwal, MD, FASCO, Professor and Presidential Endowed Chair of Cancer Research at Huntsman Cancer Institute, University of Utah, and global lead study investigator. “The FDA’s approval of the talazoparib and enzalutamide combination…represents a treatment option deserving of excitement and attention.”

The recommended dose of talazoparib is 0.5 mg orally, once daily, with enzalutamide (recommended dose, 160 mg orally once daily) until disease progression or unacceptable adverse events. This combination treatment should be accompanied by a concurrent GnRH analog or previous bilateral orchiectomy.

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Last modified: June 29, 2023