Exploration of tumor genomics associated with prolonged benefit from or resistance to talazoparib monotherapy in patients with metastatic castration-resistant prostate cancer

Background Poly(ADP-ribose) polymerase (PARP) inhibition is synthetically lethal in cells with deleterious alterations in DNA damage response genes involved in homologous recombination repair (HRR). Alterations in HRR genes, including BRCA1/2 , have been identified in ~25% of prostate cancer samples and linked with worse clinical outcomes. We explored relationships between tumor genetics and prolonged benefit with talazoparib in TALAPRO-1. Methods The phase II TALAPRO-1 trial evaluated talazoparib monotherapy in pretreated patients with metastatic castration-resistant prostate cancer with HRR gene alterations. Tumor genetics were retrospectively assessed in subgroups in the efficacy population (n = 104) based on radiographic progression-free survival (rPFS: ≥12 months; ≥2 to <12 months; <2 months). Serial circulating tumor DNA samples from weeks 1, 9, and 25 and the safety follow-up visit (SFUV) were assessed for emergent changes in mutational profiles using FoundationOne®Liquid CDx. Results Among 16 patients with rPFS ≥12 months, 15 (94%) exhibited tumor BRCA2 alterations vs. 6/27 (22%) patients with rPFS <2 months ( p < 0.00001). HRR gene reversions predicted to restore HRR gene function were detected in 7/27 patients ( BRCA1 [n = 1], BRCA2 [n = 5], PALB2 [n = 1]) evaluable for emergent variants at week 25 and/or the SFUV. Emergent PARP1 variants predicted to truncate PARP1 and/or inhibit talazoparib binding were evident in 5/27 evaluable patients. Conclusion: Patients experiencing prolonged benefit typically exhibited tumor BRCA2 copy number loss. Reversion mutations of HRR genes and emergent PARP1 variants likely reflect selective pressure to escape talazoparib synthetic lethality and/or PARP trapping. ClinicalTrials.gov identifier NCT03148795