Analysis Highlights rPFS-OS Correlation With Frontline Talazoparib-Enzalutamide in mCRPC

A post hoc analysis of the phase 3 TALAPRO-2 trial (NCT03395197) showed a consistent positive moderate-to-strong correlation between radiographic progression-free survival (rPFS) and overall survival (OS) across unselected, HRR-deficient, and BRCA-mutated (BRCAm) patient populations randomized to either talazoparib (Talzenna) plus enzalutamide (Xtandi) or single agent enzalutamide in the first-line metastatic castration-resistant prostate cancer (mCRPC) setting.

Using individual patient-level data from the TALAPRO-2 final OS data cutoff of September 3, 2024, blinded independent central review (BICR)–assessed rPFS demonstrated Spearman ρ values of 0.812, 0.752, and 0.724 in the combined unselected (n = 805), HRR-deficient (n = 399), and BRCA-mutated (n = 155) cohorts, respectively—all meeting the prespecified threshold for moderate-to-strong correlation, which was at least 0.4. Results, which were shared at the 2026 AUA Annual Meeting, were consistent across all three statistical models employed and in analyses within individual treatment arms.

“This analysis represents the first individual patient-level analysis to evaluate rPFS/OS correlation for a PARP inhibitor in the first-line mCRPC setting, including the biomarker-defined subgroups. These findings provide new evidence validating the relationship between rPFS and OS across a clinically relevant population in a contemporary treatment landscape,” said Neeraj Agarwal, MD, FASCO. Agarwal is a professor of medicine at the Huntsman Cancer Institute, University of Utah Comprehensive Cancer Center, in Salt Lake City.

Design of TALAPRO-2 and the Methodology of Correlation Analysis

TALAPRO-2 was a randomized, double-blind, placebo-controlled phase 3 trial evaluating talazoparib (Talzenna) plus enzalutamide (Xtandi) vs placebo plus enzalutamide as first-line treatment in patients with asymptomatic or mildly symptomatic mCRPC. Eligible patients had an ECOG performance status of 0 or 1, were on ongoing androgen deprivation therapy, and had a Brief Pain Inventory–Short Form question 3 score below 4.

The trial enrolled patients in two cohorts: cohort 1 comprised an unselected population (n = 805), with patients randomized 1:1 regardless of HRR status; and cohort 2 enrolled patients with confirmed HRR-deficient disease (n = 399), defined by alteration in at least one of 11 eligible HRR genes (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C) assessed using FoundationOne CDx or FoundationOne Liquid CDx assays. All patients underwent prospective genomic testing.

The trial met its primary end point of rPFS by BICR in both cohorts, and final results demonstrated a statistically significant OS benefit with talazoparib plus enzalutamide in both the unselected and HRR-deficient populations.^1,2

For this analysis, the primary end point was rPFS assessed per PCWG3 guidelines by BICR, defined as time from randomization to first radiographic disease progression in soft tissue per RECIST 1.1 or in bone, or death, whichever occurred first. The α-protected key secondary end point was OS, defined as the time from randomization to death from any cause.

Correlations between BICR- and investigator-assessed rPFS and OS were calculated using the following three complementary statistical methods:

• Spearman ρ via Clayton copula
• Kendall τ via Clayton copula
• Kendall τ from frailty variance.

Agarwal noted that the frailty model τ was specifically included to account for censoring and time-to-event dynamics not captured by the rank-based methods. Correlation coefficients were prespecified as weak (< 0.4), moderate (0.4–0.7), or strong (> 0.7). Analyses were conducted both in combined treatment arms and separately within each individual arm across six populations of interest: unselected, HRR deficient, HRR nondeficient/unknown, BRCA murated, BRCA nondeficient/unknown, and patients with or without prior taxane or androgen receptor pathway inhibitor (ARPI) exposure.

Correlation Results Across Biomarker-Defined Cohorts and Treatment Arms

In the unselected cohort 1, BICR-assessed rPFS demonstrated consistently strong correlations with OS across all three models: Spearman ρ of 0.812 (combined), 0.842 (talazoparib plus enzalutamide arm; n = 402), and 0.779 (placebo plus enzalutamide arm; n = 403); Kendall τ via Clayton copula of 0.627, 0.661, and 0.593, respectively; and Kendall τ from frailty variance of 0.757, 0.776, and 0.720, respectively.

In the HRR-deficient cohort 2, BICR-assessed Spearman ρ values were 0.752 (combined), 0.803 (talazoparib plus enzalutamide; n = 200), and 0.714 (placebo plus enzalutamide; n = 199). In the BRCA-mutated population (n = 155)—defined as patients with BRCA1 or BRCA2 alterations, or BRCA co-occurring with other gene mutations from cohort 2—BICR Spearman ρ values were 0.724 (combined), 0.836 (talazoparib plus enzalutamide; n = 71), and 0.649 (placebo plus enzalutamide; n = 84).

Investigator-assessed rPFS produced similar or marginally higher correlation coefficients across all three cohorts and arms. In the unselected cohort, investigator Spearman ρ reached 0.823 (combined), 0.849 (talazoparib plus enzalutamide), and 0.794 (placebo plus enzalutamide).

In HRR- and BRCA-nondeficient/unknown subgroups, rPFS by both BICR and investigator assessment showed moderate-to-strong correlation with OS across all models and regardless of treatment arm. Moderate-to-strong positive correlations were also observed across subgroups stratified by prior taxane or ARPI exposure (range, 0.434–0.844). The only weak correlation identified in the analysis was a BICR Kendall τ via Clayton copula of 0.365 in the placebo plus enzalutamide arm of the BRCA-mutated subgroup—a finding Agarwal noted did not alter the overall conclusion, given the consistency of results across all other subgroups.

“In TALAPRO-2, rPFS showed a consistently positive, moderate-to-strong correlation with OS across unselected, HRR-deficient, and BRCA-mutated populations across three different statistical methods,” Agarwal said. “These results are consistently observed across the groups.”

Clinical and Regulatory Significance of Establishing rPFS as a Surrogate End Point in First-Line mCRPC

Agarwal emphasized that establishing rPFS as a valid surrogate for OS carries direct implications for drug development in first-line mCRPC, as rPFS events occur earlier than OS events and could support regulatory approvals without requiring full survival maturation.

He also noted in his presentation that prostate-specific membrane antigen PET imaging was not used in TALAPRO-2, and that all prospective genomic testing was conducted at enrollment, enabling the first patient-level correlation analysis for a PARP inhibitor, inclusive of biomarker-defined subgroups in this setting.

Investigators concluded that the findings provide new evidence validating the rPFS–OS relationship across clinically relevant populations in a contemporary treatment landscape in which standard-of-care treatment includes androgen receptor pathway inhibition.

DISCLOSURES: Agarwal reported consulting/advisory roles with Pfizer, EVERSANA, and other companies with commercial interests in prostate cancer therapies. Full disclosures were not detailed in the presentation.

REFERENCES

1. Agarwal N, Paganelli S, Wang D, et al. Radiographic progression-free survival as a meaningful endpoint in metastatic castration-resistant prostate cancer (mCRPC): The TALAPRO-2 randomized clinical trial. Presented at: 2026 American Urological Association Annual Meeting; May 15-18, 2026; Washington, DC. Abstract PD23-06.

2. Agarwal N, Azad AA, Carles J, et al. Talazoparib plus enzalutamide in men with metastatic castration-resistant prostate cancer: final overall survival results from the randomised, placebo-controlled, phase 3 TALAPRO-2 trial. Lancet. 2025 Aug 2;406(10502):447-460. doi:10.1016/S0140-6736(25)00684-1

3. Fizazi K, Azad AA, Matsubara N, et al. Talazoparib plus enzalutamide in men with HRR-deficient metastatic castration-resistant prostate cancer: final overall survival results from the randomised, placebo-controlled, phase 3 TALAPRO-2 trial. Lancet. 2025 Aug 2;406(10502):461-474. doi:10.1016/S0140-6736(25)00683-X