Talazoparib Plus Enzalutamide Approved for HRR Gene–Mutated Metastatic Castration-Resistant Prostate Cancer

Prostate cancer.

The FDA has approved talazoparib (Talzenna®, Pfizer, Inc.) in addition to enzalutamide for homologous recombination repair (HRR) gene–mutated metastatic castration-resistant prostate cancer (mCRPC).  

Why it matters: “Despite significant advances in the therapeutic landscape of mCRPC in recent years, currently available therapies are not curative, and subsequent progression of disease usually reflects reactivation of the androgen receptor (AR) signaling pathway. Therefore, new therapeutic approaches, including novel therapies and treatment combinations, are required for patients with mCRPC,” wrote Neeraj Agarwal, MD, Professor of Medicine and a Presidential Endowed Chair of Cancer Research at the Huntsman Cancer Institute, University of Utah, and colleagues, in their published results of the TALAPRO-2 trial (NCT03395197), on which approval was based. “PARP inhibitors in combination with androgen receptor–targeted therapy have demonstrated potential in the treatment of mCRPC.”

What they studied: Safety and efficacy were evaluated in the phase 3, double-blind, placebo-controlled trial in which 399 patients with HRR gene–mutated mCRPC were randomized 1:1 to receive either 0.5 mg of talazoparib or placebo, plus 160 mg of enzalutamide daily. The primary end point measured was radiographic progression-free survival per RECIST v1.1 for soft tissue and Prostate Cancer Working Group 3 criteria for bone, assessed by blinded independent central review.

Key eligibility criteria: A prior orchiectomy was required for participating patients. If not performed, patients were required to receive a gonadotropin-releasing hormone (GnRH) analog. Excluded were patients with prior systemic therapy for mCRPC; however, patients were permitted who had prior CYP17 inhibitors or docetaxel for metastatic castration-sensitive prostate cancer (mCSPC).

What they found:

  • Talazoparib plus enzalutamide produced a significantly improved radiographic progression-free survival, with a median not being reached, compared with placebo plus enzalutamide which produced a median of 13.8 months
  • An exploratory analysis based on BRCA mutation status found a hazard ratio for radiographic progression-free survival of 0.20 in patients with BRCA-mutated mCRPC, and a hazard ratio of 0.72 in patients with non–BRCA-mutated, HRR gene–mutated mCRPC

Adverse events: The most common adverse events in ≥10% of those being treated with talazoparib, 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. A blood transfusion was needed by 39% of patients receiving talazoparib plus enzalutamide, including 22% who received multiple transfusions. Two patients were diagnosed with myelodysplastic syndrome/acute myeloid leukemia.

What’s next: Further investigation of PARP inhibitors are ongoing in other phase 3 trials, including at least two other trials currently studying talazoparib with enzalutamide to a greater extent.

Conclusion: “Talazoparib plus enzalutamide resulted in clinically meaningful and statistically significant improvement in radiographic progression-free survival versus standard-of-care enzalutamide as first-line treatment for patients with mCRPC,” concluded Dr. Agarwal and colleagues. “Final overall survival data and additional long-term safety follow-up will further clarify the clinical benefit of the treatment combination in patients with and without tumor HRR gene alterations.”

Instructions: The recommended dosage of talazoparib is 0.5 mg orally, once daily in combination with enzalutamide, recommended at 160 mg orally, once daily, until disease progression or unacceptable toxicity. It is also recommended that patients receiving talazoparib plus enzalutamide should receive a GnRH analog concurrently or should have had bilateral orchiectomy.

For More Information

Agarwal N, Azad A, Shore ND, et al (2022). Talazoparib plus enzalutamide in metastatic castration-resistant prostate cancer: TALAPRO-2 phase III study design. Future Oncol, 18(4):425-436. DOI:10.2217/fon-2021-0811

Agarwal N, Azad A, Shore ND, et al (2023). Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet, S0140-6736(23)01055-3. DOI:10.1016/S0140-6736(23)01055-3

Clinicaltrials.gov (2023). Talazoparib + enzalutamide vs. enzalutamide monotherapy in mCRPC (TALAPRO-2). NLM identifier: NCT03395197.

Talzenna® (talazoparib) prescribing information (2023). Pfizer Inc. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/211651s010lbl.pdf

US Food and Drug Administration (2023). FDA approves talazoparib with enzalutamide for HRR gene-mutated metastatic castration-resistant prostate cancer. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-enzalutamide-hrr-gene-mutated-metastatic-castration-resistant-prostate

Image credit: Nephron. Licensed under CC BY-SA 4.0

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