saruparib (AZD5305) / AstraZeneca - LARVOL DELTA

PETRANHA: Study of AZD5305 When Given in Combination With New Hormonal Agents in Patients With Metastatic Prostate Cancer (clinicaltrials.gov) - P1/2 | N=174 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting

Enrollment closed • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Phase 1/2a trial of new generation PARP1-selective inhibitor saruparib + next generation selective ER degrader (SERD) camizestrant in patients (pts) with advanced/relapsed ER+/HER2-negative or low (HER2−) breast cancer (PETRA Module 6) (SABCS 2025) - P1/2, P3 | "Pts could receive prior CDK4/6 inhibitors or fulvestrant, but not oral SERDs. Saruparib + camizestrant was well tolerated with no new safety signals versus prior monotherapy studies of each drug. PK of saruparib in combination with camizestrant was consistent with monotherapy data. Preliminary efficacy of the combination was promising and compared favorably with camizestrant monotherapy."

Clinical • Metastases • P1/2 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • BRCA1 • BRCA2 • ER • HER-2 • PALB2

Combination therapy overcomes secondary PARPi resistance in ATM-deficient prostate cancer. (PubMed, NPJ Precis Oncol) - "To address this, we generated in vitro prostate cancer models of acquired PARPi resistance to olaparib and saruparib, a novel selective PARP1 inhibitor and pursued functional characterization and drug sensitivity studies. Consistently, we demonstrate in vivo that the combination of PARPi-ATRi in resistant models restores treatment sensitivity through enhancing replication stress. Collectively, these findings highlight an interplay between ATM-ATR signaling as a key mediator of PARPi sensitivity in ATM-deficient mPC and identify a promising therapeutic combination to prolong treatment response and potentially improve patients' outcomes."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ATM • CHEK1 • HRD

Phase III study: saruparib + camizestrant vs CDK4/6i regimens in HR+/HER2– ABC with BRCA/PALB2 mutations (EvoPAR-Breast01) (ABC8 2025) - No abstract available

P3 data • Oncology • BRCA • CDK4 • HER-2 • PALB2

A Master Protocol Study to Investigate Biomarker-guided Novel Anticancer Agent(s) as Monotherapy or Combination Therapy in Participants With Advanced/Recurrent Ovarian Cancer (clinicaltrials.gov) - P1/2 | N=30 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting

Biomarker • Enrollment closed • Monotherapy • Oncology • Ovarian Cancer • Solid Tumor

A randomized phase III study of first-line saruparib (AZD5305) plus camizestrant vs 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-Breast01) (DGHO 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. Overall survival (OS) is a secondary endpoint. Approximately 500 participants will be randomized."

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

Saruparib: Data from P1/2 trial (NCT07060365) for newly diagnosed BRCA1/2m advanced/recurrent ovarian cancer post 2026 (AstraZeneca) - Q3 2025 Results

P1/2 data • Oncology • Ovarian Cancer

Potent combination activity of B7-H4 TOP1i ADC puxitatug samrotecan with the monovalent bispecific anti-PD-1/TIGIT antibody rilvegostomig and PARP1 inhibitor saruparib in experimental cancer models (SITC 2025) - "Flow cytometry of the dissociated tumors revealed a greater than 2-fold increase in intratumoral CD3 positive T cells, including a greater than 3-fold increase in cytotoxic effector CD8 positive T cells after triplet therapy compared to untreated mouse tumors. Further, there were decreased intratumoral myeloid derived suppressor cells (MDSCs) and increased macrophages expressing the co-stimulatory molecule CD86 in the triplet therapy group compared to the untreated group.Conclusions Robust anti-tumor activity and tumor immune microenvironment modulation can be achieved with the combination of patuxitug-samrotecan, saruparib and rilvegostomig.Ethics Approval The studies described were approved by the Institutional Animal Care and Use Committee of Astrazeneca under protocol AUP22-25."

Preclinical • Endometrial Cancer • Oncology • Solid Tumor • BIRC5 • CD8 • CD86 • TIGIT • VTCN1

Discovery of selective PARP1/EZH2 inhibitor inducing PANoptosis in triple-negative breast cancer. (PubMed, Eur J Med Chem) - "In this study, we combined the structure of the latest second-generation selective PARP1 inhibitor AZD5305 to design and synthesize a series of second-generation selective PARP1/EZH2 dual inhibitors...Meanwhile, compared with the previous first-generation inhibitors, its permeability has improved, but its overall pharmacokinetic characteristics still need to be further optimized. However, as a novel selective PARP multifunctional molecule, it remains a highly promising potential compound for the for the treatment of TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • PARP2

KBD111 is a highly selective, long-acting and brain-penetrant PARP1 inhibitor (ESMO 2025) - "Background Currently, several pan-PARP inhibitors such as olaparib, niraparib, and rucaparib are approved for the treatment of cancers with homologous recombination deficiency (HRD)...Results KBD111 exhibited over 5,000-fold selectivity for PARP2 by DNA-trapping assays, demonstrated potent anti-proliferative activity against BRCA-mutant cancer cell lines, while showing markedly reduced cytotoxicity toward normal CD34 + hematopoietic stem cells (IC 50 >10,000 nM) compared to talazoparib (IC 50 = 27 nM)...Furthermore, KBD111 achieved superior tumor growth inhibition compared to AZD5305 in DLD-1 BRCA2 - / - xenograft models following once-weekly oral dosing. In an intracranial MDA-MB-436-luc model, KBD111 also demonstrated enhanced efficacy relative to AZD9574 under QW oral dosing...A phase 1 trial is planned for 2026. Legal entity responsible for the study The authors."

Oncology • BRCA • BRCA2 • CD34 • HRD • PARP2

First interim efficacy analysis of the phase I/II PETRANHA trial of saruparib + androgen receptor pathway inhibitors (ARPI) in patients (pts) with metastatic prostate cancer (mPC) (ESMO 2025) - P1/2 | "Methods Pts, allocated by investigator choice, received saruparib 60 mg once daily (OD) + enzalutamide 160 mg OD (Arm 1), abiraterone 1000 mg OD + 5 mg prednisone OD or twice daily (BD; Arm 2), or darolutamide 600 mg BD (Arm 3) until disease progression or intolerable adverse event (AE)...Arm 4 (+ apalutamide 240 mg OD) is ongoing dose escalation and was not included in this analysis...EvoPAR-01 is an ongoing phase 3 study evaluating this combination in mCSPC. Table: 2384MO mCRPC Prior ARPI N=19 mCRPC ARPI-naïve N=31 mCSPC N=27 Median duration of saruparib / ARPI exposure, months (range) 5.5 (1.2–17.7) / 5.5 (1.1–17.7) 14.7 (0.3–24.8) / 15.7 (0.4–24.8) 17.8 (0.2–28.2) / 19.7 (0.2–28.2) Any AE, n (%) 18 (94.7) 31 (100) 26 (96.3) Any AE causally related to saruparib, n (%) 16 (84.2) 28 (90.3) 23 (85.2) Any AE Gr ≥3, n (%) 6 (31.6) 16 (51.6) 14 (51.9) Any serious AE, n (%) 4 (21.1) 10 (32.3) 4 (14.8) Saruparib / ARPI discontinuation due to AE, n (%) 1 (5.3) / 1..."

Clinical • Metastases • P1/2 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • HRD

Resistance to trastuzumab deruxtecan acquired through multifaceted pathway alterations in preclinical models (AACR-NCI-EORTC 2025) - "These preclinical studies demonstrate that T-DXd resistance in HER2-expressing cell lines emerges via multifaceted mechanisms, including reduced HER2 expression, altered ADC trafficking/internalization, increased efflux, and changes in payload sensitivity."

Preclinical • Oncology • ABCC1 • ABCG2 • TOP2A

AstraZeneca advances its ambition to redefine cancer care with new data across its diverse, industry-leading portfolio and pipeline at the European Society for Medical Oncology (ESMO) Congress, October 17-21, 2025. (AstraZeneca Press Release)

Clinical data • Platinum resistant • pMMR • Tumor mutational burden • Castration-Resistant Prostate Cancer • Cholangiocarcinoma • Colorectal Cancer • Endometrial Cancer • Gastric Cancer • Hormone Sensitive Prostate Cancer • Non Small Cell Lung Cancer • Ovarian Cancer • Triple Negative Breast Cancer

Saruparib Plus ARPI Shows Promising Efficacy in Metastatic Prostate Cancer (Targeted Oncology) - "Data from the efficacy-evaluable population showed that objective response rates were 88.5% (23/26) in patients with metastatic castration-sensitive prostate cancer (mCSPC), 25% (2/8) in patients with metastatic castration-resistant prostate cancer (mCRPC) who had prior ARPI, and 73.3% (11/15) in patients with ARPI-naive mCRPC. Rates of prostate specific antigen (PSA) reduction >90% were 100%, 5.6%, and 53.3% in the 3 groups, respectively, and rates of undetectable PSA (<0.2 ng/mL), were 83.3%, 5.3%, and 29.0%, respectively."

P1/2 data • Castration-Resistant Prostate Cancer • Hormone Sensitive Prostate Cancer

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: Mar 2027 ➔ Sep 2027 | Trial primary completion date: Mar 2027 ➔ Sep 2027

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

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 | Recruiting | Sponsor: SWOG Cancer Research Network | Not yet recruiting ➔ Recruiting

Biomarker • Enrollment open • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • SLFN11

A Master Protocol Study to Investigate Biomarker-guided Novel Anticancer Agent(s) as Monotherapy or Combination Therapy in Participants With Advanced/Recurrent Ovarian Cancer (clinicaltrials.gov) - P1/2 | N=30 | Recruiting | Sponsor: AstraZeneca | Not yet recruiting ➔ Recruiting

Biomarker • Enrollment open • Monotherapy • Oncology • Ovarian Cancer • Solid Tumor

PETRANHA: Study of AZD5305 When Given in Combination With New Hormonal Agents in Patients With Metastatic Prostate Cancer (clinicaltrials.gov) - P1/2 | N=175 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Apr 2026 ➔ Apr 2031 | Trial primary completion date: Apr 2026 ➔ Apr 2031

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

EvoPAR - eine randomisierte, doppelblinde, Placebo-kontrollierte, multizentrische Phase III-Studie mit adaptivem Design zu AZD5305 vs. Placebo jeweils in Kombination mit einer neuen hormonellen Substanz (NHA) nach Prüfarztwahl bei Männern mit mHSPC (DGU 2025) - "The results of the Phase III PROpel study showed a significant improvement in rPFS in mCRPC patients who received the combination of olaparib and abiraterone compared to patients who received abiraterone alone. In addition to the primary endpoint of rPFS in the ITT population and the secondary endpoint of overall survival, PFS2, TFST, ORR, and other parameters will be investigated. Stratification will be performed according to BRCA/HRR status, disease volume, and the investigator's choice of NHA."

Clinical • P3 data • Castration-Resistant Prostate Cancer • Prostate Cancer • BRCA • PARP2

PETRA: Study of AZD5305 as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Malignancies (clinicaltrials.gov) - P1/2 | N=702 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting

Enrollment closed • Monotherapy • Biliary Cancer • Bladder Cancer • Breast Cancer • Cervical Cancer • Colorectal Cancer • Endometrial Cancer • Estrogen Receptor Positive Breast Cancer • Gastric Cancer • Genito-urinary Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Small Cell Lung Cancer • Solid Tumor

EvoPAR-PR02: A Study of Metastases Free Survival With Saruparib vs Placebo Added to a Standard RT/ADT in Men With High-risk Prostate Cancer With a BRCA Mutation (clinicaltrials.gov) - P3 | N=700 | Recruiting | Sponsor: AstraZeneca | Not yet recruiting ➔ Recruiting

Enrollment open • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • BRCA

PETRANHA: Study of AZD5305 When Given in Combination With New Hormonal Agents in Patients With Metastatic Prostate Cancer (clinicaltrials.gov) - P1/2 | N=175 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Apr 2031 ➔ Apr 2026 | Trial primary completion date: Apr 2031 ➔ Apr 2026

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

Discovery of PARP1- and CDK2-selective inhibitors for targeted therapy in cancer (ACS-Fall 2025) - "The first program targeted homologous recombination repair deficient tumors, such as those harboring a BRCA mutation (BRCAm), through PARP1 inhibition, structure-based drug design campaign that led to the discovery of new generation, selective PARP1 inhibitor and DNA trapper Saruparib (AZD5305) and CNS-penetrant PARP1-selective inhibitor and DNA trapper AZD9574. The second campaign targeted cyclin E (CCNE)-amplified or overexpressed tumors through inhibition of CDK2 activity, which led to the discovery of CDK2-selective inhibitor AZD8421. AZD8421 is highly selective for CDK2 over other members of the CDK family as well as the broader kinome and demonstrated efficacy in CCNE-amplified ovarian PDX models."

Oncology • BRCA • HRD

Saruparib: Data from P3 EvoPAR-Prostate01 trial (NCT06120491) for metastatic CSPC post 2026 (AstraZeneca) - H1 and Q2 2025 Results: Data from P1 ASCERTAIN trial (NCT05938270) for newly diagnosed prostate cancer in H1 2026

P1 data • P3 data • Genito-urinary Cancer • Hormone Sensitive Prostate Cancer • Oncology • Prostate Cancer

Saruparib + camizestrant: Data from P3 EvoPAR-Breast01 trial (NCT06380751) for HR+/HER2-negative advanced breast cancer post 2026 (AstraZeneca) - H1 and Q2 2025 Results

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