Yet inevitable therapeutic resistance limits durability of clinical benefit and now defines the central pharmacological challenge of the field, driving development of next-generation DDR inhibitors including saruparib, ART6043, RP-3467, ART0380/alnodesertib, ceralasertib, and peposertib. We propose a biomarker-guided adaptive treatment algorithm integrating longitudinal circulating tumor DNA monitoring, functional RAD51 foci assays, and AI-driven multi-omics integration to enable real-time resistance detection and mechanism-guided therapy switching. This framework advances DDR-targeted oncology from static biomarker selection toward a dynamic, resistance-aware, mechanism-matched therapeutic strategy for patients with metastatic solid tumors.

13 days ago

Review • Journal • BRCA Biomarker • PARP Biomarker

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • ABCB1 (ATP Binding Cassette Subfamily B Member 1) • RAD51 (RAD51 Homolog A) • STING (stimulator of interferon response cGAMP interactor 1) • TP53BP1 (Tumor Protein P53 Binding Protein 1)

ceralasertib (AZD6738) • saruparib (AZD5305) • peposertib (M3814) • ART6043 • alnodesertib (ART0380)

16d

Testing the Addition of An Anti-cancer Drug, M3814 (Peposertib), to the Usual Radiation-Based Treatment (Lutetium Lu 177 Dotatate) for Pancreatic Neuroendocrine Tumors (clinicaltrials.gov)

P1, N=29, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2026 --> Dec 2026 | Trial primary completion date: Jun 2026 --> Dec 2026

16 days ago

Trial completion date • Trial primary completion date

peposertib (M3814) • Lutathera (lutetium Lu 177 dotatate)

20d

Testing the Addition of an Anti-cancer Drug, M3814, to the Usual Treatment (Mitoxantrone, Etoposide, and Cytarabine) for Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov)

P1, N=48, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2026 --> Jun 2027 | Trial primary completion date: Jun 2026 --> Jun 2027

20 days ago

Trial completion date • Trial primary completion date

RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia) • CD4 (CD4 Molecule)

cytarabine • etoposide IV • mitoxantrone • peposertib (M3814) • Starasid (cytarabine ocfosfate)

2ms

ETCTN 10563: Testing Low-Dose Common Chemotherapy (Liposomal Doxorubicin) in Combination With an Anti-Cancer Drug, Peposertib, in Advanced Sarcoma (clinicaltrials.gov)

P1, N=30, Recruiting, National Cancer Institute (NCI) | Trial completion date: May 2026 --> Nov 2026 | Trial primary completion date: May 2026 --> Nov 2026

2 months ago

Trial completion date • Trial primary completion date

pegylated liposomal doxorubicin • Myocet (non-pegylated liposomal doxorubicin) • peposertib (M3814) • Duomeisu (pegylated liposomal doxorubicin)

2ms

P1/2, N=90, Recruiting, National Cancer Institute (NCI) | Trial completion date: Apr 2026 --> Apr 2027 | Trial primary completion date: Apr 2026 --> Apr 2027

2 months ago

Trial completion date • Trial primary completion date

Bavencio (avelumab) • peposertib (M3814) • Xofigo (radium Ra-223 dichloride)

4ms

Targeting the Non-Homologous End-Joining Pathway Sensitizes MDM2-Amplified Liposarcoma to Doxorubicin by Enhancing p53-Mediated Senescence. (PubMed, Cancer Res)

Three parallel genome-wide CRISPR-Cas9 knockout screens were conducted in DDLPS cells to sensitize to palbociclib (CDK4 inhibitor), nutlin-3a (MDM2 inhibitor) or doxorubicin...Genetic perturbation of TDP2 or pharmacological inhibition of DNA-PKcs using peposertib synergized with prolonged administration of low-dose doxorubicin to induce cell cycle arrest and senescence, and subsequent senolytic treatment with Bcl2 inhibitor navitoclax triggered senescent cells to undergo apoptosis...These findings provide a rationale for targeting the NHEJ pathway to enhance the efficacy of low-dose doxorubicin in DDLPS, highlighting a potential therapeutic strategy exploiting p53-mediated cell cycle arrest and senescence. Furthermore, this study provides evidence of maintained baseline p53 activity in MDM2-amplified DDLPS.

4 months ago

Journal

CCNE1 (Cyclin E1) • MDM2 (E3 ubiquitin protein ligase) • CDK2 (Cyclin-dependent kinase 2) • PRKDC (Protein Kinase, DNA-Activated, Catalytic Subunit) • E2F3 (E2F transcription factor 3)

Ibrance (palbociclib) • doxorubicin hydrochloride • navitoclax (ABT 263) • peposertib (M3814)

4ms

Testing the Combination of New Anti-cancer Drug Peposertib With Avelumab and Radiation Therapy for Advanced/Metastatic Solid Tumors and Hepatobiliary Malignancies (clinicaltrials.gov)

P1/2, N=103, Active, not recruiting, National Cancer Institute (NCI) | Suspended --> Active, not recruiting

4 months ago

Enrollment closed • Tumor mutational burden

Bavencio (avelumab) • peposertib (M3814)

6ms

Testing the Combination of New Anti-cancer Drug Peposertib With Avelumab and Radiation Therapy for Advanced/Metastatic Solid Tumors and Hepatobiliary Malignancies (clinicaltrials.gov)

P1/2, N=103, Suspended, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Jul 2027 | Trial primary completion date: Dec 2025 --> Jul 2027

6 months ago

Trial completion date • Trial primary completion date • Tumor mutational burden

Bavencio (avelumab) • peposertib (M3814)

6ms

Testing the Addition of an Anti-cancer Drug, M3814, to the Usual Treatment (Mitoxantrone, Etoposide, and Cytarabine) for Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov)

P1, N=48, Active, not recruiting, National Cancer Institute (NCI) | Suspended --> Active, not recruiting

6 months ago

Enrollment closed

RARA (Retinoic Acid Receptor Alpha) • PML (Promyelocytic Leukemia) • CD4 (CD4 Molecule)

cytarabine • etoposide IV • mitoxantrone • peposertib (M3814) • Starasid (cytarabine ocfosfate)

7ms

NRG-HN008: Testing the Addition of M3814 (Peposertib) to Radiation Therapy for Patients With Advanced Head and Neck Cancer Who Cannot Take Cisplatin (clinicaltrials.gov)

P1, N=21, Active, not recruiting, National Cancer Institute (NCI) | N=42 --> 21 | Trial completion date: Dec 2025 --> Dec 2026

7 months ago

Enrollment change • Trial completion date

CD4 (CD4 Molecule)

peposertib (M3814)