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.

GOV IDENTIFIER: NCT03148795.