Investigational Drug
AZD5305
TrialFetch AI Analysis
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Overview
Saruparib (AZD5305) is an investigational, orally administered, next-generation poly(ADP-ribose) polymerase inhibitor being developed by AstraZeneca. It is designed to selectively target PARP1 in tumors with homologous-recombination repair (HRR) deficiencies, particularly those carrying BRCA1, BRCA2, PALB2, RAD51C, or RAD51D alterations. Clinical development includes monotherapy and combination studies in breast, ovarian, pancreatic and prostate cancers; randomized phase 3 trials are underway. (ascopubs.org)
Mechanism of action
Saruparib selectively inhibits PARP1 catalytic activity and traps PARP1 on damaged DNA, disrupting DNA repair and replication. This produces synthetic lethality in HRR-deficient cancer cells. Preclinical testing found approximately 500-fold selectivity for PARP1 over PARP2 and a cellular PARylation-inhibition IC₅₀ of 2.3 nM. Avoiding PARP2 inhibition is intended to reduce hematologic toxicity and widen the therapeutic window relative to first-generation dual PARP1/2 inhibitors. (pmc.ncbi.nlm.nih.gov)
Efficacy
In the phase 1/2a PETRA trial, 31 previously treated, PARP-inhibitor–naive patients with advanced HER2-negative breast cancer and eligible HRR mutations received the recommended dose of 60 mg once daily. The objective response rate was 48.4% (15/31; 80% CI 35.7%–61.3%), median duration of response was 7.3 months, and median progression-free survival was 9.1 months. Responses were reported in tumors with BRCA1, BRCA2 or PALB2 mutations. These are uncontrolled, early-phase results and cannot establish comparative benefit. (aacr.org)
Early combination findings have also been reported. In 35 evaluable patients with advanced ER-positive/HER2-negative breast cancer, saruparib plus camizestrant produced an objective response rate of 22.9%, median response duration of 5.5 months, and median progression-free survival of 4.4 months. Among nine evaluable patients with BRCA1/2 or PALB2 mutations, the response rate was 33.3%. (aacrjournals.org)
Safety
Among 141 PETRA participants with different tumor types treated at 60 mg, 92.2% experienced an adverse event and 12.1% experienced a serious adverse event. Treatment-related adverse events occurred in 76.6%; treatment-related serious events occurred in 2.1%. Dose reductions for treatment-related toxicity occurred in 14.2%, and treatment-related discontinuations in 3.5%. Common treatment-related toxicities included anemia, neutropenia, thrombocytopenia, fatigue and asthenia. Longer follow-up and randomized trials are needed to characterize uncommon or delayed risks. (aacr.org)
Further reading
- Preclinical characterization of AZD5305
- Discovery and medicinal chemistry of AZD5305
- PETRA first-in-human clinical abstract
- AACR summary of updated PETRA results
- Patient-derived BRCA1/2-associated cancer-model study
Last updated: Sep 2026
Active trials using AZD5305
Found 5 active trials using this drug:
TrialFetch AI summary: Adults with progressive metastatic castration-resistant prostate cancer after androgen receptor pathway inhibitor therapy receive oral AZD9750, an androgen receptor–degrading PROTAC, alone or with saruparib, a PARP1-selective inhibitor. Cohorts include both taxane-exposed and taxane-naive patients.
ClinicalTrials.gov ID: NCT07336446
TrialFetch AI summary: Adults with extensive-stage SCLC who complete first-line platinum–etoposide plus durvalumab without progression are assigned by tumor subtype and SLFN11 status to maintenance durvalumab alone or durvalumab plus a biomarker-directed agent. The added agent is saruparib (PARP1 inhibitor), ceralasertib (ATR inhibitor), or monalizumab (NKG2A-blocking antibody), depending on the assigned cohort.
ClinicalTrials.gov ID: NCT06769126
TrialFetch AI summary: Adults with previously untreated unresectable locally advanced or metastatic HR-positive, HER2-negative breast cancer and a germline BRCA1, BRCA2, or PALB2 loss-of-function mutation are randomized to saruparib, a selective PARP1 inhibitor, plus camizestrant, an estrogen-receptor degrader; physician-selected CDK4/6 inhibition plus standard endocrine therapy; or CDK4/6 inhibition plus camizestrant.
ClinicalTrials.gov ID: NCT06380751
TrialFetch AI summary: Men with metastatic castration-sensitive prostate cancer and ECOG performance status 0–1 are enrolled in separate cohorts based on homologous-recombination repair mutation status. Patients receive investigational saruparib, a PARP1-selective inhibitor that traps PARP1 on damaged DNA, or placebo with physician-selected abiraterone, darolutamide, or enzalutamide plus ongoing castration therapy.
ClinicalTrials.gov ID: NCT06120491
TrialFetch AI summary: Adults with previously treated advanced solid tumors, measurable disease, and ECOG performance status 0–1 receive AZD5335, a folate receptor alpha–targeted antibody–drug conjugate delivering a topoisomerase I inhibitor. It is studied alone or with the PARP1 inhibitors saruparib or AZD9574, bevacizumab, or carboplatin with or without bevacizumab; module-specific eligibility may apply.
ClinicalTrials.gov ID: NCT05797168
