Ceralasertib

Shows activity

Also known as:

AZD6738

Cancer types include:

breast cancer cervical cancer colon cancer head and neck cancer kidney cancer

HealthScout AI Analysis

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Overview

Ceralasertib (AZD6738) is an oral, selective inhibitor of the serine/threonine kinase ATR, a master regulator of the DNA damage response to replication stress. It is being studied as monotherapy and in combinations (e.g., with PARP inhibition, chemotherapy, and PD-1/PD-L1 blockade) across multiple solid tumors. It is not FDA-approved. Preclinical and translational work suggest greatest activity in tumors with high replication stress and/or defects in DNA repair pathways (e.g., ATM loss, BRCA1/2 alterations). (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

ATR senses replication stress and halts cell-cycle progression via CHK1; ceralasertib blocks ATR signaling, impairing S/G2 checkpoints, increasing DNA double-strand breaks (γH2AX), and promoting cell death, with synthetic-lethal effects in ATM-deficient contexts and synergy with PARP inhibition and certain chemotherapies. (pubmed.ncbi.nlm.nih.gov)

Efficacy

Selected human studies (non-exhaustive):

Melanoma (post–anti-PD-1): Phase II ceralasertib + durvalumab (n=30) showed ORR 31.0%, disease control rate (DCR) 63.3%, median PFS 7.1 months, median OS 14.2 months. Responses occurred across cutaneous, acral, and mucosal subtypes. (pubmed.ncbi.nlm.nih.gov)
Advanced gastric cancer: Phase II ceralasertib + durvalumab (n=31) reported ORR 22.6% (95% CI 9.6–41.1), DCR 58.1%, median PFS 3.0 months, median OS 6.7 months; exploratory analyses suggested longer PFS in tumors with ATM loss and/or high HRD mutational signature. (pubmed.ncbi.nlm.nih.gov)
Ovarian cancer:
PARP inhibitor–resistant, HR-deficient, platinum-sensitive HGSOC (CAPRI, acquired PARPi resistance; n=12 efficacy-evaluable): ceralasertib + olaparib produced ORR 50% (6 PRs); grade 3/4 AEs in 38%. (aacrjournals.org)
Platinum-resistant, PARPi-naïve HGSOC (CAPRI platinum-resistant cohort; n=12 evaluable): no objective responses; median PFS 4.2 months overall (8.2 months in BRCA1-mutated subset). (pubmed.ncbi.nlm.nih.gov)
Basket study of advanced cancers with DDR alterations (n=25): ceralasertib + olaparib yielded overall ORR 8.3% and CBR 62.5%; signals of activity in ATM-mutated tumors and PARPi-resistant BRCA1/2-mutated HGSOC. (pubmed.ncbi.nlm.nih.gov)
Chemotherapy combinations:
Weekly paclitaxel (Phase I, n=57): ORR 22.6% overall; in melanoma (n=33, post–anti-PD-1), ORR 33.3%; RP2D ceralasertib 240 mg BID days 1–14 plus paclitaxel. (aacrjournals.org)
Carboplatin (Phase I, n=36): preliminary activity with two confirmed PRs; RP2D established as ceralasertib 40 mg QD days 1–2 with carboplatin AUC5 q3w. (aacrjournals.org)
ATM-altered tumors (monotherapy): PLANETTE Phase 2a (conference report). In advanced solid tumors with centrally confirmed ATM alterations (n=28), ORR 7.1% (1 CR in breast cancer, 1 PR in endometrial cancer); limited activity also in mCRPC cohort (composite response rate 7.7%). (aacrjournals.org)

Overall, clinical activity appears context-dependent: notable signals in combination with PD-L1 inhibition in melanoma and gastric cancer, with PARP inhibition in selected ovarian cancer settings (particularly after PARPi resistance in HR-deficient disease), and with paclitaxel in melanoma; limited monotherapy activity in unselected ATM-altered tumors. (pubmed.ncbi.nlm.nih.gov)

Safety

Across studies, the most common adverse events are hematologic and generally manageable with dose modifications: - Hematologic: anemia, thrombocytopenia, neutropenia (often grade ≥3 with chemotherapy or PARP inhibitor combinations). (aacrjournals.org) - Non-hematologic: fatigue, nausea, anorexia; with durvalumab combinations, anemia (grade ≥3 in ~33%) and rare serious events (e.g., one death from febrile neutropenia in a patient with pre-existing infection) were reported. (ascopubs.org)

Dose and schedule materially affect tolerability; e.g., carboplatin combinations required very short ceralasertib dosing windows to mitigate myelosuppression, while paclitaxel and olaparib regimens used intermittent ceralasertib dosing (often 7–14 days per 28-day cycle). (aacrjournals.org)

Active trials using Ceralasertib

Found 5 active trials using this drug:

PRISM: PRecIsion in SCLC Via a Multicohort Study: Randomized Phase II Studies Evaluating Maintenance Durvalumab With or Without Biomarker-Directed Therapy for Extensive Stage Small Cell Lung Cancer (ES-SCLC)

Sponsor: SWOG Cancer Research Network (federal) Phase: 2 Start date: Jan. 10, 2025

HealthScout AI summary: Adults with extensive-stage SCLC who have not progressed after induction platinum–etoposide plus durvalumab and have adequate tissue for central subtyping (A/N/I/P) and SLFN11 testing are randomized to durvalumab maintenance alone versus durvalumab plus a biomarker-directed agent: PARP1 inhibitor saruparib for subtype P or SLFN11+ A/N; ATR inhibitor ceralasertib for SLFN11– A/N; or NKG2A inhibitor monalizumab for subtype I. Treated, stable brain metastases allowed; leptomeningeal disease excluded.

ClinicalTrials.gov ID: NCT06769126

Phase 1/1B Study of DS-8201a in Combination With ATR Inhibition (AZD6738) in Advanced Solid Tumors With HER2 Expression (DASH Trial)

Sponsor: National Cancer Institute (NCI) (federal) Phase: 1 Start date: Aug. 9, 2021

HealthScout AI summary: This trial enrolls adults with advanced or metastatic HER2-expressing solid tumors—particularly colorectal and gastroesophageal cancers after progression on standard therapy—and evaluates intravenous trastuzumab deruxtecan (a HER2-targeted antibody-drug conjugate) in combination with oral ceralasertib (a selective ATR kinase inhibitor targeting DNA damage response pathways).

ClinicalTrials.gov ID: NCT04704661

A Phase II Study of Chemo-Immunotherapy Followed by Durvalumab (MEDI4736) and Ceralasertib (AZD6738) in Treatment Naïve Patients With Extensive Stage Small Cell Lung Cancer (ES-SCLC) Big Ten Cancer Research Consortium BTCRC-LUN18-363

Sponsor: Muhammad Furqan (other) Phase: 2 Start date: April 20, 2021

HealthScout AI summary: Untreated adults with extensive-stage SCLC (ECOG 0–1), including those with treated/stable brain metastases, receive induction platinum–etoposide plus durvalumab followed by maintenance durvalumab with ceralasertib. Ceralasertib is an oral ATR kinase inhibitor targeting the DNA damage response to potentiate cytotoxic and PD-L1–directed immunotherapy.

ClinicalTrials.gov ID: NCT04699838

Overcoming PARP Inhibitor Resistance in BRCA Germline Mutation Positive Advanced Breast Cancer

Sponsor: M.D. Anderson Cancer Center (other) Phase: 2 Start date: July 28, 2020

HealthScout AI summary: Eligible patients are adult women with HER2-negative, germline BRCA-mutated advanced or metastatic breast cancer previously treated with a PARP inhibitor, randomized to olaparib plus cediranib (a VEGFR 1/2/3 tyrosine kinase inhibitor targeting angiogenesis) or olaparib plus ceralasertib (an ATR kinase inhibitor targeting the DNA damage response pathway). Both regimens are oral and require patients to have measurable disease and good performance status.

ClinicalTrials.gov ID: NCT04090567

Phase II Trial of Ceralasertib (AZD6738) Alone and in Combination With Olaparib or Durvalumab in Patients With Selected Solid Tumor Malignancies

Sponsor: Rahul Aggarwal (other) Phase: 2 Start date: Jan. 17, 2019

HealthScout AI summary: Adults with advanced solid tumors after ≥1 prior therapy, enriched for ARID1A-altered cancers, ATM-deficient tumors (including mCRPC), and a post–checkpoint inhibitor endometrial cancer cohort; measurable disease required. Patients receive the ATR inhibitor ceralasertib (monotherapy for BAF250a-negative ARID1A or ATM-loss, ceralasertib + PARP inhibitor olaparib for BAF250a-positive ARID1A, or ceralasertib + anti–PD-L1 durvalumab for endometrial), leveraging DNA damage response targeting and potential synergy with PARP inhibition or immunotherapy.

ClinicalTrials.gov ID: NCT03682289