saruparib (AZD5305) / AstraZeneca - LARVOL DELTA

Modular Clinical Pharmacology Study to Evaluate the Drug-drug Interaction Potential and Relative Bioavailability of Saruparib (clinicaltrials.gov) - P1 | N=45 | Recruiting | Sponsor: AstraZeneca | Not yet recruiting ➔ Recruiting

Enrollment open • Oncology • Solid Tumor

Targeting PARP for the prevention of BRCA1-deficient triple-negative breast cancers (AACR 2025) - "Both talazoparib and AZD5305 greatly suppress the growth of syngrafted BRCA1-deficient tumors in mice. AZD5305 also delayed the development of TNBC mammary tumors in MMTV-Cre/BRCA1co/co/p53+/- mice. Based on these results, in the future, PARP inhibitors may be effective drugs to reduce the risk of BRCA1-deficient breast cancer."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • BRCA2 • PARP1

The potent and selective PARP1 inhibitor and trapper SNV1521 exhibits combination activity with targeted and chemotherapeutics (AACR 2025) - "When comparing with the target efficacious concentration using a BRCA2-deficient cell line versus the NOEL for suppression of heme progenitors, SNV1521 showed an expanded margin versus either olaparib or saruparib...In a PDX model of breast cancer, the combination of topotecan with SNV1521 showed deeper tumor regression than either agent alone. Moreover, this activity showed durable anti-tumor activity after cessation of dosing. In summary, these data support the continued clinical development of SNV1521 as monotherapy and also in combination with drugs that are mechanistically synergistic but cannot be effectively combined with less selective PARP1 inhibitors because of overlapping toxicities."

Breast Cancer • Oncology • Solid Tumor • BRCA • BRCA2 • PARP2

XL309 is a potent, selective, and orally bioavailable USP1 inhibitor active as monotherapy and in combination with PARP inhibitors or irinotecan (AACR 2025) - P1 | "XL309 also elicited durable tumor regression in combination with saruparib and irinotecan in a CDX model, and with olaparib in a PDX model... XL309 is potentially a best-in-class USP1 inhibitor. PK assessments in conjunction with preclinical antitumor activity suggest that once daily oral administration of XL309 may achieve clinical activity alone or in combination with PARP inhibitors. XL309 is currently under investigation in a phase 1 first-in-human trial as monotherapy and in combination with olaparib in patients with advanced solid tumors (NCT05932862)."

Combination therapy • Monotherapy • Oncology • Solid Tumor • BRCA • BRCA1 • BRCA2 • PCNA • USP1

Combination of the PARP1-selective inhibitor saruparib with androgen receptor pathway inhibition provides combination benefit in preclinical models of prostate cancer with or without homologous recombination repair deficiency (AACR 2025) - P1 | "We evaluated the activity of the PARP1-selective inhibitor and trapper saruparib (AZD5305) in combination with the ARPi enzalutamide in a range of preclinical models in vitro and in vivo...Strikingly, this was not observed with the weaker PARP1 trapper veliparib, suggesting a requirement for trapping-induced DNA damage...These preclinical data demonstrate combination activity of saruparib and ARPi in HRRm as well as non-HRRm prostate cancer models and provide mechanistic evidence that combination benefit is driven by PARP1 trapping inducing DNA damage, and PARP1 inhibition and ARPi inhibiting the repair of this damage, leading to accumulation of cytotoxic genomic instability to the cancer cells. A clinical study ASCERTAIN (NCT05938270) has been initiated, where the focus is on collection of pre- and post- treatment biopsies from monotherapy and combinations of saruparib, and the ARPi darolutamide, with the aim of increasing further understanding of mechanisms of..."

Preclinical • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • BRCA2 • CDK12 • HRD

Combined a B7-H3-targeting antibody-drug conjugate, 7MW3711, and PARP inhibitors synergistically potentiates the antitumor activity in B7-H3-positive cancers (AACR 2025) - "In vivo, mice bearing ovarian and SCLC tumor xenografts were treated with the combination of 7MW3711 and PARPi. Evaluation of the drug resistance ability in cell lines expressing P-gp revealed 7MW3711 exhibited > 3-fold more potent than DS7300 (B7-H3-directed DXd ADC), indicating that 7MW3711 has a lower efflux efficiency in drug-resistant strains. These data provide evidence for the potential utility of 7MW3711 combination with PARPi for treatment of B7-H3-expressing tumors and support the rationale for further clinical studies."

Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • H2AX

AZD5335, a folate receptor alpha-targeted ADC, enhances ovarian cancer treatment with bevacizumab, paclitaxel and/or carboplatin (AACR 2025) - "AZD5335, an FRα-targeting antibody conjugated to a topoisomerase 1 inhibitor (TOP1i) payload, is currently being investigated in the FONTANA Phase I/IIa clinical trial (NCT#05797168), either as a single agent or in combination with a PARP1-selective inhibitor (saruparib). A series of in vitro studies will also define the ADC/SOC drug interactions and further delineate underlying mechanisms driving enhanced efficacy. These studies inform our ongoing clinical development of AZD5335 in ovarian cancer."

Epithelial Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • FOLR1

A Randomized Phase 3 Study of First-Line Saruparib (AZD5305) Plus Camizestrant Versus CDK4/6i Plus Physician's Choice Endocrine Therapy or CDK4/6i Plus Camizestrant in Patients With HR+/ HER2– Advanced Breast Cancer With BRCA1/BRCA2/PALB2 Mutations (EvoPAR-B) (MBCC 2025) - P3 | "Participants will be randomized 2:2:1 to receive saruparib plus camizestrant, physician's choice CDK4/6i (abemaciclib, ribociclib, or palbociclib) plus physician's choice ET (fulvestrant, letrozole, anastrozole, or exemestane), or physician's choice CDK4/6i plus camizestrant, respectively. Status Participant enrollment is ongoing across 185 trial locations in 20 countries. Approximately 500 participants will be randomized across the 3 arms."

Clinical • Metastases • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • BRCA1 • BRCA2 • CDK4 • HER-2 • HRD • PALB2

S2409: Using Biomarker Tests to Select and Test New, Personalized Treatments for Extensive Stage Small Cell Lung Cancer, PRISM Study (clinicaltrials.gov) - P2 | N=900 | Not yet recruiting | Sponsor: SWOG Cancer Research Network | Initiation date: Mar 2025 ➔ Sep 2025

Trial initiation date • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • SLFN11

CONCORDE: A Platform Study of Novel Agents in Combination With Radiotherapy in NSCLC (clinicaltrials.gov) - P1 | N=200 | Recruiting | Sponsor: University of Leeds | Trial primary completion date: Apr 2025 ➔ Mar 2026

Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

D5330C00004: Ascending Doses of Ceralasertib in Combination With Chemotherapy and/or Novel Anti Cancer Agents (clinicaltrials.gov) - P1/2 | N=357 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Mar 2025 ➔ Dec 2025 | Recruiting ➔ Active, not recruiting

Enrollment closed • Trial completion date • Breast Cancer • Colorectal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Head and Neck Cancer • HER2 Breast Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • ATM • BRCA • HER-2 • HRD • RAD51C • RAD51D

An Update on the CONCORDE study: A Phase Ib Platform Study of DNA Damage Repair Inhibitors (DDRis) in Combination With Conventional Radiotherapy in NSCLC (BTOG 2025) - P1 | "In 2 study arms, participants also receive consolidation durvalumab ±DDRi for up to 12 months...The primary objective is to assess safety and to determine the recommended phase II dose of each DDRi. Since 17/03/21, 4 arms have opened: A (olaparib, PARPi), B (AZD1390, ATMi), C (ceralasertib, ATRi) and E (saruparib, PARP-1i)... CONCORDE continues to recruit patients to three study arms (A,C,E). The platform demonstrated excellent capability in identifying excess toxicity in DDRi-RT combinations, leading to Arm–B closure. Analysis of patient-reported outcomes and efficacy are ongoing."

Combination therapy • P1 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • PARP1

An update on the CONCORDE study: A phase Ib platform study of DNA damage repair inhibitors (DDRIs) in combination with conventional radiotherapy in NSCLC (ELCC 2025) - P1 | "Recruitment update: Since 17/03/21, 4 arms have opened: A (olaparib, PARPi), B (AZD1390, ATMi), C (ceralasertib, ATRi) and E (saruparib, PARP-1i)...DDRIs have been successfully escalated to dose level 2 (C + E) or 3 (A) with integration of consolidation durvalumab in 2 arms (C + E)...Analysis of patient-reported outcomes and efficacy are ongoing. A multimodality translational program to identify toxicity biomarkers is in development."

Combination therapy • P1 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PARP1

Modular Clinical Pharmacology Study to Evaluate the Drug-drug Interaction Potential and Relative Bioavailability of Saruparib (clinicaltrials.gov) - P1 | N=45 | Not yet recruiting | Sponsor: AstraZeneca

New P1 trial • Oncology • Solid Tumor

Duplexed CeTEAM drug biosensors reveal determinants of PARP inhibitor selectivity in cells. (PubMed, J Biol Chem) - "Our results reveal that most PARPi are equipotent for both PARPs, including the next-generation drug, senaparib. However, benzimidazole carboxamide (niraparib) derivatives demonstrated PARP1-selective tendencies, while pthalazinones (olaparib) favored PARP2. AZD5305, a reported PARP1-selective inhibitor with characteristics of both series, was the exception and appears ∼1600-fold more potent towards PARP1. In agreement with current understanding, we see that trapping-associated S/G2-phase transitions positively correlate with PARP1/2 binding potency, while some potent binders, such as veliparib, did not - likely reflecting their allosteric influence on DNA retention...The PARP1/2 CeTEAM platform thus provides a structural roadmap for the development of selective PARPi and should facilitate the discovery of targeted therapies. Furthermore, our results highlight that multiplexing CeTEAM biosensors and layered genetic perturbations can systematically profile determinants of..."

Journal • Oncology • PARP2

TalaCom: Phase Ib investigator-initiated trial combining talazoparib and axitinib in patients with DNA damage response mutated cancers or BRCA1/2 wildtype ovarian cancer incorporating prospective intrapatient dose titration (ESMO-TAT 2025) - P1 | "22/24 (92%) evaluable pts achieved RECIST SD or PR; 13/24 (54%) had tumor regressions, and 5/24 (21%) achieved RECIST PRs: 2 pts with BRCA2m HGSOC (one who progressed on prior olaparib, saruparib and camonsertib); 1 pt with BRCA2m peritoneal mesothelioma; 2 pts with mCRPC without DDR mutations (one who progressed on prior olaparib). The combination of axi + tala was generally manageable with durable antitumor activity in heavily pretreated HGSOC and CRPC pts, including pts who progressed on prior PARPi. Biomarker and PK analyses are ongoing."

Clinical • P1 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • High Grade Serous Ovarian Cancer • Mesothelioma • Oncology • Ovarian Cancer • Peritoneal Mesothelioma • Prostate Cancer • Solid Tumor • BRCA • BRCA1 • BRCA2 • BRIP1 • CDK12 • CHEK2 • PALB2 • RAD51C

BLUESTAR: A Phase I/IIa Study of AZD8205 Given Alone or in Combination With Anticancer Drugs, in Participants With Advanced or Metastatic Solid Malignancies (clinicaltrials.gov) - P1/2 | N=370 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Jun 2026 ➔ May 2027 | Trial primary completion date: Jun 2026 ➔ May 2027

Monotherapy • Trial completion date • Trial primary completion date • Biliary Cancer • Biliary Tract Cancer • Breast Cancer • Endometrial Cancer • Hepatology • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor

Targeting highly aggressive ductal prostate tumours with poly ADP ribose polymerase inhibitor (PARPi) and androgen receptor signaling inhibitor (ARSi) combination therapy. (ASCO-GU 2025) - "These organoids were exposed to different PARP inhibitors (Talazoparib, Saruparib) and androgen signalling inhibitors (Enzalutamide, Apalutamide, Darolutamide) for up to 11 days. Our results show that PARPi increases the efficacy of ARSi in DAC. This is notable given the poor response of DAC to AR-directed treatments and provides the rationale for a pre-planned phase 1/2 study."

Combination therapy • Genito-urinary Cancer • Oncology • Prostate Cancer • AR • BRCA2

Phase III, double-blind, placebo-controlled, 2-cohort, randomized study of saruparib (AZD5305) in combination with androgen receptor pathway inhibitors in patients with metastatic hormone-sensitive prostate cancer with and without homologous recombination repair mutation (EvoPAR-Prostate01). (ASCO-GU 2025) - P1/2, P3 | "The phase III EvoPAR-Prostate01 study (NCT06120491) is evaluating the efficacy and safety of saruparib plus physician's choice of ARPI (abiraterone, darolutamide, or enzalutamide) compared with placebo plus physician's choice of ARPI in participants with mHSPC. Approximately 1,800 participants (550 HRRm; 1,250 non-HRRm) will be randomized. Enrollment began in November 2023 and is ongoing."

Clinical • Combination therapy • Metastases • P3 data • Castration-Resistant Prostate Cancer • Castration-Sensitive Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ATM • BARD1 • BRCA1 • BRCA2 • CDK12 • HRD • PALB2 • PARP2 • RAD51B • RAD51C • RAD51D

PETRANHA: Study of AZD5305 When Given in Combination With New Hormonal Agents in Patients With Metastatic Prostate Cancer (clinicaltrials.gov) - P1/2 | N=190 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Nov 2030 ➔ Jul 2031 | Trial primary completion date: Nov 2030 ➔ Jul 2031

Trial completion date • Trial primary completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Saruparib: Data from P1/2a PETRA trial (NCT04644068) for advanced solid malignancies post 2026 (AstraZeneca) - Q4 & FY2024 Results: Data from P1/2a PETRANHA trial (NCT05367440) for metastatic prostate cancer post 2026

P1/2 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Saruparib: Data from P1 ASCERTAIN trial (NCT05938270) for newly diagnosed prostate cancer in 2026 (AstraZeneca) - Q4 & FY2024 Results

P1 data • Genito-urinary Cancer • Oncology • Prostate Cancer

Saruparib: Data from P3 EvoPAR-Prostate01 trial (NCT06120491) for metastatic CSPC post 2026 (AstraZeneca) - Q4 & FY2024 Results: Data from P3 EvoPAR-Breast01 trial (NCT06380751) in combination with camizestrant for HR+/HER2-negative advanced breast cancer post 2026

P3 data • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Prostate Cancer

Using Biomarker Tests to Select and Test New, Personalized Treatments for Extensive Stage Small Cell Lung Cancer, PRISM Study (clinicaltrials.gov) - P2 | N=900 | Not yet recruiting | Sponsor: SWOG Cancer Research Network

New P2 trial • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

A randomized phase III study of first-line saruparib (AZD5305) + camizestrant vs CDK4/6i plus physician's choice endocrine therapy or + camizestrant in patients w/ BRCA1/BRCA2/PALB2 mutations & HR+/HER2- advanced breast cancer (EvoPAR-Breast01) (SABCS 2024) - P3 | "Participants will be randomized 2:2:1 to receive saruparib plus camizestrant, physician's choice CDK4/6i (abemaciclib, ribociclib, or palbociclib) plus physician's choice ET (fulvestrant, letrozole, anastrozole, or exemestane), or physician's choice CDK4/6i plus camizestrant, respectively. Participant enrollment is ongoing. Approximately 500 participants will be randomized across the three arms."

Clinical • Metastases • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • BRCA1 • BRCA2 • CDK4 • HER-2 • HRD • PALB2 • PGR