The phase 2 ZZFIRST trial met its primary PSA response end point with enzalutamide plus talazoparib in high-volume mHSPC, though the triplet showed added toxicity.
The combination of enzalutamide (Xtandi) and talazoparib (Talzenna) added to androgen deprivation therapy (ADT) produced a 12-month PSA response rate of 73.0% (95% CI, 55.9%-86.2%) in patients with high-volume metastatic hormone-sensitive prostate cancer (mHSPC), meeting the trial's pre-specified efficacy threshold (P < .001), according to final results from the investigator-initiated phase 2 ZZFIRST trial (NCT04332744) presented at the 2026 ASCO Annual Meeting.¹
Although the 73.0% PSA response rate with the triplet numerically exceeded the 64.7% rate seen with enzalutamide plus ADT alone, the between-arm difference was not statistically significant (P = .5402). After a median follow-up of 3.6 years, radiographic progression-free survival (PFS) favored the triplet numerically (median, 45.3 vs 31.1 months; HR, 0.62; 95% CI, 0.28-1.37; P = .2332), as did PSA PFS (HR, 0.46; 95% CI, 0.21-1.04; P = .0560; stratified HR, 0.44; 95% CI, 0.20-1.00; P = .0441).
ZZFIRST is a randomized, open-label, investigator-initiated phase 2 trial conducted across 8 sites in Spain. Eligible patients were men 18 years or older with histologically confirmed prostate adenocarcinoma (small cell and neuroendocrine histology excluded) and high-volume metastatic disease by CHAARTED criteria, with no prior systemic therapy for metastatic disease other than ADT initiated up to 28 days before cycle 1.1,2
All 54 enrolled patients received a 2-cycle (56-day) lead-in of enzalutamide plus ADT, with baseline and on-treatment tumor biopsies collected, before 2:1 randomization stratified by HRR mutation status to talazoparib 0.5 mg once daily plus enzalutamide 160 mg once daily plus ADT (n = 37) or enzalutamide 160 mg once daily plus ADT (n = 17), continued until radiographic progression or toxicity. Baseline HRR gene alterations were present in 13.5% of the triplet arm and 11.8% of the control arm; most patients (81.1% and 76.5%, respectively) were HRR wild-type.1
In the HRR wild-type subgroup (n = 43), PSA PFS favored the triplet (HR, 0.37; 95% CI, 0.15-0.92; P = .0257), while radiographic PFS did not reach significance (HR, 0.68; 95% CI, 0.28-1.62; P = .3767).
Paired baseline and on-treatment biopsies showed that enzalutamide-based AR inhibition upregulated inflammatory and epithelial-mesenchymal transition signatures while suppressing AR signaling and proliferation-associated gene sets. However, RAD51 and γH2AX immunofluorescence did not show a consistent on-treatment increase.
All patients in both arms experienced at least 1 treatment-emergent adverse event (TEAE). Grade 3 or higher TEAEs occurred in 67.6% of patients on the triplet vs 35.3% on enzalutamide plus ADT alone. Hematologic toxicity was more common with talazoparib: anemia of any grade occurred in 67.6% (grade ≥3, 40.5%) vs 0%, and neutropenia occurred in 32.4% (grade ≥3, 8.1%) vs 5.9%. Fatigue (83.8% vs 58.8%) and pulmonary embolism (8.1% vs 0%) were also more frequent with the triplet.
Talazoparib-related dose reductions occurred in 37.8% of triplet-arm patients, and 32.4% permanently discontinued talazoparib because of TEAEs. Two deaths (5.4%) related to treatment occurred in the triplet arm, both from myelodysplastic syndrome/acute myeloid leukemia; both patients had predisposing factors, including clonal hematopoiesis and germline mutations. No treatment-related deaths occurred in the control arm.
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