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

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)

HealthScout AI Analysis

Goal: Evaluate whether adding the PARP1-selective inhibitor saruparib (AZD5305) to a physician’s choice next-generation hormonal agent (NHA) improves radiographic progression-free survival versus placebo plus NHA in metastatic castration-sensitive prostate cancer (mCSPC), and to assess effects on survival, subsequent therapy, symptoms, quality of life, and safety in biomarker-defined cohorts (HRR-mutated and non-HRR-mutated).

Patients: Adult men (≥18 years) with histologically confirmed metastatic castration-sensitive prostate adenocarcinoma, ECOG 0–1, with at least one bone and/or measurable soft-tissue lesion suitable for serial imaging, on continuous ADT or post-orchiectomy. Both HRR-mutated and non-HRR-mutated patients are enrolled, with central confirmation of HRR status via tumor tissue and/or ctDNA. Key exclusions include prior MDS/AML, significant bleeding risk or persistent severe cytopenias, uncontrolled GI conditions affecting absorption, unstable CNS/spinal cord compression, significant cardiac comorbidities/arrhythmias, recent anticancer therapy for metastatic disease beyond allowed exceptions, and inability to be evaluated for bone and soft tissue progression.

Design: Global, randomized, double-blind, placebo-controlled, two-cohort phase III study. Approximately 1800 participants stratified by HRR mutation status (about 550 HRRm and 1250 non-HRRm) are randomized 1:1 to saruparib plus NHA or placebo plus NHA. Treatment continues until radiographic progression or other discontinuation criteria, with survival follow-up. An independent DMC oversees safety and tolerability.

Treatments: Experimental: Saruparib (AZD5305) plus physician’s choice NHA (abiraterone, darolutamide, or enzalutamide). Control: Placebo plus physician’s choice NHA. Saruparib is a next-generation, highly selective PARP1 inhibitor with approximately 500-fold selectivity over PARP2, designed to retain antitumor activity via PARP1 trapping and synthetic lethality in HRR-deficient tumors while potentially lowering hematologic toxicity associated with PARP2 inhibition. Early-phase data (PETRA, phase 1/2a) in HER2-negative breast cancer reported an objective response rate near 48% at the recommended 60 mg daily dose, with a median PFS around 9 months and relatively low rates of grade ≥3 hematologic toxicity, supporting further evaluation in HRR-driven settings. The NHAs are standard-of-care androgen signaling inhibitors used in mCSPC.

Outcomes: Primary: Radiographic progression-free survival per investigator using RECIST 1.1 (soft tissue) and PCWG3 (bone), or death. Key secondary endpoints include overall survival; PFS2; time to first subsequent therapy or death; symptomatic skeletal event–free survival; time to first castration-resistant event; time to pain progression; time to deterioration in urinary symptoms, fatigue, and physical function; health-related quality of life measures; PSA-based endpoints (≥50% and ≥90% declines, undetectable PSA rate, time to PSA progression); safety and tolerability (TEAEs, SAEs, dose modifications). Additional endpoints include BRCA/HRR mutation status, saruparib plasma concentrations, and development/validation of companion diagnostics.

Burden on patient: Moderate. Patients will undergo standard-of-care imaging at regular intervals to assess rPFS, routine lab monitoring for safety and PSA kinetics, and continuous ADT plus daily oral NHA with study drug or placebo. Added burdens include mandatory submission of archival or fresh FFPE tumor tissue and serial blood draws for ctDNA and pharmacokinetics in the saruparib arm, along with patient-reported outcome questionnaires at scheduled visits. Visit frequency and imaging are typical for phase III mCSPC trials; however, additional biomarker sampling and occasional PK assessments increase on-site time and venipuncture compared with standard therapy alone. Overall travel and testing are consistent with large phase III prostate trials, without procedures such as intensive dose-escalation PK schedules or inpatient monitoring.

Last updated: Oct 2025

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.

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