Trial: Saruparib (AZD5305) vs Placebo in Men W…

Trial Details

Sponsor: AstraZeneca (industry)

Phase: 3

Start date: Nov. 21, 2023

Planned enrollment: 1800

Trial ID: NCT06120491

More trial details at ClinicalTrials.gov

Show Summary from Sponsor

Investigational Drug AI Analysis

Show for: AZD5305 (saruparib)

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)

TrialFetch AI Analysis

Goal: Determine whether adding saruparib to a physician-selected new hormonal agent improves radiographic progression-free survival in metastatic castration-sensitive prostate cancer, separately evaluating patients with and without homologous-recombination repair mutations (HRRm).

Patients: Men aged 18 years or older with metastatic, castration-sensitive prostate adenocarcinoma, measurable or assessable bone and/or soft-tissue disease, ECOG performance status 0–1, and recently initiated androgen-deprivation therapy or prior bilateral orchiectomy. Central testing of tumor tissue and/or circulating tumor DNA assigns patients to HRRm or non-HRRm cohorts. Major exclusions include prior treatment for metastatic disease except specified exceptions, persistent severe cytopenias, and unstable brain metastases or spinal cord compression.

Design: Randomized, double-blind, placebo-controlled trial with two biomarker-defined cohorts (approximately 550 HRRm and 1,250 non-HRRm patients). Within each cohort, patients are assigned 1:1 to saruparib or placebo alongside a physician-selected hormonal agent. Treatment and imaging continue until progression or treatment discontinuation; survival follow-up continues through study completion.

Treatments: Patients receive saruparib or matching placebo with physician-selected abiraterone acetate, darolutamide, or enzalutamide, on a background of castration therapy. Saruparib (AZD5305) is an investigational oral PARP1-selective inhibitor that inhibits PARP1 and traps it on damaged DNA, potentially exploiting homologous-recombination repair defects. In an uncontrolled phase 1/2a study in previously treated, HRR-mutated breast cancer, its objective response rate was 48.4% among 31 patients; this does not establish benefit in prostate cancer or in combination with hormonal therapy.

Outcomes: The primary endpoint is investigator-assessed radiographic progression-free survival using RECIST 1.1 for soft tissue and PCWG3 criteria for bone, or death. Secondary measures include overall survival, progression after subsequent therapy, time to subsequent treatment, symptomatic skeletal events, castration resistance, PSA responses and progression, pain, urinary symptoms, fatigue, physical function, quality of life, pharmacokinetics, biomarker and diagnostic-assay performance, and adverse events.

Burden on patient: Estimated moderate burden: oral treatment avoids infusion visits, but patients need regular clinic assessments and repeated CT/MRI and bone-disease evaluations until progression, with survival follow-up afterward. Screening requires a tumor tissue sample and blood for molecular testing; whether collection of a new biopsy is necessary is not specified. Additional blood sampling for pharmacokinetics and safety, plus repeated symptom and quality-of-life questionnaires, adds to routine metastatic prostate cancer care.

Last updated: Sep 2026

Eligibility

Show Criteria

Inclusion Criteria:

* Male ≥ 18 years of age.

* Histologically documented prostate adenocarcinoma which is de novo or recurrent and castration-sensitive. Participants with pathologic features of small cell, neuroendocrine, sarcomatoid, spindle cell, or signet cell histology are not eligible.

* Metastatic disease as documented by the investigator prior to randomisation, with clear evidence of ≥ 1 bone lesion and/or ≥ 1 soft tissue lesion that is suitable for repeated assessment with CT and/or MRI.

* Participant is receiving ADT with a GnRH analogue or has undergone bilateral orchiectomy starting ≥ 14 days and \< 4 months prior to randomisation.

* ECOG performance status of 0 or 1 with no deterioration over the 2 weeks prior to randomisation.

* Provision of FFPE tumour tissue sample and blood sample (for ctDNA).

* Confirmed HRRm status by central tumour tissue and/or ctDNA test is required to determine cohort eligibility.

* Adequate organ and bone marrow function as described in study protocol.

* Participants must not father children or donate sperm from signing ICF, during the study intervention and for 6 months after the last dose of study intervention.

* Participants must use a condom from signing ICF, during study intervention, and for 6 months after the last dose of study drug, with all sexual partners.

Exclusion Criteria:

* Participants with a history of MDS/AML or with features suggestive of MDS/AML (as determined by prior diagnostic investigation). In case there is no clinical MDS/AML suspicion, no specific screening for MDS/AML (by BM/bone biopsy) is required.

* Participants with any known predisposition to bleeding.

* Any history of persisting (\> 2 weeks) severe cytopenia.

* Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD5305 and/or the assigned NHA.

* History of another primary malignancy, with exceptions.

* Persistent toxicities (CTCAE Grade ≥ 2) caused by previous anticancer therapy.

* Spinal cord compression or brain metastases unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to start of study intervention.

* Cardiac criteria, including history of arrhythmia and cardiovascular disease.

* Any prior anticancer pharmacotherapy or surgery for metastatic prostate cancer, with exceptions.

* Prior treatment within 14 days with blood product support or growth factor support.

* Participants who are unevaluable for both bone and soft tissue progression.

Sites (410)

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Chermside, 4032, Australia

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Melbourne, 3000, Australia

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South Brisbane, 4101, Australia

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Krems, 3500, Austria

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Linz, 4020, Austria

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Vienna, 1020, Austria

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Vienna, 1090, Austria

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Calgary, Alberta, T2V 1P9, Canada

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Calgary, Alberta, T2N 5G2, Canada

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Abbotsford British Columbia, British Columbia, V2S 2J4, Canada

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Vancouver, British Columbia, V5Z 1H7, Canada

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Kelowna, British Columbia, V1Y 5L3, Canada

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Abbotsford British Columbia, British Columbia, V2T 1X8, Canada

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Kingston, Ontario, K7L 5P9, Canada

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Mississauga, Ontario, L5M 2N1, Canada

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Newmarket, Ontario, L3Y 2P9, Canada

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Ottawa, Ontario, K1H 8L6, Canada

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Toronto, Ontario, M4N 3M5, Canada

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Toronto, Ontario, M5G 2M9, Canada

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Chicoutimi, Quebec, G7H 5H6, Canada

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Greenfield Park, Quebec, J4V 2H1, Canada

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Montreal, Quebec, H2X 3E4, Canada

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Montreal, Quebec, H3T 1E2, Canada

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Montreal, Quebec, H4A 3J1, Canada

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Québec, Quebec, G1J 1Z4, Canada

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Saskatoon, Saskatchewan, S7N 4H4, Canada

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Poitiers, 86021, France

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Paris, 75679, France

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Nice, 06100, France

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Montpellier, 34298, France

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Lyon, 69373, France

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Clermont-Ferrand, 63011, France

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Bordeaux, 33000, France

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Tübingen, 72076, Germany

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Heidelberg, 69120, Germany

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Hamburg, 20246, Germany

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Münster, 48149, Germany

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Nürtingen, 72622, Germany

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Rozzano, 20089, Italy

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Milan, 20133, Italy

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Kuala Lumpur, 59100, Malaysia

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Kota Kinabalu, 88996, Malaysia

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Kuala Lumpur, 50586, Malaysia

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Johor Bahru, 81100, Malaysia

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George Town, 10450, Malaysia

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Kuching, 93586, Malaysia

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Nijmegen, 6525 GA, Netherlands

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Hilversum, 1213 XZ, Netherlands

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Seongnam-si, 13620, South Korea

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Daejeon, 35015, South Korea

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Seoul, 03080, South Korea

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Seoul, 03722, South Korea

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Seoul, 05505, South Korea

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Seoul, 06351, South Korea

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Seoul, 06591, South Korea

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Suwon, 16247, South Korea

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L'Hospitalet de Llobregat, 08908, Spain

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Madrid, 28040, Spain

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Madrid, 28041, Spain

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Istanbul, 34722, Turkey (Türkiye)

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Fatih-Istanbul, 34098, Turkey (Türkiye)

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Cordaleo, 35575, Turkey (Türkiye)

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Bornova-Izmir, 35100, Turkey (Türkiye)

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Ankara, 06590, Turkey (Türkiye)

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Ankara, 06340, Turkey (Türkiye)

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Cambridge, CB2 0QQ, United Kingdom

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Guildford, GU2 7XX, United Kingdom

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New Haven, Connecticut, 06510, United States

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Durham, North Carolina, 27710, United States

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Providence, Rhode Island, 02903, United States

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Myrtle Beach, South Carolina, 29572, United States

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San Antonio, Texas, 78229, United States

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Salt Lake City, Utah, 84132, United States

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