Enzalutamide plus talazoparib demonstrates clinical activity in mHSPC

Combination treatment with enzalutamide (Xtandi) and the PARP inhibitor talazoparib (Talzenna) showed encouraging clinical activity in patients with high-volume metastatic hormone-sensitive prostate cancer (mHSPC), although the regimen also demonstrated a notable toxicity burden, according to results from the phase 2 ZZFIRST trial (NCT04332744).¹

The findings were presented by Joaquin Mateo, MD, PhD, at the 2026 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois.

“Treatment intensification with AR pathway inhibitors is now a standard of care in mHSPC,” Mateo explained. “However, there is significant interpatient variability in outcomes, and despite treatment intensification, high volume disease still represents a subset of patients with aggressive biology and an unmet medical need.”

About the ZZFIRST trial

ZZFIRST is an investigator-initiated phase 2 trial that enrolled men with high-volume mHSPC, regardless of homologous recombination repair (HRR) mutation status. Patients initially received a 2-month lead-in period with androgen deprivation therapy (ADT) plus enzalutamide. Paired tumor biopsies were obtained during this interval to characterize biologic changes induced by AR inhibition. Participants were then randomly assigned in a 2:1 fashion to receive ADT plus enzalutamide and talazoparib (n = 37) or ADT plus enzalutamide alone (n = 17).

A total of 54 patients underwent randomization and received at least 1 dose of assigned therapy. Baseline characteristics were generally balanced, although a greater proportion of patients with visceral metastases were assigned to the experimental arm (48.6% vs 29.4%, respectively). Genomic profiling was successfully performed in 50 patients.

The primary end point was achievement of a prostate-specific antigen (PSA) nadir below 0.2 ng/mL by month 12, benchmarked against an historical control of patients with high volume mHSPC. The comparison between the 2 treatment arms was considered exploratory per the study design. Secondary end points included PSA progression-free survival (PFS), radiographic PFS (rPFS), and safety.

Efficacy data

The primary end point was met, with the experimental arm exceeding the predefined benchmark derived from historical controls (P < .001). In the study, 73.0% (95% CI, 55.9 to 86.2) of patients in the enzalutamide + talazoparib + ADT arm achieved a 12-month PSA less than 0.2 ng/mL vs 64.7% (95% CI, 38.2 to 85.8) among those who received enzalutamide + ADT alone (P = .5402).

There was a trend toward benefit with the intervention arm regarding the 2 secondary end points of radiographic PFS (rPFS) and PSA PFS, though neither met the threshold for statistical significance at a median follow-up of 3.6 years. The median rPFS was 45.3 months in the intervention arm vs 31.1 months in the control arm (HR, 0.62; 95% CI, 0.28 to 1.37; P = .2332). Similarly, the median PSA PFS was not reached in the intervention arm vs 30.7 months in the control arm (HR, 0.46; 95% CI, 0.21 to 1.04; P = .0560).

These trends were consistent in patients with HRR wild-type mutations (n = 43), with a HR of 0.68 for rPFS (95% CI, 0.28 to 1.62; P = .3767) and 0.37 for PSA PFS (95% CI, 0.15 to 0.92; P = .0257).

Safety profile

Safety findings raised concerns regarding tolerability. In the treatment arm, 37.8% of patients required dose reductions of talazoparib and 8.1% required dose reductions of enzalutamide due to treatment-emergent adverse events (TEAEs). Twelve percent of patients required reductions due to TEAEs in the control arm. Further, 32% of patients in the treatment arm permanently discontinued the talazoparib because of adverse events, predominantly anemia.

Higher rates of fatigue (83.8% vs 58.8%), anemia (67.6% vs 0%) neutropenia (32.4% vs 5.9%), and pulmonary embolism (8.1% vs 0%) were also observed in the experimental arm. Investigators reported 2 cases of secondary myeloid neoplasms after 3 to 4 years of talazoparib exposure, both with predisposing factors.

Transcriptomic analysis

One of the distinctive aspects of the study involved serial tumor biopsies aimed at determining whether AR inhibition creates an HR-deficient state, a hypothesis derived largely from preclinical studies. Transcriptomic analyses (n = 34) showed suppression of AR signaling and DNA repair signatures, accompanied by increased inflammatory and epithelial-mesenchymal transition signatures. However, functional assessments using RAD51 assays did not demonstrate impaired homologous recombination activity. Similar findings were reproduced in an independent neoadjuvant cohort.

The findings could have implications for understanding the mechanism underlying AR-PARP inhibitor combinations and may help refine biomarker-driven approaches.

Limitations and conclusions

Mateo acknowledged several limitations, including the small sample size and limited number of patients with HRR-mutated tumors. However, he noted that the objective of the study was not to compare the effect in that population, as that was assessed in the phase 3 TALAPRO-3 trial.

Related: TALAPRO-3: Talazoparib plus enzalutamide improves rPFS in HRR gene-altered mCSPC

In addition, obtaining paired metastatic biopsies proved challenging, reducing the number of evaluable specimens for some translational analyses. He also acknowledged that the lead-in treatment phase with enzalutamide alone differs from what has been done in prior trials combining AR and PARP inhibitors.

“We observed signs of clinical activity for enzalutamide and talazoparib in high volume mHSPC, but with increased toxicity,” Mateo concluded during the presentation. “The study of pair biopsies show us that AR inhibition results in transcriptomic reprogramming, but not in HR deficiency. Biology and biomarkers should inform the development and use of AR-PARP combinations in clinical practice to maximize benefit-risk for our patients.”

REFERENCE

1. Mateo J, Castro E, Zacchi F, et al. Final results from ZZFIRST: A randomized phase 2 trial of enzalutamide (EZ) and talazoparib (TALA) in metastatic hormone-naïve prostate cancer (mHNPC). J Clin Oncol. 44, 2026 (suppl 16; abstr 5006). doi:10.1200/JCO.2026.44.16_suppl.5006