ZZ-FIRST Trial: Adding Talazoparib to Enzalutamide Shows No Clear Additional Benefit in Metastatic Prostate Cancer

A randomised phase 2 trial published in Nature Medicine has investigated whether adding the PARP inhibitor talazoparib to enzalutamide and androgen deprivation therapy (ADT) can improve outcomes in men with high-volume metastatic hormone-sensitive prostate cancer (mHSPC), regardless of their homologous recombination repair (HRR) mutation status.

The study, known as ZZ-FIRST enrolled 54 patients across eight centres in Spain. After two months of initial treatment with enzalutamide and ADT, participants were randomised to continue enzalutamide alone (17 patients) or receive enzalutamide plus talazoparib (37 patients), with ADT maintained in both groups.

The trial met its predefined primary endpoint, with 73% of patients receiving the combination achieving a PSA below 0.2 ng/mL at 12 months, exceeding the prespecified efficacy threshold. However, 64.7% of patients receiving enzalutamide alone achieved the same result, and the difference between groups was not statistically significant.

After a median follow-up of 3.6 years, median radiographic progression-free survival was 45.3 months with the combination versus 31.1 months with enzalutamide alone (HR 0.62). Time to castration resistance was also numerically longer with the combination, at 30.4 versus 22.8 months. However, these exploratory comparisons did not establish a statistically significant improvement, and no overall survival advantage was demonstrated.

Grade 3 or higher adverse events occurred in 68% of patients receiving the combination, compared with 35% in the control group. Severe anaemia affected approximately 41% of patients receiving talazoparib. Two patients in the combination group developed fatal therapy-emergent myeloid malignancies after prolonged exposure; both had underlying genetic alterations associated with susceptibility to these conditions.

Beyond the clinical results, the study provides an important insight into the relationship between androgen receptor inhibition and DNA repair. One hypothesis supporting combinations of androgen receptor pathway inhibitors (ARPIs) and PARP inhibitors is that suppressing androgen signalling might induce a BRCA-like state, often described as induced BRCAness, even in tumours without inherited or acquired HRR defects. Such a change could theoretically make these tumours more sensitive to PARP inhibition.

Analysis of tumour biopsies confirmed that enzalutamide reduced the expression of several genes involved in DNA repair. However, the investigators found that these changes closely followed the suppression of cell proliferation. Functional analyses using RAD51, a marker of homologous recombination activity, and γH2AX, a marker of DNA damage, did not reveal convincing evidence of impaired homologous recombination repair following hormonal treatment. Similar findings were observed in an independent cohort of patients treated with ADT.

This distinction is important: reduced expression of DNA repair genes does not necessarily mean that cancer cells have lost their ability to repair DNA. The findings therefore challenge the hypothesis that androgen receptor inhibition consistently induces a therapeutically exploitable BRCA-like deficiency in otherwise HRR-proficient prostate tumours.

The functional analyses were limited by the small number of evaluable on-treatment biopsies, particularly for RAD51, and cannot exclude such effects in every biological or clinical setting.

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