Ceralasertib Monotherapy in Patients with ATM-Altered Advanced Solid Tumors or Metastatic Castration-Resistant Prostate Cancer: Data from the Phase IIa PLANETTE Study

PURPOSE: Ceralasertib is an oral ataxia telangiectasia and Rad3-related (ATR) inhibitor with preclinical activity in ataxia-telangiectasia mutated (ATM)-altered cancers. The phase IIa PLANETTE study evaluated ceralasertib in previously treated advanced solid tumors (cohort A) or metastatic castration-resistant prostate cancer (cohort B) with ATM alterations (ATM mutations and/or ATM protein deficiency). PATIENTS AND METHODS: Patients received ceralasertib 160 mg twice daily on days 1 to 14 of a 28-day cycle. Efficacy was evaluated in patients with centrally confirmed ATM alterations. The primary endpoint was objective response rate (ORR; cohort A) or composite response rate (CRR: radiographic response, prostate-specific antigen response, or circulating tumor cell conversion; cohort B). Secondary endpoints included progression-free survival (PFS) and safety. RESULTS: Cohorts A and B included 30 and 15 patients, respectively. ORR (cohort A) was 7.1% [80% confidence interval (CI), 1.9-17.9; n = 2/28]: one complete response ongoing at 14.1 months (breast cancer) and one partial response ongoing at 7.4 months (endometrial cancer). CRR (cohort B) was 7.7% (80% CI, 0.8-28.6; n = 1/13). In patients with centrally confirmed ATM protein loss, the ORR was 18.2% (80% CI, 4.9-41.5; n = 2/11) and CRR was 0% (80% CI, 0-28; n = 0/7). The median PFS was 3.7 months in each cohort (cohort A, 80% CI, 1.9-5.6; cohort B, 80% CI, 1.9-not calculable). Grade ≥3 adverse events (AE) occurred in 50% of cohort A and 53.3% of cohort B patients. The most common AEs overall were asthenia/fatigue, nausea, and anemia. CONCLUSIONS: Ceralasertib monotherapy was tolerated; however, responses were limited. Alternative patient selection and combination treatments are being explored. SIGNIFICANCE: In the phase IIa PLANETTE study in advanced/metastatic ATM-altered cancers, ceralasertib 160 mg twice daily (days 1-14, 28-day cycle) was tolerated; objective responses were limited, corroborating previous findings with ATR inhibitors in ATM-deficient tumors. Optimizing biomarker-based patient selection beyond ATM deficiency represents a key aspect of future ATR inhibitor development.