camonsertib (RP-3500) / Repare Therap - LARVOL DELTA

IND.241: A Canadian Cancer Trials Group liquid-biopsy informed platform trial to evaluate treatment in CDK4/6-inhibitor resistant ER+/HER2- metastatic breast. (ASCO 2025) - P2 | "Substudy B is evaluating lunresertib (PKMYT1 inhibitor) + gemcitabine in patients +/-CCNE1 overexpression / amplification. Substudy C is evaluating niraparib (PARP inhibitor) + fulvestrant (ET) in patients +/- alterations in BRCA1/2 (germline/somatic) or PALB2 (germline)...Substudy D, which has recently been added, is evaluating lunresertib + camonsertib (ATR inhibitor) in patients +/- CCNE1 overexpression/amplification, FBXW7 or PPP2R1A alterations. Additional substudies are in development for inclusion in this platform trial."

Biopsy • Liquid biopsy • Metastases • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • BRCA1 • BRCA2 • CCNE1 • ER • FBXW7 • HER-2 • PALB2 • PKMYT1 • PPP2R1A

The cold immunological landscape of ATM-deficient cancers. (PubMed, J Immunother Cancer) - "ATM deficiency, while compromising DNA repair and enhancing sensitivity to radiation and ATR inhibition, does not increase tumor antigenicity or immunogenicity. Altogether, our results have important implications for the design of novel combination therapies for ATM null tumors and highlight the importance of antigenicity in the immunological consequences of defective DNA repair."

IO biomarker • Journal • Ataxia • Breast Cancer • Colorectal Cancer • Immune Modulation • Immunology • Lung Cancer • Movement Disorders • Oncology • Pancreatic Cancer • Primary Immunodeficiency • Solid Tumor • Triple Negative Breast Cancer • ATM

Molecular architecture and inhibition mechanism of human ATR-ATRIP. (PubMed, Sci Bull (Beijing)) - "Here, we determined the cryo-EM structures of the human ATR-ATRIP complex in the presence of VE-822 and RP-3500, two ATR inhibitors currently in Phase II clinical trials, achieving an overall resolution of approximately 3 Å. The binding and selectivity of RP-3500 depend on two bound water molecules, which may be further enhanced by the substitution of these bound waters. Our study provides a structural framework for understanding ATR regulation and holds promise for assisting future efforts in rational drug design targeting ATR."

Journal • Ataxia • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency

OncoKBTM, MSK's precision oncology knowledge base: 2024 updates (AACR 2025) - "OncoKB promoted BRAF fusions to Level 1 following inclusion as patient eligibility criteria in the FDA drug label for tovorafenib (low-grade glioma). Additionally, OncoKB included KRAS G12C in colorectal cancer and IDH1 mutations in myelodysplastic syndromes as Level 1 following FDA approval of adagrasib + cetuximab and ivosidenib, respectively...Lastly, novel biomarkers including FBXW7 and PPP2R1A alterations (endometrial and ovarian cancer), SMARCA4 mutations (non-small cell lung cancer and esophageal adenocarcinoma) and MTAP deletions (all solid tumors) were included in OncoKB based on compelling preclinical and emerging clinical evidence in association with lunresertib + camonsertib, PRT3789, and AMG193 and MRTX1719, respectively...OncoKB also implemented major software updates to support data integration into the EPIC platform. Future OncoKB efforts are focused on whole genome/exome curation, inclusion of biomarkers for non-NGS-based precision oncology therapies,..."

Tumor mutational burden • Brain Cancer • CNS Tumor • Colorectal Cancer • Endometrial Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Glioma • Hematological Malignancies • Lung Cancer • Microsatellite Instability • Myelodysplastic Syndrome • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Small Intestinal Carcinoma • Solid Tumor • BRAF • FBXW7 • IDH1 • KRAS • MSI • MTAP • POLD1 • PPP2R1A • SMARCA4 • TMB

Decitabine (DAC) induces a DNA damage response (DDR) and synergizes with replication checkpoint inhibitors in acute myeloid leukemia (AML) (AACR 2025) - "(nM)Molm13 (TP53WT)Molm13 (TP53-/-)U937 (TP53G187fs*/-)KG1a (TP53V225fs*/-)Primary AML (TP53WT orTP53MT)UnitsDecitabineDNMT16.25 – 20025 ± 11350 ± 260310 ± 1806.1 ± 1.6NDEC50, nM (mean, SD)CeralasertibATR250 – 5000.93 (0.66 – 1.24)0.90 (0.84 – 0.96)0.15 (0.08 – 0.21)0.74 (0.63 – 1.02)0.66 (0.43 – 2.43)CI with decitabine (median, IQR) CamonsertibATR10 – 1000.27 (0.19 – 0.59)0.24 (0.22 – 0.34)0.34 (0.21 – 0.39)NDNDPrexasertibCHK1/21.0 – 6.00.89 (0.82 – 1.06)0.78 (0.68 – 0.90)0.95 (0.93 – 1.08)ND0.88 (0.29 – 1.28)MK-8776CHK1250 – 1,0000.57 (0.48 – 0.80)0.76 (0.73 – 1.19)0.89 (0.57 – 1.39)NDNDRabusertibCHK1600 – 1,000NDNDND0.51 (0.48 – 0.56)NDAdavosertibWEE1100 – 4000.70 (0.63 – 1.11)0.99 (0.78 – 1.14)0.67 (0.60 – 0.74)0.67 (0.37 – 0.93)0.65 (0.43 – 0.88)Table 1. U937 data were replicated using annexin V. Prexasertib showed no activity in KG1a cells (suggesting drug efflux) requiring the use of the alternate CHK1 inhibitor, rabusertib. Abbreviations: ATR,..."

Checkpoint inhibition • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • ANXA5 • ATR • DNMT1

IND.241: A Canadian cancer trials group liquid-biopsy informed platform trial to evaluate treatment in CDK4/6-inhibitor resistant ER+/HER2- metastatic breast cancer (AACR 2025) - "Substudy B is evaluating lunresertib (PKMYT1 inhibitor) + gemcitabine in patients +/-CCNE1 overexpression / amplification. Substudy C is evaluating niraparib (PARP inhibitor) + fulvestrant (ET) in patients +/- alterations in BRCA1/2 (germline/somatic) or PALB2 (germline)... IND.241 employs a biomarker-driven platform trial designed to evaluate CDK4/6i resistant ER+/HER2- MBC, using non-invasive ctDNA tumor genotyping to select patients for biomarker-driven substudies with the goal of defining the ctDNA landscape across 1L to 3L treatments."

Biopsy • Liquid biopsy • Metastases • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • BRCA1 • BRCA2 • CCNE1 • ER • FBXW7 • HER-2 • PALB2 • PKMYT1 • PPP2R1A

Discovery of selective and orally bioavailable PKMYT1 inhibitor: characterization of anti-tumor activities as single and dual agents (AACR 2025) - "Preclinical validation of this hypothesis demonstrated that combining PKMYT1 inhibitors with ATR inhibitors, such as prexasertib and RP-3500, resulted in enhanced antitumor activity in CCNE1-amplified cancer models. Additionally, we observed synergistic effects when combining PKMYT1 inhibitors with standard-of-care chemotherapies that induce DNA damage, such as gemcitabine and hydroxyurea...In conclusion, our study underscores the therapeutic potential of selective PKMYT1 inhibitors in CCNE1-amplified cancers and provides a strong rationale for their combination with ATR inhibitors and DNA-damaging chemotherapies. These findings support the continued development and clinical evaluation of PKMYT1 inhibitors as a novel approach to cancer treatment."

Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Oncology • Solid Tumor • CCNE1 • CDK1 • PKMYT1

Rb loss-related DNA damage repair deficiency mediates the synthetically lethal effect of ATR/PKMYT1 co-inhibition in TNBC and CDK4/6i-resistant ER+ breast cancer (AACR 2025) - "By investigating the synthetic lethality of ATR/PKMYT1 co-inhibition, we aimed to identify biomarkers predictive of treatment response, specifically examining Rb status and its effect on DNA damage repair mechanisms. The study tested the combination of ATR inhibitor (RP3500) and PKMYT1 inhibitor (RP6306) in TNBC and ER-positive parental and palbociclib-resistant breast cancer cell lines, as well as in patient-derived xenograft (PDX) models. ATR and PKMYT1 co-inhibition is a promising therapeutic strategy for TNBC and CDK4/6i-resistant breast cancer. The synthetic lethality of this combination is enhanced in Rb-deficient models, where Rb1 loss impairs DNA damage repair capabilities, amplifying the anti-tumor effects."

Synthetic lethality • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDK4 • ER • PKMYT1 • RB1

Efficacy and safety of the combination PKMYT1-inhibitor lunresertib and ATR-inhibitor camonsertib in patients with ovarian and endometrial cancers: Phase I MYTHIC study (NCT04855656) (AACR 2025) - P1 | "Lunre + cam is a tolerable and effective oral combination therapy of two novel targeted agents in molecularly-selected OC and EC with poor prognostic features and no approved targeted therapies. Enrollment closed in Dec 2024, the presentation will provide updated data for potential late-stage clinical development."

Clinical • P1 data • Carcinosarcoma • Endometrial Cancer • Oncology • Ovarian Cancer • Sarcoma • Solid Tumor • CCNE1 • CDK1 • FBXW7 • PKMYT1 • PPP2R1A

Repare Therapeutics Announces Six Abstracts Accepted for Presentation at AACR Annual Meeting 2025 (Businesswire) - "Repare Therapeutics Inc...announced the acceptance of two abstracts for mini-oral presentation and the acceptance of four abstracts for poster presentation at the American Association for Cancer Research (AACR) Annual Meeting, taking place April 25-30, 2025, in Chicago, Illinois."

P1 data • Preclinical • Endometrial Cancer • Gastric Cancer • Neuroblastoma • Ovarian Cancer

Targeting CCNE1 amplified ovarian and endometrial cancers by combined inhibition of PKMYT1 and ATR. (PubMed, Nat Commun) - "Mechanistically, low doses of RP-6306 with RP-3500 increase CDK1 activation more so than monotherapy, triggering rapid and robust induction of premature mitosis, DNA damage, and apoptosis in a CCNE1-dependent manner. These findings suggest that targeting CDK1 activity by combining RP-6306 with RP-3500 is an effective therapeutic approach to treat CCNE1-amplifed OVCAs and EMCAs."

Journal • Endometrial Cancer • Oncology • Ovarian Cancer • Solid Tumor • CCNE1 • CDK1 • PKMYT1

TalaCom: Phase Ib investigator-initiated trial combining talazoparib and axitinib in patients with DNA damage response mutated cancers or BRCA1/2 wildtype ovarian cancer incorporating prospective intrapatient dose titration (ESMO-TAT 2025) - P1 | "22/24 (92%) evaluable pts achieved RECIST SD or PR; 13/24 (54%) had tumor regressions, and 5/24 (21%) achieved RECIST PRs: 2 pts with BRCA2m HGSOC (one who progressed on prior olaparib, saruparib and camonsertib); 1 pt with BRCA2m peritoneal mesothelioma; 2 pts with mCRPC without DDR mutations (one who progressed on prior olaparib). The combination of axi + tala was generally manageable with durable antitumor activity in heavily pretreated HGSOC and CRPC pts, including pts who progressed on prior PARPi. Biomarker and PK analyses are ongoing."

Clinical • P1 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • High Grade Serous Ovarian Cancer • Mesothelioma • Oncology • Ovarian Cancer • Peritoneal Mesothelioma • Prostate Cancer • Solid Tumor • BRCA • BRCA1 • BRCA2 • BRIP1 • CDK12 • CHEK2 • PALB2 • RAD51C

TRESR: Study of RP-3500, Camonsertib, in Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=285 | Active, not recruiting | Sponsor: Repare Therapeutics | Recruiting ➔ Active, not recruiting

Enrollment closed • Oncology • Solid Tumor

Morpheus Lung: A Study Of Multiple Immunotherapy-Based Treatment Combinations In Participants With Metastatic Non-Small Cell Lung Cancer (Morpheus- Non-Small Cell Lung Cancer) (clinicaltrials.gov) - P1/2 | N=314 | Active, not recruiting | Sponsor: Hoffmann-La Roche | N=675 ➔ 314

Enrollment change • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-L1

RP-6306 in Patients With Advanced Cancer (clinicaltrials.gov) - P2 | N=78 | Recruiting | Sponsor: Canadian Cancer Trials Group | Trial completion date: Jun 2025 ➔ May 2026 | Trial primary completion date: Dec 2024 ➔ Dec 2025

Trial completion date • Trial primary completion date • Breast Cancer • Colorectal Cancer • Endometrial Cancer • Esophageal Cancer • Gastric Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Triple Negative Breast Cancer • CCNE1 • HER-2 • KRAS • TP53 • UGT1A1

Repare Therapeutics Announces Portfolio Re-Prioritization, Partnering Initiatives and Cost Reductions (Businesswire) - "Repare Therapeutics...announced a re-alignment of resources and a re-prioritization of its clinical portfolio to focus on the continued advancement of its Phase 1 clinical programs, RP-1664 (PLK4 inhibitor) and RP-3467 (Polθ ATPase inhibitor). Repare also announced its intention to seek partnering opportunities across its portfolio, including for lunresertib and camonsertib ('Lunre+Camo') prior to any start of pivotal development. The consequent savings of late-stage clinical funding combined with planned cost and headcount reductions are expected to extend Repare’s cash runway into mid-2027."

Commercial • Solid Tumor

Recent Pipeline Progress & Upcoming Milestones of Prioritized Clinical Programs (Businesswire) - "(i) RP-3467: Potential best-in-class Polθ ATPase inhibitor...Upcoming Expected Milestones: Q3 2025: Topline safety, tolerability and early efficacy data from the POLAR trial in monotherapy and in combination with olaparib.... (ii) Lunresertib and Camonsertib...Upcoming Expected Milestone: Q2 2025: Enrollment completion of MYTHIC trial evaluating lunresertib in combination with Debio 0123 (WEE1 inhibitor)."

Enrollment status • P1 data • Solid Tumor

Repare Therapeutics Announces Positive Results of the Lunresertib and Camonsertib Combination from the MYTHIC Phase 1 Gynecologic Expansion Clinical Trial (Businesswire) - P1 | N=364 | MYTHIC (NCT04855656) | Sponsor: Repare Therapeutics | "Key efficacy outcomes in evaluable patients with endometrial cancer (N=27): ORR was 25.9% (confirmed ORR in 5 out of 7 patients); Clinical benefit was observed in 48.1% of patients, with responses frequently occurring after 12 weeks or more; At the 24-week landmark analysis, nearly half of patients experienced durable clinical benefit (24-week PFS [PFS24w] = 43% [95% CI, 21-63%])....Key efficacy outcomes in evaluable patients with PROC (N=24): ORR was 37.5% (confirmed ORR in 4 out of 9 patients); Clinical benefit was observed in 79% of patients; PFS at the 24-week landmark analysis was PFS24w = 45% [95% CI, 22-66%]....Repare...intends to start the first Phase 3 Lunre+Camo trial in endometrial cancer in the second half of 2025. Additionally, the Company expects to initiate a small contribution of components trial in up to 40 patients with endometrial cancer in the first quarter of 2025."

New trial • P1 data • Endometrial Cancer • Ovarian Cancer

Repare Therapeutics to Host Webcast to Report Data from the Lunresertib and Camonsertib Combination Phase 1 MYTHIC Clinical Trial (Businesswire) - "Repare Therapeutics...announced it will host a conference call and live webcast to present the latest data from its ongoing Phase 1 MYTHIC clinical trial evaluating lunresertib in combination with camonsertib at the recommended Phase 2 dose in an expansion cohort in patients with platinum-resistant ovarian and endometrial cancers harboring CCNE1 amplification or FBXW7 or PPP2R1A mutations, on Thursday, December 12, 2024 at 4:30 p.m. Eastern Time."

P1 data • Endometrial Cancer • Ovarian Cancer

CORONADO CLL: RP-3500 and Olaparib in DNA Damage Repair Pathway Deficient Relapsed/Refractory Chronic Lymphocytic Leukemia (clinicaltrials.gov) - P1/2 | N=5 | Terminated | Sponsor: University of Utah | N=39 ➔ 5 | Trial completion date: Aug 2027 ➔ Oct 2024 | Recruiting ➔ Terminated; This study was terminated due to sponsor de-activation of all programs associated with RP-3500 (camonsertib).

Enrollment change • Trial completion date • Trial termination • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • BCL2 • CCND1 • CD20 • CD5 • FCER2 • POT1 • SF3B1 • TP53

Repare Therapeutics Announces Agreement with the US National Cancer Institute to Advance the Development of Camonsertib (Businesswire) - "Repare Therapeutics Inc...announced a Cooperative Research and Development Agreement (CRADA) has been executed to advance the development of camonsertib as an anticancer agent in collaboration with the Cancer Therapy Evaluation Program (CTEP) of the US National Cancer Institute (NCI), part of the US National Institutes of Health."

Licensing / partnership • Oncology • Solid Tumor

Repare Therapeutics Provides Business and Clinical Update and Reports Third Quarter 2024 Financial Results (Businesswire) - "'We look forward to reporting data from our MYTHIC dose expansion clinical trial evaluating lunresertib in combination with camonsertib at the recommended Phase 2 dose at a company event in December, with the plan to begin a registrational trial in 2025'...Repare expects to report initial data from Module 4 of the MYTHIC trial in 2025...Repare expects to report initial data from the TRESR clinical trial in 2025."

P1 data • P1/2 data • Oncology • Solid Tumor

Individualised schedule optimisation improves rates and severity of anaemia in patients (pts) treated with lunresertib (lunre), a PKMYT1 inhibitor, and camonsertib (cam), an ATR inhibitor, in the phase I MYTHIC study (NCT0485565) (EORTC-NCI-AACR 2024) - "For the lunre + cam combination, individualised weekly schedule selection and modification— rather than a daily dose reduction—proved to be an effective strategy for reducing severe anaemia and need for transfusions, while appearing to maintain efficacy."

Clinical • P1 data • Oncology • CDK1 • PKMYT1

Genomic biomarkers predict response to combined ATR inhibition and radiotherapy. (PubMed, Clin Cancer Res) - "A recent study reports the novel ATR kinase inhibitor, RP-3500, synergizes with radiation to control Atm-/- tumors in vivo. RP-3500 did not radiosensitize wild-type or Brca-1 deficient tumors, highlighting the need for a genotype-tailored approach."

Biomarker • Journal • Oncology • BRCA • BRCA1

Repare Therapeutics Announces Phase 1 Data Highlighting Camonsertib in Combination with Radiotherapy Treatment Presented at the ASTRO Annual Meeting (Businesswire) - P1/2 | N=84 | NCT05566574 | "These data from a clinical trial conducted in collaboration with investigators at Memorial-Sloan Kettering Cancer Center were presented at the American Society for Radiation Oncology (ASTRO) annual meeting....Seventeen (17) patients with metastatic tumors harboring ATM mutations were enrolled in the trial; of which 12 had pathogenic ATM mutations and 5 had ATM mutations with variants of unknown significance (VUS). Primary cancer histology included gastrointestinal (n=5), pancreas (n=5), breast (n=2), lung (n=2), bladder (n=2), and thyroid (n=1)....At 2-months, there were 2 complete responses (CR), 5 partial responses (PR), and 4 stable disease (SD) in the pathogenic ATM mutation group versus 1 PR and 4 SD in the VUS group. At 6-months, in 9 evaluable patients, 2 CR, 4 PR, and 1 SD were reported in the pathogenic group versus 1 SD and 1 progressive disease (PD) in the VUS group."

P1 data • Bladder Cancer • Breast Cancer • Non Small Cell Lung Cancer • Pancreatic Cancer • Thyroid Gland Carcinoma