Berzosertib

Overview

Berzosertib (VX-970, VE-822; also M6620) is an investigational, first‑in‑class, small‑molecule inhibitor of the serine/threonine kinase ATR, a key regulator of the DNA damage response to replication stress. It has been evaluated mostly in combination with DNA‑damaging chemotherapy across multiple tumor types. Randomized phase 2 data exist in platinum‑resistant ovarian cancer, relapsed small‑cell lung cancer (SCLC), metastatic urothelial carcinoma, and metastatic castration‑resistant prostate cancer (mCRPC). (aacrjournals.org)

Mechanism of action

• ATR senses single‑stranded DNA and replication stress, activating the ATR–CHK1 axis to pause the cell cycle and enable repair. Berzosertib is an ATP‑competitive ATR inhibitor that abrogates this checkpoint, increasing cytotoxicity from DNA‑damaging agents (e.g., gemcitabine, cisplatin, topotecan, radiation). Preclinical work and reviews describe radiosensitization and chemosensitization effects consistent with this mechanism. (aacrjournals.org)

Efficacy

• Platinum‑resistant high‑grade serous ovarian cancer (randomized phase 2, NCI‑9944): Adding berzosertib to gemcitabine improved investigator‑assessed progression‑free survival (median 22.9 vs 14.7 weeks; HR 0.57; one‑sided P=0.044). Final overall survival (OS) with longer follow‑up did not significantly improve in the intent‑to‑treat population, but signals of benefit were seen in predefined or exploratory subgroups: platinum‑free interval ≤3 months (HR 0.48; one‑sided P=0.04) and “replication stress–low” tumors (HR 0.39; 90% CI 0.17–0.91) or ATM‑negative/low tumors (HR 0.50; one‑sided P=0.06). (pubmed.ncbi.nlm.nih.gov)

• Relapsed SCLC (randomized phase 2, topotecan ± berzosertib): The combination did not improve PFS (median 3.9 vs 3.0 months; HR 0.80; P=0.44) but significantly improved OS (median 8.9 vs 5.4 months; HR 0.53; P=0.03). Objective response rate (ORR) numerically favored the combination (26% vs 6%) without statistical significance. (pmc.ncbi.nlm.nih.gov)

• Metastatic urothelial carcinoma (randomized phase 2, cisplatin/gemcitabine ± berzosertib): No PFS benefit (median 8.0 months in both arms); response rate 54% with berzosertib vs 63% control; OS trended shorter with berzosertib (14.4 vs 19.8 months). (ascopubs.org)

• mCRPC (randomized phase 2, carboplatin + berzosertib vs docetaxel + carboplatin): Trial halted for futility at interim; ORR 0% with carboplatin + berzosertib vs 15% with docetaxel + carboplatin; higher grade ≥3 adverse events with berzosertib arm. (ascopubs.org)

• Early‑phase combination studies:

• Gemcitabine ± cisplatin: Recommended phase 2 dose (RP2D) established; preliminary disease control/partial responses observed. (pubmed.ncbi.nlm.nih.gov)
• Cisplatin combinations: RP2D identified; partial responses seen even after prior platinum. (pubmed.ncbi.nlm.nih.gov)
• NSCLC (phase 1b, berzosertib + gemcitabine): ORR 10.5% overall, with higher ORR in subsets with higher TMB or genomic LOH; regimen tolerated. (pubmed.ncbi.nlm.nih.gov)
• Topotecan combinations (nonrandomized SCLC POC): single‑arm ORR 36% informed the subsequent randomized study. (ascopost.com)

Safety

• Across studies, myelosuppression is the dominant toxicity, reflecting overlapping effects with cytotoxic partners:
• Ovarian cancer (gemcitabine ± berzosertib): grade 3/4 neutropenia 47% vs 39%; thrombocytopenia 24% vs 6%; one treatment‑related death in each arm (pneumonitis with berzosertib combination; sepsis with gemcitabine alone). (pubmed.ncbi.nlm.nih.gov)
• Urothelial carcinoma (cisplatin/gemcitabine ± berzosertib): higher grade 3/4 thrombocytopenia (59% vs 39%) and neutropenia (37% vs 27%) with berzosertib; more toxicity‑related discontinuations; lower cumulative cisplatin dose delivered in the combination arm. (ascopubs.org)
• Relapsed SCLC (topotecan ± berzosertib): adverse event profiles were similar overall; grade 3/4 thrombocytopenia 50% vs 55% (combo vs control). (pmc.ncbi.nlm.nih.gov)
• Early‑phase work identified RP2Ds with gemcitabine or cisplatin backbones and manageable hematologic toxicity profiles. (pubmed.ncbi.nlm.nih.gov)

Further reading

• Lancet Oncology randomized phase 2 in platinum‑resistant ovarian cancer (primary PFS analysis). (pubmed.ncbi.nlm.nih.gov)
• JCO Precision Oncology final OS/biomarker analyses in ovarian cancer. (ascopubs.org)
• JAMA Oncology randomized phase 2 in relapsed SCLC (topotecan ± berzosertib). (pmc.ncbi.nlm.nih.gov)
• ASCO 2021 randomized phase 2 in metastatic urothelial carcinoma (cisplatin/gemcitabine ± berzosertib). (ascopubs.org)
• ASCO 2021 randomized phase 2 in mCRPC (carboplatin + berzosertib vs docetaxel + carboplatin). (ascopubs.org)
• Phase 1 combination studies with gemcitabine and/or cisplatin; NSCLC expansion cohort. (pubmed.ncbi.nlm.nih.gov)
• Mechanistic overview and radiosensitization data in preclinical models. (aacrjournals.org)

Notes: As of October 2025, berzosertib remains investigational; no regulatory approvals were identified in the cited literature. Efficacy signals appear context‑dependent, with the most consistent benefit observed in platinum‑resistant ovarian cancer subgroups selected by clinical (very short platinum‑free interval) or biomarker features (low replication stress/ATM‑low), while randomized studies in urothelial cancer and mCRPC were negative and the SCLC trial showed an OS advantage without PFS improvement. (ascopubs.org)

Last updated: Oct 2025