Talzenna Plus Xtandi Shows Significant Overall Survival Improvement in Metastatic Castration-Resistant Prostate Cancer

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The combination of Talzenna (talazoparib; Pfizer) plus Xtandi (enzalutamide; Astellas and Pfizer) produced a statistically significant improvement in overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) regardless of mutation status, according to results from the Phase III TALAPRO-2 trial (NCT03395197).^1,2 Pfizer noted that these results represent the first combination of an oral poly ADP-ribose polymerase (PARP) inhibitor and an androgen receptor pathway inhibitor (ARPI) to achieve these results in patients mCRPC.

“The TALAPRO-2 results showed that Talzenna plus Xtandi is the first and only PARP inhibitor in combination with an ARPI to significantly improve survival in patients with metastatic castration-resistant prostate cancer, regardless of mutation status,” said Roger Dansey, MD, chief development officer, Oncology, Pfizer, in a press release.¹

Talzenna plus Xtandi was approved by the FDA in June 2023 to treat patients with homologous recombination repair (HRR) gene–mutated mCRPC. Talzenna is also indicated to treat adults with deleterious or suspected deleterious germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer.³

Xtandi has multiple approvals in prostate cancer, most recently in November 2023 to treat nonmetastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis. To date, more than 300,000 patients in the United States have been prescribed Xtandi, which has demonstrated improved OS in those with mCRPC, nmCSPC, and metastatic castration-sensitive prostate cancer.⁴

The multicenter, randomized, double-blind, placebo-controlled TALAPRO-2 trial enrolled 1,035 patients with mCRPC who were not previously administered life-prolonging systemic therapy after confirmed diagnosis of mCRPC.

Cohort 1 of the trial was comprised of all-comers (n=805), with 169 having homologous recombination repair (HRR) gene-mutated mCRPC and 636 who did not. Cohort 2 was comprised of patients with HRR gene mutations (n=399), which included 169 patients from Cohort 1 and 230 who were enrolled in Cohort 2. Patients with castrate testosterone levels were randomly assigned to receive Talzenna 0.5 mg/day plus Xtandi 160 mg/day, or placebo plus Xtandi 160 mg/day.

The trial’s primary endpoint was radiographic progression-free survival (rPFS) defined in both cohorts as time from the date of randomization to first objective evidence of radiographic progression as determined by blinded independent review or death, whichever occurred first. The trial’s secondary endpoints included OS, objective response rate, duration of response, and prostate-specific antigen response.

Investigators observed a statistically significant and clinically meaningful improvement in the final analysis for OS in both cohorts compared with Xtandi plus placebo. The results of the final analysis showed that the clinically meaningful improvement in rPFS from the prior primary analysis was maintained across both cohorts.

The primary analysis data, released in February 2024, showed that Talzenna plus Xtandi lowered the risk of disease progression or death by 37% compared with placebo plus Xtandi (Hazard Ratio [HR]: 0.63; 95% Confidence Interval [CI], 0.51–0.78; P< 0.001). Further, median rPFS in the Talzenna plus Xtandi cohort was not reached at the time of primary analysis compared with 21.9 months in the placebo plus Xtandi cohort.⁵

In terms of safety, the profile of Talzenna plus Xtandi was generally consistent with what has previously been reported with both drugs, and no new safety signals were identified. Deeper data from the TALAPRO-2 trial will be presented at an upcoming medical congress and submitted to global health authorities for regulatory filings to potentially expand the approved indication for Talzenna, according to Pfizer.

“These [OS] results indicate potentially practice-changing efficacy for Talzenna in combination with Xtandi for men with [mCRPC],” TALAPRO-2 global lead investigator Neeraj Agarwal, MD, FASCO, professor and Presidential Endowed Chair of Cancer Research at Huntsman Cancer Institute, University of Utah, said in a press release. “[mCRPC] is the most advanced and aggressive stage of the disease, and the TALAPRO-2 results provide much-needed hope to patients who remain in high unmet need for effective treatment options.”¹

References

1. Pfizer’s TALZENNA® in Combination with XTANDI® Prolongs Overall Survival in Phase 3 TALAPRO-2 Trial. News release. Pfizer. October 10, 2024. https://www.pfizer.com/news/press-release/press-release-detail/pfizers-talzennar-combination-xtandir-prolongs-overall

2.Talazoparib+Enzalutamide vs. Enzalutamide Monotherapy in mCRPC (TALAPRO-2). ClinicalTrials.gov. Updated September 5, 2024. Accessed October 10, 2024. https://www.clinicaltrials.gov/study/NCT03395197

3. Pfizer’s Talzenna in Combination with Xtandi Receives US FDA Approval. News release. Pfizer. June 20, 2023. Accessed October 10, 2024. https://www.pfizer.com/news/press-release/press-release-detail/pfizers-talzennar-combination-xtandir-receives-us-fda

4. Pfizer and Astellas' XTANDI® Approved by U.S. FDA in Earlier Prostate Cancer Treatment Setting. Astellas Pharma Inc. News release. November 17, 2023. Accessed October 10, 2024. https://www.astellas.com/en/news/28626

5. Pfizer Announces Positive TALZENNA® and XTANDI® Combination Data from Phase 3 TALAPRO-2 Study. News release. Pfizer. February 16, 2023. Accessed October 10, 2024. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-announces-positive-talzennar-and-xtandir-combination