AZD5305

Shows activity

Also known as:

saruparib

Cancer types include:

breast cancer ovarian cancer prostate cancer small cell lung cancer uterine cancer

TrialFetch AI Analysis

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Overview

AZD5305 (saruparib) is an oral, next‑generation, highly selective PARP1 inhibitor and trapper being developed for tumors with homologous recombination repair (HRR) defects. Compared with first‑generation dual PARP1/2 inhibitors, saruparib was designed to retain antitumor activity while reducing PARP2‑related hematologic toxicity, thereby broadening combination potential. Preclinical and early‑phase clinical data support activity with a favorable tolerability profile, and multiple phase 3 studies are underway. (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

Selective PARP1 inhibition and trapping: AZD5305 inhibits PARP1 with approximately 500‑fold selectivity over PARP2, inducing cytotoxicity via PARP1‑DNA trapping and synthetic lethality in HRR‑deficient cells. In preclinical systems it produced deeper, more durable tumor regressions than olaparib and showed minimal effects on hematologic parameters at efficacious exposures. (pubmed.ncbi.nlm.nih.gov)

Efficacy

PETRA (NCT04644068), first‑in‑human phase I/IIa:
In HER2‑negative, HRR‑deficient advanced breast cancer treated at the recommended phase 2 dose (RP2D) of 60 mg once daily, the objective response rate (ORR) was 48.4%, median progression‑free survival (PFS) 9.1 months, and median duration of response (DoR) 7.3 months (data presented at AACR 2024). Dose exploration also showed activity at 20 mg and 90 mg, but 60 mg was selected as RP2D based on the totality of efficacy, PK/PD, and safety. (aacr.org)
Preclinical translational data:
In patient‑derived xenograft models with BRCA1/2 alterations, saruparib achieved higher complete response rates and markedly longer preclinical PFS than olaparib; combinations with carboplatin or the ATR inhibitor ceralasertib further enhanced activity, including in models with acquired PARPi resistance. (genomemedicine.biomedcentral.com)
Ongoing/late‑phase development:
EvoPAR‑Prostate01 (NCT06120491), a phase 3, randomized, double‑blind study in metastatic castration‑sensitive prostate cancer, is testing saruparib plus a new hormonal agent vs placebo plus hormonal agent, with radiographic PFS as the primary endpoint; enrollment began in November 2023 and is ongoing. (ascopubs.org)

Safety

PETRA (RP2D 60 mg) safety overview (all tumor types):
Among 141 patients who received 60 mg, adverse events occurred in 92.2%, treatment‑related AEs in 76.6%, serious treatment‑related AEs in 2.1%, and discontinuations due to treatment‑related AEs in 3.5%. Reported common AEs included anemia, neutropenia, thrombocytopenia, fatigue, and asthenia. (aacr.org)
PETRANHA (NCT05367440), phase I/II study in metastatic prostate cancer combining saruparib (60 mg) with enzalutamide, abiraterone/prednisone, or darolutamide:
Interim analysis (data cutoff July 10, 2023; n=48) showed the combinations were generally well tolerated with no dose‑limiting toxicities; common AEs were anemia (52.1%; grade ≥3: 16.7%), fatigue (50.0%; grade ≥3: 2.1%), and neutropenia (33.3%; grade ≥3: 6.3%); discontinuations due to AEs were uncommon. No clinically significant drug–drug interactions were observed. (ascopubs.org)

Active trials using AZD5305

Found 4 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

TrialFetch 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

A Randomised, Open-Label, Phase III Study of Saruparib (AZD5305) Plus Camizestrant Compared With Physician's Choice CDK4/6 Inhibitor Plus Endocrine Therapy or Plus Camizestrant for the First-Line Treatment of Patients With BRCA1, BRCA2, or PALB2 Mutations and Hormone Receptor Positive, HER2-Negative (IHC 0, 1+, 2+/ ISH Non-amplified) Advanced Breast Cancer (EvoPAR-Breast01)

Sponsor: AstraZeneca (industry) Phase: 3 Start date: Aug. 1, 2024

TrialFetch AI summary: This trial enrolls adults with untreated, locally advanced or metastatic HR-positive, HER2-negative breast cancer and germline BRCA1, BRCA2, or PALB2 mutations, to compare saruparib (a PARP1-selective inhibitor) plus camizestrant (an oral SERD) versus physician's choice of CDK4/6 inhibitor plus endocrine therapy or plus camizestrant as first-line treatment.

ClinicalTrials.gov ID: NCT06380751

A Randomized, 2-cohort, Double-blind, Placebo-controlled, Phase III Study of Saruparib (AZD5305) in Combination With Physician's Choice New Hormonal Agents in Patients With HRRm and Non-HRRm Metastatic Castration-Sensitive Prostate Cancer (EvoPAR-Prostate01)

Sponsor: AstraZeneca (industry) Phase: 3 Start date: Nov. 21, 2023

TrialFetch AI summary: Men with metastatic castration-sensitive prostate adenocarcinoma (ECOG 0–1) are randomized to physician’s choice of abiraterone, enzalutamide, or darolutamide plus the PARP1-selective inhibitor saruparib (AZD5305) versus placebo, with parallel cohorts for HRR-mutated and non-HRR–mutated disease. Saruparib selectively inhibits and traps PARP1 to exploit HRR deficiency, aiming to improve radiographic PFS while potentially reducing hematologic toxicity seen with nonselective PARP inhibitors.

ClinicalTrials.gov ID: NCT06120491

A Modular Phase I/IIa, Open-label Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of Ascending Doses of AZD5335 Monotherapy and in Combination With Anti-cancer Agents in Participants With Solid Tumors

Sponsor: AstraZeneca (industry) Phase: 1/2 Start date: June 5, 2023

TrialFetch 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