Talazoparib plus enzalutamide improves rPFS regardless of AR alteration status in mCRPC

In patients with metastatic castration-resistant prostate cancer (mCRPC), regardless of androgen receptor (AR) Regardless of altered or amplified status, talazoparib combined with enzalutamide/Enzalutamide significantly improved radiographic progression-free survival (rPFS) compared with placebo combined with enzalutamide.

AR genomic alterations are associated with resistance to androgen deprivation therapy [ADT] and AR pathway inhibitors [ARPI] such as enzalutamide. In TALAPRO-2, talazoparib plus enzalutamide improved rPFS compared with placebo plus enzalutamide in patients with altered AR, findings consistent with therapeutic development of cross-talk between AR and DNA repair pathways.

Patients with AR changes had a median rPFS of 16.6 months (95% CI, 11 .1-22.0), compared with a median rPFS of 11.0 months with placebo (n=106; HR, 0.66; 95% CI, 0.46-0.93; P=0.0193). Patients without altered AR achieved unreached median rPFS (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=0.0015) with talazoparib and placebo, respectively.在两个治疗组中，总体AR改变状态与rPFS显著缩短有关[P＜0.0001]。

TALAPRO-2 is a phase 3 trial comparing talazoparib plus enzalutamide (n=402) versus placebo plus enzalutamide (n=403) in people with mCRPC. To be eligible, patients needed to have an ECOG performance status of 0 or 1 and be undergoing ADT. In the unselected patient cohort (n = 805; cohort 1), 636 patients had nonhomologous recombination repair (HRR) deficiency/unknown status and 169 patients had HRR gene mutations. Cohort 2 included 399 patients with only HRR gene mutations, including ATM, ATR, BRCA1/2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C.

The primary endpoint was rPFS by blinded independent central review (BICR). Secondary endpoints include overall survival (OS), time to cytotoxic chemotherapy, time to second progression or death, objective response rate, patient-reported outcomes and safety. Results from the third and final data cutoff in September 2024 showed that compared with placebo plus enzalutamide, tazopanib plus enzalutamide resulted in significantly improved PFS and OS. There is preclinical evidence that the combination of a PARP inhibitor and an ARPI may be effective in mCRPC patients without HRR gene alterations

For analysis, researchers retrospectively evaluated prospectively collected plasma circulating tumor DNA (ctDNA) usingFoundationOne's liquid CDx assay. A total of 681 informative test records from the safety population of the TALAPRO-2 unselected cohort were included. The remaining 108 patients could not be assessed by testing (n=52) or lacked testing records/samples (n=66). Variants were characterized as known or possible pathogenic variants, including short variants (single nucleotide variants, insertions, deletions) and amplifications. rPFS was assessed according to BICR.

Other findings showed that the median rPFS for patients with AR amplification was 13.9 months (95% CI, 11.0-18.5) in the talazoparib group (n=69) and 11.0 months in the placebo group (n=72; HR, 0.63; 95% CI, 0.40-0.97; P=0.0378). In patients without AR amplification, median rPFS was NR (95% CI, 33.1-NR) with tazopanib (n=267) and 26.1 months with placebo (n=273) (95% CI: 22.5-NR; HR: 0.67; 95% CI: 0.51-0.88; P=0.0036). AR amplification was associated with significantly shorter rPFS in both treatment groups [P<.0001]. .

Regardless ofAR short variant status, rPFS also improved numerically in the talazoparib group, although the results were not statistically significant. Among patients with the short variant, median rPFS was 20.0 months (95% CI, 11.0-NR) in the talazoparib group (n=62) and 11.1 months (95% CI, 8.3-NR) in the placebo group (n=46; HR, 0.80; 95% CI, 0.47-1.37; P=0.4181). In patients without short variants, median rPFS was NR (95% CI, 27.9-NR) for talazoparib (n=274) and 22.5 months for placebo (n=299) (95% CI, 19.3-27.4; HR, 0.64; 95% CI 0.49-0.82; P=0.0006).

The AR short variant was also associated with significantly shortened rPFS in the tazopanib plus enzalutamide group [P=0.0077], and a similar pattern was observed in the placebo plus enzalutamide group [P=0.110]. This retrospective exploratory analysis was used for hypothesis generation only. AR splice variant transcripts were not characterized, and some patients had low ctDNA levels, which may limit detection sensitivity.

References:https://www.onclive.com/view/talazoparib-plus-enzalutamide-improves-rpfs-regardless-of-ar-alteration-status-in-mcrpc