Talazoparib Plus Enzalutamide Improves rPFS Regardless of AR Alteration Status in mCRPC

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The combination of talazoparib (Talzenna) plus enzalutamide (Xtandi) significantly improved radiographic progression-free survival (rPFS) vs placebo plus enzalutamide irrespective of androgen receptor (AR) alteration or amplification status in patients with metastatic castration-resistant prostate cancer (mCRPC), according to findings from a post hoc analysis of the phase 3 TALAPRO-2 trial (NCT03395197) presented at the 2025 AACR Annual Meeting.1

“AR genomic alterations have been implicated in resistance to androgen deprivation therapy [ADT] and AR pathway inhibitors [ARPIs] such as enzalutamide. In TALAPRO-2, talazoparib plus enzalutamide improved rPFS vs placebo plus enzalutamide in patients with or without AR alterations,” Glenn Liu, MD, lead study author and professor of hematology, medical oncology and palliative care in the Department of Medicine at the University of Wisconsin School of Medicine and Public Health in Madison, said. “These findings were consistent with therapeutic exploitation of crosstalk between AR and DNA repair pathways,” Li added.

Patients with an AR alteration experienced a median rPFS of 16.6 months (95% CI, 11.1-22.0) with talazoparib (n = 121) vs 11.0 months (95% CI, 10.4-16.4) with placebo (n = 106; HR, 0.66; 95% CI, 0.46-0.93; P = .0193). Patients without an AR alteration achieved a median rPFS with talazoparib and placebo, respectively, that was not reached (NR; 95% CI, 33.1-NR) and 27.4 months (95% CI, 23.3-NR; HR, 0.60; 95% CI, 0.44-0.82; P = .0015). “Within both treatment arms, overall AR alteration status was associated with significantly shorter rPFS [P < .0001],” Liu said.

Background and Previous Trial Findings

TALAPRO-2 is a phase 3 trial that compared talazoparib plus enzalutamide (n = 402) with placebo plus enzalutamide (n = 403) in an all-comer population with mCRPC. To be eligible, patients needed to have an ECOG performance status of 0 or 1 and ongoing ADT. Within the unselected cohort of patients (n = 805; cohort 1), 636 had non–homologous recombination repair (HRR) deficient/unknown status, and 169 had HRR gene mutations. Cohort 2 included 399 patients with only HRR gene mutations, including those in ATM, ATR, BRCA1/2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C.

The primary end point was rPFS by blinded independent central review (BICR). Secondary end points included overall survival (OS), time to cytotoxic chemotherapy, time to second progression or death, objective response rate, patient-reported outcomes, and safety.

Findings from the third and last data cutoff of September 3, 2024, demonstrated a significant improvement in both rPFS and OS with talazoparib plus enzalutamide vs placebo plus enzalutamide.2 The median rPFS was 33.1 months (95% CI, 27.4-39.0) with talazoparib vs 19.5 months (95% CI, 16.6-24.7) with placebo (HR, 0.667; 95% CI, 0.551-0.807; P < .0001). The median OS was 45.8 months (95% CI, 39.4-50.8) and 37.0 months (95% CI, 34.1-40.4) with talazoparib and placebo, respectively (HR, 0.796; 95% CI, 0.661-0.958; P = .0155).

The FDA granted approval to the combination in June 2023, for the treatment of patients with HRR gene-mutated mCRPC based on TALAPRO-2 findings demonstrating improved rPFS in this subset (HR, 0.45; 95% CI, 0.33-0.61; P < .0001).3

However, there is preclinical evidence that suggests that the combination of a PARP inhibitor and an ARPI may be effective in patients with mCRPC without HRR gene alterations.1

With respect to the AR, Liu explained, “There are several different classes of these alterations, including copy number amplification of the gene body and/or upstream enhancer, intragenic structural rearrangements, and ligand-binding domain [LBD] hotspot alterations. Such alterations can upregulate AR protein levels [via amplification] or qualitatively alter AR function e.g. with production of constitutively activated AR variants [via structural rearrangements], or LBD alterations that enable activation of the AR by AR agonists or endogenous steroids, including estrogen and glucocorticoids,” Liu explained.

As such, investigators sought to evaluate the frequency of AR alterations and their potential association with treatment outcomes with talazoparib and enzalutamide.

Post Hoc Analysis Methods and Additional Data

To perform the analysis, investigators retrospectively evaluated plasma circulating tumor DNA (ctDNA) that had been prospectively collected using FoundationOne’s Liquid CDx assay. A total of 681 informative test records from the safety population of the unselected cohort from TALAPRO-2 were included. The remaining 108 patients were not evaluable by the assay (n = 52) or lacked test records/samples (n = 66).

Alterations were characterized as known or likely pathogenic variants, which included short variant alterations (single nucleotide variant, insertions, deletions), and amplifications. rPFS was evaluated according to BICR. The data cutoff was August 16, 2022.

Additional findings indicated that the median rPFS in patients with an AR amplification was 13.9 months (95% CI, 11.0-18.5) in the talazoparib arm (n = 69) vs 11.0 months (95% CI, 6.8-16.4) in the placebo arm (n = 72; HR, 0.63; 95% CI, 0.40-0.97; P = .0378). In patients without an AR amplification, the median rPFS with talazoparib (n = 267) and placebo (n = 273), respectively, was NR (95% CI, 33.1-NR) and 26.1 months (95% CI, 22.5-NR; HR, 0.67; 95% CI, 0.51-0.88; P = .0036). “Within both treatment arms, AR amplifications were associated with significantly shorter rPFS [P < .0001],” Liu said.

rPFS was also numerically improved in the talazoparib arm irrespective of AR short variant status, although the results were not statistically significant. In patients with a short variant, the median rPFS with 20.0 months (95% CI, 11.0-NR) with talazoparib (n = 62) vs 11.1 months (95% CI, 8.3-NR) with placebo (n = 46; HR, 0.80; 95% CI, 0.47-1.37; P =.4181). In patients without a short variant, the median rPFS with talazoparib (n = 274) and placebo (n = 299), respectively, was NR (95% CI, 27.9-NR) and 22.5 months (95% CI, 19.3-27.4; HR, 0.64; 95% CI, 0.49-0.82; P =.0006).

“Within the talazoparib plus enzalutamide arm, AR short variants were also associated with significantly shorter rPFS [P = .0077] with a similar pattern observed across the placebo plus enzalutamide arm [P = .110],” Liu stated.

Liu noted several limitations of the study, stating, “This retrospective exploratory analysis is intended for hypothesis generation only. AR splice variant transcripts were not characterized, and some patients had low levels of ctDNA, potentially limiting test sensitivity.”

Disclosures: Dr Liu disclosed institutional research funding from Bayer, Janssen, Pfizer, and Sanofi; and serving as co-founder and CMO of AIQ Solutions.

References

1. Liu G, Laird D, Agarwal N, et al. Exploring androgen receptor alterations and their potential association with efficacy of first-line talazoparib + enzalutamide in metastatic castration-resistant prostate cancer: a post hoc analysis of TALAPRO-2. Presented at: 2025 AACR Annual Meeting; April 25-30, 2025; Chicago, IL. LB089.
2. Agarwal N, Azad A, Carles J, et al. Final overall survival (OS) with talazoparib (TALA) + enzalutamide (ENZA) as first-line treatment in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial. J Clin Oncol. 2025;43(suppl 5):LBA18. doi:10.1200/JCO.2025.43.5_suppl.LBA1
3. FDA approves talazoparib with enzalutamide for HRR gene-mutated metastatic castration-resistant prostate cancer. FDA. June 20, 2023. Accessed April 27, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-enzalutamide-hrr-gene-mutated-metastatic-castration-resistant-prostate