Uterine Serous Carcinoma

Data presented at AACR’s Ovarian Cancer Research Symposium confirm that ovarian and endometrial cancers with CCNE1 amplifications, FBXW7 or PP2R1A mutations carry poor prognosis Significant survival disparities were identified in patients harboring lunresertib- and camonsertib-sensitizing biomarkers, including CCNE1 amplifications or mutations in FBXW7 or PPP2R1A CAMBRIDGE, Mass. & MONTREAL --(BUSINESS WIRE)--Sep. 23, 2024-- Repare Therapeutics Inc. (“Repare” or the “Company”) (Nasdaq: RPTX), a leading clinical-stage precision oncology company, presented new data on Friday highlighting the impact of alterations in FBXW7, PPP2R1A and CCNE1 in patients with metastatic ovarian and endometrial cancers based on an analysis in approximately 2,000 patients from Cancer Genome Atlas Research Network and Memorial Sloan Kettering’s Metastatic Events and Tropisms. The poster presentation was shared at the American Association of Cancer Research’s (AACR) 15th Annual Ovarian Cancer Research Symposium in Seattle , underscores inherent chemotherapy resistance and the lack of treatment options for metastatic gynecologic cancer patients with these biomarkers. “Patients with recurrent ovarian and endometrial cancers are already at a disadvantage when it comes to treatment options,” said Maria Koehler , MD, PhD, Executive Vice President and Chief Medical Officer of Repare. “These new data highlight the urgent need for innovative therapeutic approaches to address the specifically poor prognosis associated with FBXW7, PPP2R1A and CCNE1 alterations treated with standard of care-based chemotherapy. We look forward to reporting data from our MYTHIC dose expansion trial evaluating lunresertib in combination with camonsertib in patients with ovarian and endometrial cancers with these biomarkers in the fourth quarter of 2024.” Repare Therapeutics’ Phase 1 MYTHIC clinical trial (NCT04855656) is studying the combination of lunresertib, a first-in-class oral small molecule PKMYT1 inhibitor, and camonsertib, a potential best-in-class oral small molecule ATR inhibitor, in patients harboring lunresertib-sensitizing biomarkers (Lunre BM), including CCNE1 amplifications or mutations in FBXW7 or PPP2R1A. While CCNE1 amplifications occur in approximately 30% of platinum-resistant ovarian cancers,1-2 and are well established as a poor prognostic indicator in ovarian cancer,3-6 little is known about other Lunre BM in ovarian and endometrial cancers. Ovarian Cancer: The presence of Lunre BM (alterations in CCNE1, PPP2R1A, or FBXW7) in ovarian cancer patients (n=1,029) is linked to a substantially lower survival rate compared to those without these biomarkers, underscoring their prognostic significance: Median overall survival (mOS) for patients with these biomarkers (Lunre BM+) is 26 months (95% CI, 18-38), compared to 36 months (95% CI, 30-43) for patients without these biomarkers (Lunre BM-; HR = 1.46 [95% CI, 1.14-1.87], p=0.003), a 28% decrease in mOS Endometrial Cancer: Endometrial cancer patients (n=895) with biomarkers CCNE1, PPP2R1A, and FBXW7 demonstrate poorer survival outcomes, which are influenced by their association with high-risk histologies and genetic alterations: Median overall survival (mOS) for patients with these biomarkers (Lunre BM+) is 30 months (95% CI, 24-38), compared to 41 months (95% CI, 31-60) for patients without these biomarkers (Lunre BM-; HR = 1.29 [95% CI, 1.03-1.60], p=0.024), a 27% decrease in mOS The presence of these biomarkers also correlates with high-risk histologies (uterine carcinosarcoma and uterine serous carcinoma) and p53 mutant genotypes, well known for adverse prognosis About Repare Therapeutics Inc. Repare Therapeutics is a leading clinical-stage precision oncology company enabled by its proprietary synthetic lethality approach to the discovery and development of novel therapeutics. The Company utilizes its genome-wide, CRISPR-enabled SNIPRx® platform to systematically discover and develop highly targeted cancer therapies focused on genomic instability, including DNA damage repair. The Company’s pipeline includes lunresertib (also known as RP-6306 ), a PKMYT1 inhibitor currently in Phase 1/2 clinical development; camonsertib (also known as RP-3500 ), a potential leading ATR inhibitor currently in Phase 1/2 clinical development; RP-1664 , a Phase 1 PLK4 inhibitor; RP-3467 , a preclinical Polθ ATPase inhibitor program; as well as additional, undisclosed preclinical programs. For more information, please visit reparerx.com and follow @Reparerx on X (formerly Twitter) and LinkedIn. Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 and securities laws in Canada . All statements in this press release other than statements of historical facts are “forward-looking statements. These statements may be identified by words such as “aims,” “anticipates,” “believes,” “could,” “estimates,” “expects,” “forecasts,” “goal,” “intends,” “may,” “plans,” “possible,” “potential,” “seeks,” “will” and variations of these words or similar expressions that are intended to identify forward-looking statements, although not all forward-looking statements contain these words. Forward-looking statements in this press release include, but are not limited to, statements regarding: the impact of alterations in FBXW7, PPP2R1A and CCNE1 in patients with metastatic ovarian and endometrial cancers; the design, objectives, initiation, timing, progress and results of current and future clinical trials of the Company’s product candidates, including the timing of data from the expansion of its Phase 1 MYTHIC trial evaluating lunresertib alone and in combination with camonsertib; the potential of lunresertib in combination with camonsertib in patients harboring lunresertib-sensitizing biomarkers and the tolerability, efficacy and clinical progress of the Company’s product candidates. These forward-looking statements are based on the Company’s expectations and assumptions as of the date of this press release. Each of these forward-looking statements involves risks and uncertainties that could cause the Company’s clinical development programs, future results or performance to differ materially from those expressed or implied by the forward-looking statements. Many factors may cause differences between current expectations and actual results, including: the potential that success in preclinical testing and earlier clinical trials does not ensure that later clinical trials will generate the same results or otherwise provide adequate data to demonstrate the efficacy and safety of a product candidate; the impacts of macroeconomic conditions, including the conflict in Ukraine and the conflict in the Middle East , heightened inflation and uncertain credit and financial markets, on the Company’s business, clinical trials and financial position; unexpected safety or efficacy data observed during preclinical studies or clinical trials; clinical trial site activation or enrollment rates that are lower than expected; the Company’s ability to realize the benefits of its collaboration and license agreements; changes in expected or existing competition; changes in the regulatory environment; the uncertainties and timing of the regulatory approval process; and unexpected litigation or other disputes. Other factors that may cause the Company’s actual results to differ from those expressed or implied in the forward-looking statements in this press release are identified in the section titled "Risk Factors" in the Company’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2024 filed with the Securities and Exchange Commission (“SEC”) and the Québec Autorité des Marchés Financiers ("AMF") on August 6, 2024 . The Company expressly disclaims any obligation to update any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise, except as otherwise required by law. For more information, please visit reparerx.com and follow Repare on X (formerly Twitter) at @RepareRx and on LinkedIn at https://www.linkedin.com/company/repare-therapeutics/. 1. Cancer Genome Atlas Research Network. Nature. 2011;474(7353):609–615 2. Smith P, et al. Nat Commun . 2023;14(1):4387 3. Chan AM, et al. J Pathol Clin Res. 2020;6(4):252–262 4. Kang E-Y, et al. Cancer. 2023;129(5):697–713 5. Nakayama N, et al. Cancer. 2010;116(11):2621–2634 6. Stronach EA, et al. Mol Cancer Res. 2018;16(7):1103–1111. View source version on businesswire.com: https://www.businesswire.com/news/home/20240923948019/en/ Investor Relations & Media Contact: Robin Garner Vice President and Head of Investor Relations Repare Therapeutics Inc. investor@reparerx.com Source: Repare Therapeutics Inc.

Over 500 patients have been treated with azenosertib as a monotherapy across various trials to date, Zentalis' CEO pointed out. The FDA has placed three trials of Zentalis’ WEE1 candidate on partial hold in the wake of two deaths that are presumed to be from sepsis. The fatalities occurred in the phase 2 DENALI study, which was evaluating the synthetic lethal WEE1 inhibitor azenosertib in patients with platinum-resistant ovarian cancer. The hold also extends to the other studies of azenosertib as a monotherapy—a phase 2 trial in uterine serous carcinoma and a phase 1 dose-escalation study in solid tumors. “Patient safety is our top priority and any deaths that occur in the setting of clinical trials are unfortunate,” Zentalis CEO Kimberly Blackwell, M.D., said in the June 18 release. “We are working closely with the FDA to resolve this partial clinical hold as quickly as possible.” Over 500 patients have been treated with azenosertib as a monotherapy across various trials to date, Blackwell pointed out, with the DENALI trial alone enrolling over 100 patients in cohort 1b. “We look forward to sharing these results along with overall efficacy and safety data from DENALI cohort 1b later this year,” the CEO added. Azenosertib is Zentalis’ only clinical-stage asset. The biotech’s shares plummeted 30% in the wake of the news, dropping to $5.85 in pre-market trading on Tuesday morning from a Monday closing price of $8.39. The company is still on track to report topline results from the phase 1 solid tumor trial as well as a phase 1/2 trial of azenosertib in combination with GSK’s Zejula for ovarian cancer later in 2024, according to the release. “Zentalis remains committed to the azenosertib development program and bringing this potentially practice-changing therapy to patients with gynecological malignancies,” the biotech said in the release. The company previously shared data at last year’s ASCO conference from a phase 1b study of azenosertib plus the chemotherapy paclitaxel in ovarian cancer that demonstrated an overall response rate of 50%. The biotech said at the time that the data were enough to begin preparations for a phase 3 study comparing azenosertib with either carboplatin or paclitaxel in patients with Cyclin E1+status and with platinum-sensitive ovarian cancer. The original plan was to launch a late-stage trial off the back off the data in the first quarter of 2024, although this timeline has since been pushed back to 2025. Zentalis returned to ASCO earlier this month armed with data from a phase 1 trial of azenosertib in combination with the chemotherapy gemcitabine in relapsed or refractory osteosarcoma. At the maximum tolerated dose, the most common adverse events of grade 3 or above were thrombocytopenia and lymphopenia, although the company pointed out that there were no grade 4 thrombocytopenia events or instances of febrile neutropenia at this dose.

Zentalis Pharmaceuticals disclosed that the FDA has placed a partial clinical hold on three monotherapy studies of its lead candidate, the oral WEE1 inhibitor azenosertib (ZN-c3), following two patient deaths presumed to be from sepsis. The news sent company shares sliding more than 45% on Tuesday.The hold impacts the Phase I dose-escalation study ZN-c3-001 in solid tumours, the Phase II DENALI trial in platinum-resistant ovarian cancer (PROC), and the Phase II TETON study in uterine serous carcinoma. The sepsis cases occurred in the DENALI study.“Patient safety is our top priority and any deaths that occur in the setting of clinical trials are unfortunate,” stated CEO Kimberly Blackwell, adding, “we are working closely with the FDA to resolve this partial clinical hold as quickly as possible.”Despite the setback, Blackwell remains confident about azenosertib's therapeutic index, noting that over 500 patients have received the WEE1 inhibitor as monotherapy across various studies. DENALI's Cohort Ib alone enrolled over 100 PROC patients. "We look forward to sharing these results along with overall efficacy and safety data from DENALI Cohort Ib later this year," Blackwell added.Phase Ib data reported last year showed a confirmed overall response of 50% and median progression-free survival of 7.4 months when azenosertib was combined with paclitaxel in PROC patients. Azenosertib is a potentially first-in-class WEE1 inhibitor targeting tumours with genomic instability, like PROC and uterine serous carcinoma. By blocking WEE1, Zentalis says its drug causes cancer cells to accumulate DNA damage, resulting in replication stress and apoptosis.While resolving the clinical hold, Zentalis said it also plans to report Phase I/II data from the MAMMOTH study later this year evaluating azenosertib plus GSK's PARP-blocking drug Zejula (niraparib) in PROC patients. "Zentalis remains committed to… bringing this potentially practice-changing therapy to patients with gynaecological malignancies," the company stated.