Talazoparib Plus Enzalutamide Hits Primary End Point in HRR Gene–Mutated mCSPC

Talazoparib (Talzenna) in combination with enzalutamide (Xtandi) demonstrated a statistically significant and clinically meaningful improvement in radiographic progression-free survival (rPFS) compared with enzalutamide monotherapy in patients with homologous recombination repair (HRR) gene–mutated metastatic castration-sensitive prostate cancer (mCSPC).¹ These findings met the primary end point of the phase 3 TALAPRO-3 study (NCT04821622).

Top-line rPFS findings from TALAPRO-3 revealed that the results markedly exceeded the pre-specified target HR of 0.63 in favor of the combination arm. Moreover, most patients remained progression-free at the time of analysis, and a consistent efficacy benefit was observed in patients with disease harboring BRCA or non-BRCA HRR gene alterations.

At the time of the interim analysis, a strong trend toward improved overall survival (OS) in favor of the combination arm was also reported; OS was a key secondary end point of the study. Other secondary end points, including overall response rate (ORR), duration of response (DOR), and time to prostate-specific antigen (PSA) progression, were also found to be superior with the addition of talazoparib to enzalutamide. The safety profile of the combination was consistent with the known individual profiles of each agent, and no new signals were observed.

“Current treatment approaches leave many patients with HRR gene-mutated metastatic castration-sensitive prostate cancer vulnerable to early disease progression,” Neeraj Agarwal, MD, FASCO, a professor of medicine, a Presidential Endowed Chair of Cancer Research, and the director of the Genitourinary Oncology (GU) Program and the Center of Investigational Therapeutics (CIT), at Huntsman Cancer Institute at the University of Utah in Salt Lake City, and global lead investigator for TALAPRO-3, stated in a news release. “The TALAPRO-3 results demonstrate that treatment with [talazoparib] in combination with [enzalutamide] earlier in the disease course significantly extends the time patients can live without their cancer worsening.”

In June 2023, the FDA approved talazoparib plus enzalutamide (Xtandi) for use in patients with HRR gene–mutated metastatic castration-resistant prostate cancer (mCRPC).² The regulatory decision was supported by data from the phase 3 TALAPRO-2 (NCT03395197), which demonstrated that patients with HRR gene-mutated mCRPC who received the combination experienced a significant rPFS benefit compared with those treated with placebo plus enzalutamide (HR, 0.45; 95% CI, 0.33-0.61; P < .0001).

How was TALAPRO-3 designed?

TALAPRO-3 enrolled adult patients with DNA damage repair–deficient mCSPC.³ Patients were also required to have an ECOG performance status of 0 or 1, adequate organ function within 28 days before day 1 of study treatment, and metastatic disease as per a positive bone scan or CT/MRI for soft tissue.

Eligible patients were randomly assigned to receive talazoparib at 0.5 mg per day or placebo. All patients also received enzalutamide at 160 mg per day.^1,3

The primary end point was rPFS. Secondary end points included OS, ORR, DOR, PSA response, time to PSA progression, time to initiation of antineoplastic therapy, time to first symptomatic skeletal event, opiate use for prostate cancer pain, safety, and pharmacokinetic measures.

The data from TALAPRO-3 will be submitted for presentation at an upcoming medical congress and will be discussed with global health authorities for potential regulatory submissions, according to Pfizer.¹

“Alterations in DNA damage repair genes, such as HRR genes, are found in approximately 25% of metastatic prostate cancers and [are] associated with a worse prognosis and are less responsive to current standards of care, representing a group with a high unmet need,” Jeff Legos, PhD, MBA, chief oncology officer of Pfizer, added in the news release. “[Talazoparib] plus [enzalutamide] is already a standard of care in HRR gene–mutated mCRPC, and these unprecedented results demonstrate the potential to deliver benefit earlier in the disease course. These findings underscore Pfizer’s leadership in precision medicine and commitment to bringing more personalized treatment options to [individuals] living with prostate cancer.”

References

1. Talzenna plus XTANDI significantly improves radiographic progression-free survival in metastatic prostate cancer. News release. Pfizer. March 19, 2026. Accessed March 19, 2026. https://www.pfizer.com/news/press-release/press-release-detail/talzenna-plus-xtandi-significantly-improves-radiographic
2. FDA approves talazoparib with enzalutamide for HRR gene-mutated metastaic castration-resistant prostate cancer. FDA. June 20, 2023. Accessed March 19, 2026. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-enzalutamide-hrr-gene-mutated-metastatic-castration-resistant-prostate
3. Study of talazoparib with enzalutamide in men with DDR gene mutated mCSPC. ClinicalTrials.gov. Updated March 11, 2026. Accessed March 19, 2026. https://clinicaltrials.gov/study/NCT04821622