Why This Study Matters
In metastatic hormone-naive prostate cancer (mHNPC), intensifying androgen deprivation therapy (ADT) with androgen receptor pathway inhibitors has improved outcomes, yet patients with high-volume disease have the poorest prognosis, leaving a persistent unmet need. PARP inhibitors combined with AR pathway inhibitors have shown activity in metastatic castration-resistant disease, and the authors cite PROpel, MAGNITUDE and TALAPRO-2. ZZ-FIRST asked whether adding the PARP inhibitor talazoparib to enzalutamide helps in the hormone-naive, high-volume setting, including in tumors without homologous recombination repair (HRR) gene alterations, and used paired tumor biopsies to study how AR inhibition reshapes tumor biology.
Study Design
ZZ-FIRST is a multicenter, open-label, randomized, two-arm, investigator-initiated phase 2 trial run at eight sites in Spain. All patients started enzalutamide (160 mg once daily) plus ADT. After two 28-day cycles they were randomized 1:2 to continue enzalutamide plus ADT (control) or to add talazoparib (0.5 mg once daily) to enzalutamide plus ADT (interventional). Randomization was stratified by HRR gene alteration status on the baseline tumor biopsy. The lead-in allowed on-treatment biopsies after about 4 weeks of AR pathway inhibition and before talazoparib exposure.
65 patients screened and 54 enrolled (83.1%); 17 control and 37 interventional patients (1:2 randomization); 8 sites in Spain; median follow-up 3.6 years (data cutoff 6 May 2025); enzalutamide 160 mg and talazoparib 0.5 mg daily.
Primary endpoint: 12-month confirmed PSA <0.2 ng/ml response rate from randomization. Secondary endpoints included radiographic progression-free survival (rPFS), PSA-PFS, time to castration resistance (TTCR), overall survival (OS) and safety. The trial was sponsored by Medica Scientia Innovation Research (MEDSIR) with Pfizer grants and drug supply and Astellas Pharma drug supply.
Patient Population
Enrollment ran from 14 October 2020 to 10 May 2022. Median age was 68 years (range 47–86) in the interventional arm and 69 years (range 55–82) in the control arm. Most patients had de novo metastatic disease (97.3% and 88.2%) and ECOG performance status 0 (59.5% and 76.5%); Gleason grade group 5 was present in 67.6% and 70.5%. Median baseline PSA was 159.2 ng/ml (range 0.7–2,390) in the interventional arm and 164.9 ng/ml (range 8.8–7,700) in the control arm. Visceral metastases were more frequent in the interventional arm (48.6% vs 29.4%). Baseline sequencing succeeded in 50 of 54 patients; HRR gene alterations were found in seven (14%), including BRCA2 (8%; n = 4) and BRCA1 (4%; n = 2).
Primary Endpoint and Efficacy Results
| Endpoint | Talazoparib + enzalutamide (n = 37) | Enzalutamide (n = 17) | Comparison |
|---|---|---|---|
| 12-month PSA <0.2 ng/ml (primary) | 73.0% (27/37); 95% CI 55.9–86.2 | 64.7% (11/17); 95% CI 38.3–85.8 | P < 0.001 vs 40% threshold (combination); P = 0.54 between arms (post hoc, Fisher) |
| 7-month PSA <0.2 ng/ml | 59.5% | 52.9% | Not tested in text |
| Median rPFS | 45.3 mo (95% CI 29.4–NA) | 31.1 mo (95% CI 13.5–NA) | HR 0.64 (95% CI 0.28–1.42); P = 0.2652 |
| Median PSA-PFS | NA (95% CI 30.4–NA) | 30.7 mo (95% CI 6.6–NA) | HR 0.44 (95% CI 0.20–1.00); P = 0.0441 |
| Median TTCR | 30.4 mo (95% CI 23.0–NA) | 22.8 mo (95% CI 6.3–45.4) | HR 0.59 (95% CI 0.29–1.22); P = 0.1503 |
| OS events | 15 (40.5%); median NA | 7 (41.2%); median NA | HR 1.04 (95% CI 0.42–2.56); P = 0.93 |
The hazard ratios are stratified by HRR mutational status. The authors note the primary-endpoint threshold proved conservative, since the control arm also exceeded the 40% efficacy threshold. Patients who achieved PSA <0.2 had longer rPFS (HR 3.26, 95% CI 1.47–7.24) and OS (HR 6.0, 95% CI 2.51–14.42), as reported in the paper’s Extended Data Fig. 1.
Moreover, secondary endpoint and subgroup analyses were not adjusted for multiplicity; therefore, nominal P values should be interpreted with caution.
— Quoted verbatim from the paper’s limitations paragraph.
Subgroup Analyses
All subgroup analyses were exploratory and small.
| Subgroup | Talazoparib + enzalutamide | Enzalutamide |
|---|---|---|
| HRR wild-type (n = 43): PSA <0.2 at 12 mo | 22/30 (73.3%) | 9/13 (69.2%) |
| HRR-mutated (n = 7): PSA <0.2 at 12 mo | 4/5 (80%) | 1/2 (50%) |
| TP53 wild-type: PSA <0.2 at 12 mo | 17/23 (73.9%) | 7/9 (77.8%) |
| TP53-altered: PSA <0.2 at 12 mo | 9/12 (75.0%) | 3/6 (50.0%) |
| HRR wild-type: median rPFS | 45.3 mo (95% CI 28.6–NA) | 31.1 mo (95% CI 13.5–50.7); HR 0.68 (95% CI 0.28–1.62), P = 0.38 |
| HRR wild-type: PSA-PFS | HR 0.37, P = 0.03 (CI printed in the paper as 0.15–9.92, which appears to be a typographical error in the source) | Between-arm hazard ratio; see previous column |
Among the four BRCA2-mutated patients on the combination, one stopped treatment for adverse events at 10 months, one progressed at 25 months, and two remained on treatment and progression-free at 44 and 52 months.
Safety Profile
| Adverse event | Combination, any grade | Combination, grade ≥3 | Control, any grade | Control, grade ≥3 |
|---|---|---|---|---|
| All TEAEs | 37 (100.0%) | 25 (67.6%) | 17 (100.0%) | 6 (35.3%) |
| Fatigue | 31 (83.8%) | 5 (13.5%) | 10 (58.8%) | 0 (0.0%) |
| Anemia | 25 (67.6%) | 15 (40.5%) | Not specified in source text | Not specified in source text |
| Neutropenia | 12 (32.4%) | 3 (8.1%) | Not specified in source text | Not specified in source text |
Talazoparib dose reductions, temporary interruptions and permanent discontinuations due to adverse events occurred in 14 (37.8%), 26 (70.3%) and 12 (32.4%) of 37 patients; anemia was the most common cause of permanent talazoparib discontinuation (5/37, 13.5%).
Fatal events. Two grade 5 events occurred, both in the combination arm. One death (hemophagocytic lymphohistiocytosis, after 31.2 months) was judged unrelated to study drugs after postmortem examination revealed an underlying T-cell lymphoma. The other occurred in a patient who developed acute myeloid leukemia (AML) after 32.8 months, considered related to talazoparib. A further patient developed AML after discontinuing for prolonged hematologic toxicity and died six months later. Neither AML patient had prior radiation or DNA-damaging agents. Clonal hematopoiesis-associated mutations were detected at baseline in 7 of 54 patients (13%); one AML patient carried DNMT3A p.Arg882Cys and the other a germline pathogenic FLT3 p.Tyr874Cys variant.
Interpretation and Broader Context
The authors conclude the combination showed clinical activity but "did not establish clear additional clinical benefit over enzalutamide alone in this biomarker-unselected population, while being associated with increased toxicity" (wording from the abstract). Paired biopsy analyses showed that AR inhibition suppressed proliferation- and HRR-related gene expression without clear loss of homologous recombination function (γH2AX and RAD51 assays), which they interpret as arguing against a broadly applicable synthetic-lethality rationale for ARPI–PARPi combinations in unselected patients.
Limitations
The authors list a small sample size, a conservative primary endpoint threshold, PSA <0.2 not being a validated surrogate, no multiplicity adjustment for secondary endpoint and subgroup analyses, and the enzalutamide lead-in design. The trial was open-label and randomized 1:2, leaving only 17 patients in the control arm, so the between-arm comparison of the primary endpoint was post hoc and its confidence intervals are wide. Visceral metastases were more frequent in the interventional arm (48.6% vs 29.4%). Subgroup analyses, including those in HRR-mutated patients (n = 7), were exploratory and small.