Abstract
Background: Ceralasertib, a potent, selective ATR inhibitor, is synthetically lethal in ATM-deficient preclinical models. This Phase 2a study (NCT04564027) assessed ceralasertib monotherapy in previously treated pts with ATM-altered tumors.
Methods: Adult pts had ASTs excluding NSCLC (Cohort [Co] A; data cutoff [DCO] Dec 21 2022) or mCRPC (Co B; DCO Apr 28 2023) and germline/somatic ATM pathogenic/likely pathogenic variants (PVs) by local assessment. ATM alterations were centrally confirmed by FMI F1CDx in tumor and/or FMI F1 liquid CDx in circulating tumor DNA, and/or by ATM protein deficiency by immunohistochemistry (cutoff ≤5%). Primary endpoints were objective response rate (ORR) in Co A and composite response rate (CRR) in Co B. Safety was a secondary endpoint.
Results: The initial starting dose of 240 mg BID PO ceralasertib on Days 1-14 of a 28-day cycle was reduced to 160 mg BID due to hematologic toxicity. Results are reported for 30 pts in Co A and 15 pts in Co B with a starting dose of 160 mg BID. In Co A, the 28 pts with centrally confirmed ATM alterations (93.3% [28/30] with ATM PV and 36.7% [11/30] ATM-deficient) had an ORR of 7.1% (80% CI: 1.9, 17.9): 1 complete response in breast cancer (ongoing at 12 mos) and 1 partial response in endometrial cancer (ongoing at 9 mos), both ATM-deficient. In Co B, the 13 pts with centrally confirmed ATM alterations (73.3% [11/15] with ATM PV and 46.7% [7/15] ATM-deficient) had a CRR of 7.7% (80% CI: 0.8, 26.8): 1 pt with conversion of circulating tumor cell count from unfavorable to favorable (ongoing at 3 mos) with unknown ATM expression. The safety profile was manageable (Table). Steady-state ceralasertib plasma concentrations exceeded the IC90 for ~23 hrs/day.
Conclusion: Responses to ceralasertib monotherapy were limited in ATM-altered tumors, despite reaching target plasma levels. Alternative pt selection and combination treatment strategies are being explored.
TABLE 1: NAND Efficacy, safety of ceralasertib 160 mg BID on D1-14 of D28 cycle in pts with ATM-altered ASTs/mCRPC
| . | Cohort A: ASTs . | Cohort B: mCRPC . |
|---|---|---|
| Efficacy | ||
| Response rate in pts with centrally confirmed ATM alterations, % (80% CI)* | N=28 7.1 (1.9, 17.9)† | N=13 7.7 (0.8, 26.8)‡ |
| Response rate in pts with centrally confirmed ATM PVs, % (80% CI) | N=28 7.1 (1.9, 17.9) | N=11 9.1 (1.0, 31.0) |
| Response rate in pts with centrally confirmed ATM-deficiency, % (80% CI) | N=11 18.2 (4.9, 41.5) | N=7 0.0 (0.0, 28.0) |
| Safety, n (%) | N=30 | N=15 |
| TEAEs | 30 (100) | 15 (100) |
| Grade ≥3 TEAEs | 15 (50.0) | 8 (53.3) |
| TRAEs | 21 (70.0) | 13 (86.7) |
| Grade ≥3 TRAEs | 6 (20.0) | 5 (33.3) |
| Serious TEAEs | 4 (13.3) | 4 (26.7) |
| Serious TRAEs | 2 (6.7) | 1 (6.7) |
| TEAEs leading to discontinuation | 1 (3.3)§ | 0 |
| TEAEs leading to death | 0 | 0 |
| TEAEs (any grade) occurring in ≥20% of pts in either cohort, n (%) | N=30 | N=15 |
| Nausea | 13 (43.3) | 8 (53.3) |
| Abdominal pain | 9 (30.0) | 1 (6.7) |
| Anemia | 8 (26.7) | 7 (46.7) |
| Fatigue | 8 (26.7) | 5 (33.3) |
| Asthenia | 8 (26.7) | 2 (13.3) |
| Decreased appetite | 7 (23.3) | 3 (20.0) |
| . | Cohort A: ASTs . | Cohort B: mCRPC . |
|---|---|---|
| Efficacy | ||
| Response rate in pts with centrally confirmed ATM alterations, % (80% CI)* | N=28 7.1 (1.9, 17.9)† | N=13 7.7 (0.8, 26.8)‡ |
| Response rate in pts with centrally confirmed ATM PVs, % (80% CI) | N=28 7.1 (1.9, 17.9) | N=11 9.1 (1.0, 31.0) |
| Response rate in pts with centrally confirmed ATM-deficiency, % (80% CI) | N=11 18.2 (4.9, 41.5) | N=7 0.0 (0.0, 28.0) |
| Safety, n (%) | N=30 | N=15 |
| TEAEs | 30 (100) | 15 (100) |
| Grade ≥3 TEAEs | 15 (50.0) | 8 (53.3) |
| TRAEs | 21 (70.0) | 13 (86.7) |
| Grade ≥3 TRAEs | 6 (20.0) | 5 (33.3) |
| Serious TEAEs | 4 (13.3) | 4 (26.7) |
| Serious TRAEs | 2 (6.7) | 1 (6.7) |
| TEAEs leading to discontinuation | 1 (3.3)§ | 0 |
| TEAEs leading to death | 0 | 0 |
| TEAEs (any grade) occurring in ≥20% of pts in either cohort, n (%) | N=30 | N=15 |
| Nausea | 13 (43.3) | 8 (53.3) |
| Abdominal pain | 9 (30.0) | 1 (6.7) |
| Anemia | 8 (26.7) | 7 (46.7) |
| Fatigue | 8 (26.7) | 5 (33.3) |
| Asthenia | 8 (26.7) | 2 (13.3) |
| Decreased appetite | 7 (23.3) | 3 (20.0) |
*Centrally confirmed ATM-altered patients were patients with either ATM PV confirmed by FMI F1CDx in tumor and/or by FMI F1 liquid CDx in circulating tumor DNA and/or ATM protein-deficient by immunohistochemistry assay at Ventana with cut-off ≤5%. Thus, ATM PV patients could also have ATM protein-deficiency.
†Objective response by RECIST v1.1, in centrally confirmed ATM-altered patients.
‡Composite response: by RECIST v1.1 for soft tissue and visceral lesions and PCWG3 criteria for bone lesions; confirmed conversion of circulating tumor cell count from ≥5/7.5 mL blood to <5/7.5 mL; or confirmed prostate-specific antigen decline of >50%, in centrally confirmed ATM-altered patients.
§Discontinuation due to decreased appetite classified as a serious adverse event.
ASTs, advanced solid tumors; CI, confidence interval; mCRPC, metastatic castration-resistant prostate cancer; PV, pathogenic variant; pts, patients; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event
Citation Format: Rahul Aggarwal, Antoine Italiano, Susan Domchek, Oscar Goodman, Sophie Postel-Vinay, Jesus Garcia-Donas, Tanya Dorff, Zachery Reichert, Philippe Cassier, Neal Shore, Catherine Marshall, Graeme Parr, Itziar Irurzun-Arana, Neel Shah, Natalia Lukashchuk, Olga Murina, Daniel Slade, Bienvenu Loembé, Emma Dean, Elhan Sanai, Wassim Abida. Efficacy and safety of ceralasertib in the PLANETTE study in patients (pts) with ATM-altered advanced solid tumors (ASTs) or metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT222.
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