FDA Approves Talazoparib and Enzalutamide for Metastatic Castration-Resistant Prostate Cancer with HRR Gene Mutation

On June 20, 2023, the U.S. Food and Drug Administration approved talazoparib (Talzenna, Pfizer, Inc.) in combination with enzalutamide for patients with metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene mutation, as detected by the tumor tissue and/or circulating tumor DNA (ctDNA)-based next-generation sequencing assays.

 

Study ID: NCT03395197

 

Approval was based on the TALAPRO-2 study, a randomized, double-blind, placebo-controlled Phase III trial that included 169 patients with mCRPC with HRR gene mutation out of 805 enrolled patients. While patients with either prior orchiectomy, receipt of GnRH analogs, docetaxel, and abiraterone were included, prior treatment with second-generation androgen receptor inhibitors (enzalutamide, apalutamide, and darolutamide) was not allowed.

 

Talazoparib and enzalutamide were given orally, with doses of 0.5 and 160 mg daily until disease progression or unacceptable toxicity. The median treatment duration was not specified.

 

Efficacy was established on the primary outcome measure of radiographic progression-free survival (rPFS).

 

For HRR deficient patients, a statistically significant improvement in rPFS for the talazoparib and enzalutamide combination compared to placebo with enzalutamide was observed, with aHR 0.46; 95% CI: 0.30, 0.70; p=0.0003 (median rPFS 27.9 vs. 16.4 months). The combination therapy demonstrated significant efficacy, indicating its potential as a valuable therapeutic option in BRCA mutated mCRPC population.

 

The most common adverse reactions in the treatment arm included anemia, neutropenia, thrombocytopenia, fatigue, nausea, decreased appetite, falls, diarrhea, and nausea.

 

Nearly half of the patients developed grade 3–4 anemia after 3.3 months, necessitating dose reduction. One case of myelodysplastic syndrome and one case of acute myeloid leukemia occurred during follow-up.

 

The study indicated that the combination of talazoparib and enzalutamide significantly improves rPFS in patients with mCRPC with HRR gene mutation.

 

The recommended doses are talazoparib 0.5 mg and enzalutamide 160 mg, taken orally once daily until disease progression or unacceptable toxicity. Despite specific adverse effects, the notable improvement in rPFS marks a significant advancement in the therapeutic options for this patient population.

 

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