Abstract CT027: TALAPRO-1 final data: Talazoparib (TALA) monotherapy in men with DNA damage response alterations (DDRalt) and metastatic castration-resistant prostate cancer (mCRPC): Exploration of DDRalt germline/somatic origin and zygosity

Background: TALAPRO-1 enrolled patients (pts) with RECIST1.1-measurable disease, progressive mCRPC, and tumor DDRalt (tDDRalt) considered sensitizing to PARP inhibitors (ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C). Pts had received ≥1 taxane-based chemotherapy and progressed on ≥1 novel hormonal therapy. The primary endpoint was objective response rate (ORR per RECIST1.1; central review). Exploratory ad hoc biomarker analyses assessed germline/somatic origin and zygosity of tDDRalt and associations with antitumor activity. Data cutoff was Sept 4, 2020. Methods: Tumor tissue was tested using FoundationOne®, and saliva using an Ambry CustomNext-Cancer panel. Known/likely pathogenic tDDRalt variants were categorized as germline (also present in saliva), somatic (not present in saliva), or unknown origin (ATR and FANCA not in germline panel). tDDRalt zygosity was assessed using somatic-germline-zygosity (SGZ). Categorization was limited to short variants. Results: 128 pts were enrolled and 127 received ≥1 TALA dose (safety population). Of 52 enrolled tumor DDR-deficient pts evaluable for both germline and tumor DDR mutations and associated comparisons, 27 (52%) had ≥1 tDDRalt of germline origin, 24 (46%) of somatic origin, and 2 (4%) of unknown origin. One pt had both germline and somatic tDDRalt. The most common tDDRalt were BRCA2 (14 germline; 10 somatic) and ATM (4 germline; 7 somatic). ORR was 25.9% (7/27) in pts with tDDRalt of germline origin and 9.1% (2/22) in pts with only somatic tDDRalt (P = 0.159, 2-sided Fisher's exact test). ORR was 50.0% (7/14) in pts with tumor BRCA2alt of germline origin and 20.0% (2/10) in pts with somatic BRCA2alt (not significantly different; P = 0.210). Overall, of 77 pts in the safety population evaluable for SGZ, tDDRalt were predicted to be with loss of heterozygosity (LOH) in 16 (20.8%) pts, heterozygous in 17 (22.1%) pts and with zygosity unknown in 44 (57.1%) pts. ORR in tumors categorized as tDDRalt with LOH was 43.8% (7/16) and for those categorized as heterozygous tDDRalt was 11.8% (2/17) (odds ratio [95% CI] 5.83 [0.811-65.84]; P = 0.057). Conclusions: In this heavily pretreated mCRPC population, based on this retrospective ad hoc exploratory subgroup analysis, pts with germline and/or homozygous tDDRalt appeared to be numerically most likely to respond to TALA. Potential reasons include gene-specific imbalances in origin/zygosity of alterations and/or sensitivity to TALA. Further inves