Talazoparib Monotherapy in Metastatic Castration-resistant Prostate Cancer with DNA Damage Response Alterations-Genomic Features Associated with Response to Therapy.

BACKGROUND AND

OBJECTIVE

The impact of alterations beyond DNA damage response-homologous recombination repair (DDR-HRR) genes on outcomes with poly(ADP-ribose) polymerase inhibitor monotherapy remains unknown. This study aims to explore the impact of genomic features and co-occurring alterations on treatment outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) and DDR-HRR alterations in TALAPRO-1.

METHODS

TALAPRO-1 evaluated talazoparib monotherapy in heavily pretreated patients with mCRPC and DDR-HRR alterations. We used tumor and saliva alteration results, and somatic-germline-zygosity prediction to assess genomic alterations.

KEY FINDINGS AND LIMITATIONS: Associations between antitumor activity and gene alteration origin, selected non-DDR-HRR gene alteration status, tumor mutational burden, and genomic loss of heterozygosity (gLOH) were explored. Objective response rates (ORRs) and median overall survival (OS) with 95% confidence intervals (Clopper-Pearson method) and p values (two-sided Fisher's exact test) were calculated. Commonly altered non-DDR-HRR genes included TMPRSS2, TP53, PTEN, androgen receptor (AR), MYC, and SPOP. ORRs were 30.0% and 34.5% in men with TP53 and PTEN alterations, respectively, and 28.6% and 26.8% in men without TP53 or PTEN alterations, respectively. In tumors bearing ATM alterations, ORR was greater in those with (two of four) versus without PTEN alterations (zero of 13; p = 0.044). ORR was significantly higher for gLOH-high than for gLOH-low patients (53.3% vs 12.0%; p = 0.0017). The median OS for gLOH-high patients was 23.7 mo versus 18.7 mo for gLOH-low patients (hazard ratio 0.92, 95% confidence interval 0.52-1.64). Our analyses are retrospective and limited by small subgroup sizes.

CONCLUSIONS AND CLINICAL IMPLICATIONS: In men with mCRPC, high gLOH status was associated with enhanced responses to talazoparib.