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| Ref Type | abstract | ||||||||||||
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| Authors | 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 | ||||||||||||
| Title | Abstract CT222: 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) | ||||||||||||
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| URL | https://aacrjournals.org/cancerres/article/84/7_Supplement/CT222/742542/Abstract-CT222-Efficacy-and-safety-of-ceralasertib | ||||||||||||
| Abstract Text | 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. | ||||||||||||
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| ATM inact mut | prostate cancer | no benefit | Ceralasertib | Phase II | Actionable | In a Phase IIa trial (PLANETTE), Ceralasertib (AZD6738) treatment demonstrated manageable safety but limited efficacy in patients with metastatic castration-resistant prostate cancer harboring ATM mutations and/or ATM loss (n=15), with a composite response rate of 7.7% (1/13) in patients with confirmed ATM mutations (Cancer Res (2024) 84 (7_Supplement): CT222; NCT04564027). | detail... |
| ATM negative | Advanced Solid Tumor | no benefit | Ceralasertib | Phase II | Actionable | In a Phase IIa trial (PLANETTE), Ceralasertib (AZD6738) treatment demonstrated manageable safety but limited efficacy in patients with advanced solid tumors excluding non-small cell lung cancer harboring ATM mutations and/or loss of ATM protein expression (n=30), resulting in an objective response rate of 7.1% (2/28, 1 complete and 1 partial response) (Cancer Res (2024) 84 (7_Supplement): CT222; NCT04564027). | detail... |
| ATM negative | prostate cancer | no benefit | Ceralasertib | Phase II | Actionable | In a Phase IIa trial (PLANETTE), Ceralasertib (AZD6738) treatment demonstrated manageable safety but limited efficacy in patients with metastatic castration-resistant prostate cancer harboring ATM mutations and/or loss of ATM protein expression (n=15), resulting in a composite response rate of 7.7% (1/13) (Cancer Res (2024) 84 (7_Supplement): CT222; NCT04564027). | detail... |
| ATM inact mut | Advanced Solid Tumor | no benefit | Ceralasertib | Phase II | Actionable | In a Phase IIa trial (PLANETTE), Ceralasertib (AZD6738) treatment demonstrated manageable safety but limited efficacy in patients with advanced solid tumors excluding non-small cell lung cancer harboring ATM mutations and/or loss of ATM protein expression (n=30), resulting in an objective response rate of 7.1% (2/28, 1 complete and 1 partial response) (Cancer Res (2024) 84 (7_Supplement): CT222; NCT04564027). | detail... |