ATR Inhibitor RP-3500 Offers Favorable and Differentiated Safety in Solid Tumors

The highly selective ATR inhibitor RP-3500 was shown to have a promising safety profile and efficacy in a first-in-human biomarker-driven phase 1/2 study (NCT04497116). Results were presented during the American Association for Cancer Research-National Cancer Institute-European Organization for Research and Treatment of Cancer Virtual International Conference on Molecular Targets and Cancer Therapeutics by lead author Timothy A. Yap, PhD, MBBS, FRCP.¹

“This trial is unique as it limited patient accrual only to those with tumors harboring synthetic lethal genomic alterations that predicted for sensitivity to ATR inhibitors,” Yap, an associate professor in the Department for Investigational Cancer Therapeutics (Phase I Program) and Department of Thoracic/Head and Neck Medical Oncology and a medical oncologist and physician-scientist at The University of Texas MD Anderson Cancer Center in Houston, said during a virtual presentation of the data. RP-3500 has demonstrated single-agent activity in tumor models across different histologies and DNA damage repair (DDR) defects, Yap said. Early data from the ongoing study were being presented at the data cutoff date of August 15, 2021, in which 101 patients were included. “We expect the final analysis of this portion of the study in the first half of 2022,” he said.

Primary end points were safety, tolerability, recommended phase 2 dose, and schedule. Other end points were pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. Kinetics of circulating tumor DNA (ctDNA) were also evaluated, Yap added.

Forty-two patients were male and the median age was 63 years (range, 33-77). Patients had an equal performance status of 0 to 1 and were heavily pretreated with nearly half (45%) receiving 4 or more lines of prior therapy. Notably, 62% of patients received prior platinum therapy, 28% received prior PARP inhibitors, and 20% received a prior PD-1/L1 inhibitor.

The most frequently observed tumor types were ovarian (n = 19), prostate (n = 18), and breast cancers (n = 13), with the most frequent genotypes reported as ATM (37), BRCA1 (31), BRCA2 (13), and CDK12 (7). Single-agent RP-3500 was tested at multiple doses and schedules and, as a result, investigators recommended a dose of 160 mg once daily and administered on a 3 days on/4 days off schedule.

When comparing a 3 days on/4 days off schedule to a 5 days on/2 days off schedule, Yap commented that for all grade treatment-emergent adverse events occurring in at least 10% of the 101 patients, the former schedule was more favorable. “For example, grade 3 anemia was observed in only 14.5% of patients in the 3/4 schedule, with no grade 4 anemia seen in that cohort,” Yap said. In the 5/2 schedule, 44% of patients exhibited grade 3 anemia, and 21.8% of all patients exhibited grade 3 anemia. At the preferred 3/4 schedule, investigators reported that dose interruptions, reductions, and transfusions were infrequent with no discontinuations related to RP-3500 emergent adverse events (TABLE¹).

The drug’s pharmacokinetic profile showed that it met efficacy targets at greater than or equal to 100 mg, with a half-life of about 6 hours. A food effect study demonstrated that RP-3500 can be given with or without food.

Pharmacodynamics revealed a robust pathway modulation in paired tumor biopsies. “These [pharmacodynamic] effects were observed across multiple dose levels and genotypes with 10 mg of RP-3500, the lowest dose where these biomarker changes were observed,” Yap said.

In early analysis, treatment was ongoing in 54 (53.5%) of 101 patients, and early analysis of treatment duration showed clinical activity across tumor types. Additionally, copy number analysis of enrolled gene alterations is ongoing, said Yap. Early efficacy analysis demonstrated broad spectrum efficacy an meaningful clinical benefit in 34 (49%) of 69 evaluable patients.

Investigators also observed deep molecular responses in ctDNA for 37 patients with tumors with genomic alterations. Preliminary analysis suggests ctDNA response may predict clinical benefit. Further analyses will be undertaken to correlate ctDNA responses with clinical efficacy and duration of response to evaluate the predictive power of ctDNA, said Yap.

“The favorable and differentiated safety profile, along with promising and distinct efficacy, suggests a clear direction for further development of RP-3500,” Yap said. “The next steps include the opening of phase 2 expansion cohorts, as well as combination studies that are ongoing or that will open shortly,” he concluded.

_REFERENCE:

_{1. Yap TA, Lee E, Spigel D, et al. First-in-Human biomarker-driven phase 1 TRESR trial of ATR inhibitor RP-3500 in patients with advanced solid tumors harboring synthetic legal genomic alterations. Presented at: American Association for Cancer Research-National Cancer Institute-European Organization for Research and Treatment of Cancer Virtual International Conference on Molecular Targets and Cancer Therapeutics; October 7-10, 2021.}