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|Authors||Timothy A. Yap, Ian M. Silverman, Elisa Fontana, Elizabeth Lee, David Spigel, Martin Højgaard, Stephanie Lheureux, Niharika Mettu, Benedito A. Carneiro, Louise Carter, Ruther Plummer, Joseph D. Schonhoft, Danielle Ulanet, Parham Nejad, Peter Manley, Jorge S. Reis-Filho, Yi Xu, Victoria Rimkunas, Maria Koehler, Ezra Rosen|
|Title||Abstract CT030: Genomic and pathologic determinants of response to RP-3500, an ataxia telangiectasia and Rad3-related inhibitor (ATRi), in patients (pts) with DNA damage repair (DDR) loss-of-function (LOF) mutant tumors in the Phase 1/2 TRESR trial|
|Abstract Text||Background: RP-3500 is a potent, oral ATRi developed to treat tumors with LOF gene alterations predicted to exhibit synthetic lethality with ATRi (STEP2 genes). Biomarker analyses from TRESR (NCT04497116) identified predictors of sensitivity to RP-3500. Methods: Biomarker data were centrally assessed from: Tumor/normal sequencing including zygosity analysis (SNiPDx targeted NGS panel), ctDNA, and ATM IHC. Correlations with clinical outcomes: Overall Response (OR: RECIST 1.1 confirmed/unconfirmed CR/PR, PSA or CA125 response), PFS, and CBR (OR or therapy duration >16 weeks [w]) were assessed. Results: 120 pts (ovarian [n=22], prostate [n=22], breast [n=17], pancreatic [n=12], other [n=47]) with LOF alterations (ATM [n=44], BRCA1 [n=25], BRCA2 [n=15], CDK12 [n=9], RNASEH2 [n=5], PALB2 [n=5], SETD2 [n=5], other [n=12]) were enrolled based on local tumor NGS (n=71), germline testing (n=29), ctDNA (n=13), or IHC (n=7). Prior therapies included PARPi (39/120) and platinum (81/120). Locally and centrally assessed biomarker status were concordant for tumor NGS (45/46), germline (20/20) and ctDNA (7/8). Alterations were germline in 50/88 (57%) and somatic in 36/88 (41%) pts; clonal hematopoiesis was the source of ATM LOF in 2/88 (2%) pts. Gene zygosity was biallelic in 49/68 (72%) and monoallelic in 19/68 (28%) tumors. ATM protein loss was detected in 11/13 (85%) biallelic (discordance explained by missense mutations) and 5/8 (63%) monoallelic ATM LOF. Reversions were detected at baseline in 6 pt tumors (BRCA1 [n=3], BRCA2 [n=1], PALB2 [n=1], NBN [n=1]). In pts receiving RP-3500 >100mg and ≥1 response evaluation, OR was 13% (13/98; responses in tumors with ATM, BRCA1, BRCA2, CDK12, RAD51C, SETD2 genotypes); CBR was 47% in 77 pts with follow-up >16w , mPFS was 15w; 40/98 pts remain on RP-3500 (up to 50+w). CBR was >60% and mPFS not reached on 17 pts with ovarian tumors. Compared with monoallelic loss, tumors with biallelic loss had significantly higher CBR (20/34 [59%] vs 1/10 [10%], p=0.01) and trend for longer mPFS (19w vs 6w, p=0.08). CBR was 64% (7/11) vs 0% (0/3) in biallelic vs monoallelic tumors with ATM LOF (p=0.19), and 64% (7/11) vs 0% (0/2) in tumors with BRCA1 LOF (p=0.19). Two pts with post-PARPi BRCA1 reversions had treatment durations of 17w and 29w. Conclusions: RP-3500 has clinical activity across STEP2 genotypes including those pretreated with PARPi and with BRCA1 reversions. IHC is an imperfect surrogate for ATM zygosity. ATM alterations originating from clonal hematopoiesis of indeterminate potential (CHIP) can be misdiagnosed as tumor derived. High concordance of local and central testing supports the use of local NGS to identify LOF alterations. Improved CBR with RP-3500 therapy in tumors with biallelic LOF supports the use of gene zygosity as a predictor of benefit.|
|Molecular Profile||Treatment Approach|
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|ATM inact mut||Advanced Solid Tumor||predicted - sensitive||RP-3500||Phase Ib/II||Actionable||In a Phase I/II trial (TRESR), RP-3500 treatment resulted in a response rate of 13% (13/98), clinical benefit rate (CBR) of 47% (36/77), and median progression-free survival (mPFS) of 15 weeks in solid tumor patients with inactivating mutations in DNA damage repair genes, including ATM, with a CBR of >60% and mPFS not reached in 17 ovarian tumor patients, and with biallelic ATM inactivation CBR was 64% (7/11) vs 0% (0/3) with monoallelic inactivation (Cancer Res 2022;82(12_Suppl): CT030, NCT04497116).||detail...|
|RAD51C inact mut||Advanced Solid Tumor||predicted - sensitive||RP-3500||Phase Ib/II||Actionable||In a Phase I/II trial (TRESR), RP-3500 treatment resulted in a response rate of 13% (13/98), clinical benefit rate (CBR) of 47% (36/77), and median progression-free survival (mPFS) of 15 weeks in solid tumor patients with inactivating mutations in DNA damage repair genes, including RAD51C, with a CBR of >60% and mPFS not reached in 17 ovarian tumor patients (Cancer Res 2022;82(12_Suppl): CT030, NCT04497116).||detail...|