TALAPRO-1: Talazoparib monotherapy in metastatic castration-resistant prostate cancer (mCRPC) with tumor DNA damage response alterations (DDRm)—Exploration of germline DDR alteration landscape and potential associations with antitumor activity.

Abstract

157 Background: TALAPRO-1 enrolled men with progressive mCRPC with measurable soft-tissue disease and tumor DDRm involved directly or indirectly in homologous recombination repair (HRR) (11 gene panel). These men had received 1–2 taxane chemotherapy and progressed on ≥1 novel hormonal therapy. The primary endpoint was objective response rate ([ORR] per RECIST 1.1; central review). Exploratory ad hoc biomarker analyses assessed germline DDR/HRR (gHRR) alteration landscape and associations with antitumor activity. Methods: Alterations were defined as known/likely pathogenic variants. gHRR alteration (gHRRm) frequency was assessed in the study population evaluable for saliva sequencing (n = 91) using Ambry CustomNext-Cancer (9/11 genes from the tumor panel assessed). Potential associations between gHRRm status and antitumor activity were explored in the HRR-deficient measurable disease population evaluable for gHRRm (n = 70). The potential association of germline vs somatic tumor HRRm and antitumor activity was also assessed in the HRR-deficient measurable disease population (n = 104) using saliva data and somatic-germline-zygosity (SGZ) prediction (when saliva results were unavailable) to annotate tumor alteration origin. This analysis was limited to short variants. Data cutoff was Sept 4, 2020 (primary completion date). Results: Using Ambry saliva results, 19 gHRRm were identified in 18/91 (20%) evaluable patients (pts) ( BRCA2 = 10; ATM = 4; CHEK2 = 4; RAD51C = 1; 1 pt had both ATM and RAD51C). As expected for germline sequencing, all 19 alterations were short variants (12 SNV, 7 InDels). For 17/19 gHRRm, central lab tumor F1CDx records were available: in all 17 cases, identical tumor alterations were found. Of these 17 tumor HRRm, 16 were evaluable for tumor SGZ prediction of origin or zygosity: 15/16 germline, with 1/16 somatic; 9/16 homozygous (incl 7/9 BRCA2), with 7/16 heterozygous (incl 2/9 BRCA2). ORR was 31% (5/16) in men with gHRRm and 26% (14/54) in men without gHRRm ( P = 0.7519, 2-sided Fisher exact test). Based on tumor sequencing results, annotated using saliva results and SGZ predictions, ORR was 25% (10/40) in men with gHRRm and 19% (4/21) in men with only somatic HRRm ( P = 0.7528). Conclusions: Here we report a 20% incidence of gHRRm for this population of men with mCRPC preselected based on tumor HRRm status, which may be impacted by low Ns and assay specific differences in variant calling. In this population, no association with differential antitumor activity was observed with gHRRm status as assessed using germline results alone, or assessed holistically using a combination of tumor and saliva results and SGZ prediction.