RP-3500 Shows Early Activity/Safety in Advanced Solid Tumors With DDR Pathway Alterations


A novel ATR inhibitor displayed early signals of activity and was tolerable in patients with solid tumor harboring various molecular alterations.

molecular alterations

Timothy A. Yap, PhD

The novel ATR inhibitor, RP-3500, showed encouraging results as treatment of patients with advanced solid tumors who harbor selected molecular alterations, according to findings from the phase 1 TRESR study, which were announced in a press release from Repare Therapeutics, Inc.1

“Our promising early clinical data of this potent and highly selective ATR inhibitor offer a clear direction for further development of RP-3500,” said Timothy A. Yap, PhD, professor of Investigational Cancer Therapeutics, during a presentation of the data at the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics.2 “We will continue to assess RP-3500 in patients with defined molecular alterations and also in novel rational combinations.”

TRESR is a first-in-human, phase 1/2, multi-center, open-label, dose-escalation, and expansion study of RP-3500 administered alone or in combination with the oral PARP inhibitor talazoparib (Talzenna) in patients with advanced solid tumors with ATR inhibitor sensitizing mutations. The study is the largest known biomarker-selected study to test an ATR inhibitor as a single agent in cancers harboring synthetic lethal genomic alterations in DNA damage repair pathways.

Results from the monotherapy cohort of the study show that RP-3500 was safe and well-tolerated, with compelling early efficacy signals. The positive results were seen across various genotypes and tumor types in the heavily pretreated study population.

Investigators saw antitumor activity in patients with tumors harboring SNIPRX predicted genomic alternations at doses >100 mg, which includes ATMCDK12BRCA1BRCA2RAD51BRAD51C, and FZR1. These responses were across multiple tumor types. Of the 69 people assessed after a data cutoff date of June 4, 2021, 49% had a clinically meaningful benefit. Overall, tumor responses were observed in 12 patients, ongoing stable disease (SD) was seen in 14 patients, and 8 patients with SD and distinct decrease in tumor markers.

Of the 101 patients assessed until a data cutoff date of August 15, 2021, the most common treatment-emergent adverse events (TEAEs) were grade 1/2 anemia, and only 21.8% of patients experienced grade 3 anemia. Of the patients with high-grade anemia, 14.5% were treated on the recommended weekly schedule of 3 days on/4 days off. There were no grade 4 events observed during the analysis.

Further, no discontinuations related to TEAEs occurred, and dose interruptions, reductions, or red blood cell transfusions were infrequent on the recommended dosing schedule. Based on these safety findings, investigators determined the recommended phase 2 dose of RP-3500 to be 160 mg, taken weekly for 3 days on and 4 days off. This schedule assures repeated weekly exposure to RP-3500 at a dose that is effective for patients.

“Not only did RP-3500 demonstrate a favorable and differentiated safety profile, but our initial data also showed promising and distinct early efficacy,” Yap explained during his presentation. “Although this phase 1 study has only had approximately nine months of dosing at efficacious doses of 100mg or more of RP-3500, we are encouraged by what we have observed so far in this hard-to-treat advanced cancer patient population.”

In the ongoing TRESR study, a total of 239 patients will be enrolled and analyzed for the primary end point of safety and tolerability, as well as the secondary end points of pharmacokinetics, pharmacodynamics, and the preliminary clinical activity of RP-3500.

To be eligible for enrollment, patients must be 18 years of age or older with an ECOG performance status of 0 or 1, and a histologically confirmed advanced solid tumor that is measurable as per RECIST v1.1. All patients are required to have an existing biomarker profile, available tissue for biopsies, and acceptable organ function and blood counts at screening. Any toxicities of prior treatment or surgery must be resolved before patients can join the study. Female patients must have a negative pregnancy test at screening and both males and females are required to consent to contraception during the study.

Investigators of TRESR are actively recruiting patients who meet these enrollment criteria at research sites in Massachusetts, New York, North Carolina, Rhode Island, Tennessee, and Texas. Outside of the United States, patients are being recruited in Canada, the United Kingdom, and Denmark.

“Our initial data for 101 patients treated with RP-3500 in the ongoing TRESR study resulted in a firm recommendation for Phase 2 dose and schedule, suggest a favorable and differentiated safety profile, and provide compelling early evidence of broad clinical efficacy across genotypes predicted by our SNIPRX platform,” said Maria Koehler, MD, PhD, chief medical officer of Repare, in a press release. “The evolving nature of the data from this ongoing study and specifically the stable tolerability profile and maturing efficacy data offer a clear direction for further development of RP-3500. Additionally, we are excited to see that even at this early point in our clinical program, the pharmacokinetic and pharmacodynamic biomarker data already confirm proof-of-mechanism for RP-3500 in tumors with diverse molecular backgrounds.”


1. Repare Therapeutics presents preliminary phase 1 monotherapy clinical data from the ongoing first-in-human phase 1/2 TRESR study of RP-3500 in solid tumors at AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. New release. Repare Therapeutics, Inc. October 8, 2021. Accessed October 12, 2021. https://bit.ly/2YFjYs2

2. ATR inhibitor RP-3500 demonstrates safety and early clinical benefit. News release. MD Anderson Cancer Center. October 8, 2021. Accessed October 12, 2021. https://bit.ly/3avpaRP

3. Study of RP-3500 in advanced solid tumors. Clinicaltrials.gov. Accessed October 12, 2021. https://bit.ly/3BCc8Of

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