Investigational Drug
AZD9574
HealthScout AI Analysis
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Overview
AZD9574 (palacaparib) is an investigational, brain‑penetrant, PARP1‑selective inhibitor and PARP1‑DNA trapper being developed for cancers with homologous recombination repair deficiency (HRD) and for primary or secondary brain tumors. A modular, first‑in‑human Phase I/IIa study (CERTIS1; NCT05417594) is ongoing to evaluate monotherapy and combinations (including temozolomide) across advanced solid tumors; as of the latest postings, no peer‑reviewed human efficacy outcomes have been reported. (cdek.pharmacy.purdue.edu)
Mechanism of action
- Selective PARP1 inhibition and trapping: AZD9574 potently inhibits PARP1 enzymatic activity (sub‑nanomolar to low‑nanomolar range in cell systems) and traps PARP1 on damaged DNA with minimal activity on PARP2 and other PARP family members (>8,000‑fold selectivity over PARP2 in biochemical assays). The design intent is to maintain antitumor activity while potentially reducing PARP2‑related hematologic toxicity seen with first‑generation PARP1/2 inhibitors. (aacrjournals.org)
- CNS penetration: Preclinical pharmacokinetic studies in rodents and non‑human primates demonstrate blood–brain barrier penetration, supporting development for glioma and brain metastases. (aacrjournals.org)
- Medicinal chemistry: A 2024 Journal of Medicinal Chemistry report details structure‑ and property‑based optimization to achieve PARP1 selectivity with improved permeability and reduced efflux, culminating in AZD9574. (pubs.acs.org)
Efficacy
Human clinical efficacy results have not yet been published in peer‑reviewed literature as of October 7, 2025.
Key preclinical findings include:
- Potent single‑agent antitumor activity in HRD models (e.g., BRCA1/2‑deficient breast/ovarian models) with tumor regressions in xenografts. (aacrjournals.org)
- Activity in intracranial xenograft models consistent with CNS penetration. (aacrjournals.org)
- Synergy with temozolomide (TMZ) in MGMT‑methylated orthotopic glioma models, prolonging survival versus TMZ alone. (aacrjournals.org)
Safety
No peer‑reviewed human safety outcomes have been published yet. In preclinical assessments:
- AZD9574 showed minimal single‑agent hematotoxicity in vitro versus olaparib and manageable hematologic effects in rat models. (aacrjournals.org)
- The PARP1‑selective profile (sparing PARP2) is proposed to contribute to a more favorable therapeutic index; this remains to be established clinically. (aacrjournals.org)
Clinical development
- CERTIS1 (NCT05417594): Phase I/IIa, open‑label, multicenter dose‑escalation/expansion study of AZD9574 as monotherapy and in combinations (including TMZ) in advanced solid tumors (e.g., HRR‑mutated breast, ovarian, prostate, pancreatic cancers; primary/secondary CNS tumors). Status: recruiting/active at multiple U.S. centers. (cdek.pharmacy.purdue.edu)
Further reading
- Preclinical pharmacology and CNS penetration: Clinical Cancer Research, 2024 (preclinical characterization). (aacrjournals.org)
- Discovery/optimization chemistry: Journal of Medicinal Chemistry, 2024. (pubs.acs.org)
- Early conference abstracts (preclinical CNS and HRD models): AACR/Neuro‑Oncology 2022. (aacrjournals.org)
- Trial information (CERTIS1): trial listings and institutional pages. (cdek.pharmacy.purdue.edu)
If additional peer‑reviewed clinical data become available, the efficacy and safety sections should be updated accordingly.
Last updated: Oct 2025
Active trials using AZD9574
Found 3 active trials using this drug:
HealthScout AI summary: Adults with metastatic castration‑resistant prostate adenocarcinoma (ECOG 0–1) with documented progression and adequate organ function receive AZD0516, a STEAP2‑targeted antibody–drug conjugate delivering an exatecan topoisomerase I inhibitor, either as monotherapy or combined with AZD9574 (palacaparib), a selective PARP1 inhibitor. Requires available tumor tissue; excludes prior STEAP2‑targeted therapy and significant CNS, pulmonary, infectious, or cardiovascular comorbidities.
ClinicalTrials.gov ID: NCT07181161
HealthScout AI summary: Adults with advanced, measurable solid tumors (ECOG 0–1) eligible for biopsy, including FRα‑expressing cancers such as ovarian, receive the investigational FRα‑targeted topoisomerase‑I ADC AZD5335 (torvutatug samrotecan) as monotherapy or combined with bevacizumab, carboplatin (± bevacizumab), or PARP1‑selective inhibitors (saruparib or AZD9574). Aimed at patients who have exhausted standard options, with exclusions for uncontrolled CNS disease and significant comorbidities; early data suggest higher activity in FRα‑high tumors.
ClinicalTrials.gov ID: NCT05797168
HealthScout AI summary: This trial enrolls adults with advanced or metastatic solid tumors—including breast, ovarian, prostate, pancreatic (HRR-mutated), IDH1/2-mutant glioma, and other selected solid cancers—who have progressive disease and good performance status, testing the selective PARP1 inhibitor AZD9574 as monotherapy or in combination with temozolomide, trastuzumab deruxtecan, or datopotamab deruxtecan. Eligibility may require specific genetic or molecular features depending on tumor type and study module.
ClinicalTrials.gov ID: NCT05417594
