TALAPRO-2 Trial: Final Results Update For HRR Mutations (BRCA, ATM,…)

The TALAPRO-2 trial has revealed that combining talazoparib (TALA), a PARP inhibitor, with enzalutamide (ENZA), an androgen receptor inhibitor, significantly improves outcomes for men with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair mutations (HRRm).
The TALAPRO-2 trial previously demonstrated that TALA + ENZA improved radiographic progression-free survival (rPFS) and overall survival (OS) compared to ENZA with placebo (PBO) in HRRm-positive mCRPC patients. This latest analysis dives deeper, examining how specific HRR gene mutations influence the efficacy of this combination, providing insights into personalized treatment strategies.

The study randomized 399 HRRm-positive patients 1:1 to receive TALA (0.5 mg daily) plus ENZA (160 mg daily) or ENZA with placebo. HRRm status was determined using a 12-gene HRR panel (HRR12), tested via clinical assays (FoundationOne CDx and FoundationOne Liquid CDx), incorporating tumor and circulating tumor DNA (ctDNA) records. Patients with co-occurring BRCA1/2 mutations were excluded from non-BRCA analyses to isolate gene-specific effects. Efficacy endpoints included overall response rate (ORR), rPFS, and OS, assessed across key HRR gene subgroups: BRCA1, BRCA2, PALB2, CDK12, ATM, and CHEK2.
The results were compelling.
For all HRRm patients, TALA + ENZA outperformed ENZA + PBO across all endpoints: ORR was 69.4% versus 39.1% (odds ratio [OR] 0.28, 95% CI: 0.13–0.61), median rPFS was 30.7 versus 12.3 months (hazard ratio [HR] 0.47, 95% CI: 0.36–0.62), and median OS was 45.1 versus 30.8 months (HR 0.60, 95% CI: 0.46–0.78).

The benefits were most pronounced in patients with BRCA2 mutations, with an ORR of 86.4% versus 31.0% (OR 0.07, 95% CI: 0.01–0.35), rPFS not reached versus 10.9 months (HR 0.25, 95% CI: 0.15–0.42), and OS not reached versus 28.5 months (HR 0.47, 95% CI: 0.29–0.76).
Similar rPFS and OS benefits were observed for BRCA1 and PALB2 mutations, though small sample sizes (n=8 per arm) limited ORR assessments.


Patients with CDK12 mutations also benefited, with an ORR of 63.6% versus 22.2% (OR 0.16, 95% CI: 0.01–1.61), rPFS of 19.3 versus 13.8 months (HR 0.36, 95% CI: 0.19–0.70), and OS of 36.4 versus 22.8 months (HR 0.41, 95% CI: 0.23–0.74).

ATM mutations showed notable improvements with TALA + ENZA: ORR of 75.0% versus 33.3% (OR 0.17, 95% CI: 0.02–1.32), rPFS of 30.4 versus 18.3 months (HR 0.66, 95% CI: 0.37–1.18), and OS of 45.1 versus 39.5 months (HR 0.70, 95% CI: 0.38–1.29).

CHEK2 mutations had more modest benefits: ORR of 53.3% versus 42.9% (OR 0.66, 95% CI: 0.07–5.59), rPFS of 24.8 versus 18.3 months (HR 0.65, 95% CI: 0.34–1.22), and OS of 34.2 versus 39.5 months (HR 0.96, 95% CI: 0.51–1.81). The remaining six HRR12 genes couldn’t be meaningfully assessed due to low mutation prevalence.


The combination’s ability to target DNA repair-deficient tumors, particularly those with BRCA2 and CDK12 mutations, aligns with the mechanism of PARP inhibitors, which exploit DNA repair deficiencies to induce cancer cell death, enhanced by ENZA’s androgen receptor blockade.

The study’s strengths include its robust sample size (399 patients) and prospective HRRm testing, but it has limitations. Thesmall sample sizes for BRCA1 and PALB2 (n=8 per arm) limited ORR assessments, reducing statistical power.Additionally, theexploratory nature of the analysis means results are hypothesis-generating, requiring further validation in planned endpoint analyses.