saruparib (AZD5305) / AstraZeneca - LARVOL DELTA

Phase 1/2 PETRANHA trial: Saruparib + apalutamide + androgen deprivation therapy (ADT) in patients (pts) with metastatic prostate cancer (PC) (ESMO 2026) - No abstract available

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

PARTHENON: A phase I/IIa study of AZD4956, a DNA polymerase theta (POLQ) inhibitor, as monotherapy or in combination with saruparib in patients with homologous recombination repair (HRR) deficient advanced/metastatic solid tumours (ESMO 2026) - No abstract available

Clinical • Combination therapy • Metastases • Monotherapy • P1/2 data • Oncology • Solid Tumor • HRD • POLQ

Combination of PARPi and topoisomerase I inhibitors is highly effective in olaparib-resistant ovarian cancer. (PubMed, Exp Hematol Oncol) - "The combination was well tolerated and primarily worked by inducing apoptosis and increased DNA damage. These findings suggest that TOP1 inhibitors combined with PARP inhibitors could be a promising treatment strategy for olaparib-resistant ovarian cancer."

Journal • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor

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

PETRA: first-in-human Phase 1/2a trial of the first-in-class new generation poly(ADP-ribose) polymerase-1 selective inhibitor (PARP1i) saruparib (AZD5305) in patients (pts) with advanced solid tumors with BRCA1/2, PALB2 or RAD51C/D mutations (AACR 2024) - P1/2 | "Saruparib showed very encouraging efficacy, a favorable safety profile, robust target engagement, and a wide therapeutic index. The RP2D was 60 mg QD, based on improved clinical efficacy and favorable safety profile, supported by substantial PK, PD and preclinical data.Table. Saruparib Safety and Efficacy at 60 mg QD*Patients with multiple events in the same category are counted only once in that category."

Clinical • First-in-human • Metastases • P1/2 data • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • BRCA1 • BRCA2 • HER-2 • PALB2 • RAD51C • RAD51D

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

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

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

ASCERTAIN: An open-label, randomized, phase 1, window-of-opportunity study to investigate the biological effects of AZD5305 and darolutamide alone or in combination in men with prostate cancer eligible for radical prostatectomy. (ASCO-GU 2024) - P1 | "The Phase 3 PROpel study showed that first-line combination treatment with olaparib and abiraterone significantly improved radiographic progression-free survival (rPFS) over abiraterone alone in pts with metastatic castration-resistant PC (mCRPC) (hazard ratio [HR], 0.66; 95% CI, 0.54 to 0.81; p<0.001). Similarly, the Phase 3 TALAPRO-2 study showed that first-line talazoparib with enzalutamide resulted in statistically significant improvement in rPFS over enzalutamide alone in pts with mCRPC (HR, 0.63; 95% CI, 0.51 to 0.78; p<0.0001)...Enrollment began in September 2023; sites across North America, Europe and Australia will enroll up to 120 patients. Clinical trial information: NCT05938270."

Clinical • P1 data • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • PARP2

Experience pooling control arms within a complex phase I drug-radiotherapy (RT) platform trial (ESMO-TAT 2024) - P1 | "Table: 77P Treatment within each study arm Study arm 6 week RT period 1 year consolidation period CONCORDE-A Olaparib+RT No treatment RT only CONCORDE-B AZD1390+RT RT only CONCORDE-C Ceralasertib+RT Cerelasertib + durvalumab RT only Durvalumab CONCORDE-E AZD5305+RT Durvalumab RT only Results CONCORDE opened to recruitment in April 2021. Conclusions Pooling RT only patients across arms to estimate DLT rates presents a useful concurrent comparator to put the estimated DLT rate for informing dose escalation into context, and the rate in RT+DDRi patients to help attribute toxicity to the combination of DDRi and thoracic RT. The platform design necessitates fewer comparator patients, compared with multiple standalone comparison design trials."

P1 data • Lung Cancer • Oncology • Solid Tumor

Saruparib in HRDsig+ Solid Tumors (clinicaltrials.gov) - P2 | N=124 | Not yet recruiting | Sponsor: Abramson Cancer Center at Penn Medicine

New P2 trial • Platinum sensitive • Oncology • Ovarian Cancer • Solid Tumor

RAD51C breast cancer-identified variants with attenuated homologous recombination function exhibit sensitivity to combined PARP1 and ATR inhibition. (PubMed, NAR Cancer) - "While RAD51C variants with attenuated HR are largely resistant to monotherapy, cells expressing a subset of these RAD51C variants exhibit increased sensitivity to combination PARP1i and ATRi treatment, Saruparib and Ceralasertib, respectively. Collectively, we pinpoint the key functional regions of RAD51C and uncover a new C-terminal region proximal to the ATP-binding site in the folded RAD51C structure. Together, our findings suggest that variants with partial HR function can cause profound defects in the repair of replicative damage, and that this, in turn, may lead to distinct therapeutic responses."

Journal • Breast Cancer • Oncology • Solid Tumor • RAD51C

PETRA: First in class, first in human trial of the next generation PARP1-selective inhibitor AZD5305 in patients (pts) with BRCA1/2, PALB2 or RAD51C/D mutations (AACR 2022) - P1/2 | "AZD5305 is a highly selective PARP1 inhibitor and trapper with excellent physiochemical properties and a wide therapeutic index. It led to maximal target engagement and showed promising clinical activity with favorable tolerability at exposures surpassing those of 1st generation PARPi. >"

Clinical • P1 data • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • BRCA1 • BRCA2 • MUC16 • PALB2 • RAD51C • RAD51D

An Update on the CONCORDE study: A Phase Ib Platform Study of Novel Agents in Combination With Conventional Radiotherapy in NSCLC (IASLC-WCLC 2023) - P1 | "The primary objective is to assess safety and determine the recommended phase II dose of each DDRi+RT combination. As of 23/03/2023, CONCORDE-A (olaparib), CONCORDE-B (AZD1390) and CONCORDE-C (ceralasertib with consolidation durvalumab) are open to recruitment across 9 centres. The trial continues to recruit and CONCORDE-E (RT+/-AZD5305 with consolidation durvalumab) has been submitted and is due to open in May 2023. One further study arm is planned (CONCORDE-F). A parallel multimodality translational program to identify biomarkers of treatment response, toxicity and the impact on the immune system are in development."

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

Olaparib, AZD1390, ceralasertib, saruparib and consolidation durvalumab (CONCORDE) phase Ib platform study of novel DNA damage response inhibitor (DDRi) agents in combination with radiotherapy in non-small cell lung cancer (NSCLC). (ASCO 2024) - "A parallel multimodality translational program to identify biomarkers of treatment response, toxicity and the impact on the immune system are in development. Biomarkers of interest include plasma toxicity markers, immune cell profiling, radiomics and ctDNA."

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

Targeted Pathway Inhibition in Patients With Pancreatic Cancer (clinicaltrials.gov) - P1 | N=90 | Recruiting | Sponsor: OHSU Knight Cancer Institute | Trial primary completion date: Jun 2026 ➔ Jun 2027

Trial primary completion date • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Phase III, double-blind, placebo-controlled, 2-cohort, randomized study of saruparib (AZD5305) in combination with new hormonal agents in patients with metastatic castration-sensitive prostate cancer with and without homologous recombination repair mutati (AUA 2024) - No abstract available

Clinical • Combination therapy • Metastases • P3 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • HRD

Gut Microbiota-Isoallolithocholic Acid Crosstalk Promotes Calcium Oxalate Kidney Stone Formation via PARP1-Mediated Parthanatos. (PubMed, Adv Sci (Weinh)) - "Knockdown of PARP1 by adeno-associated virus microinjection or pharmacological inhibition with PARP1 inhibitor AZD5305 significantly attenuates isoalloLCA-mediated crystal deposition, renal tubular injury, and mitochondrial functional impairment in both the CaOx rat and mouse models...In vitro, isoalloLCA promoted oxalate-induced renal tubular epithelial cell injury and parthanatos via targeting PARP1, including DNA damage, excessive PARP1 activation, PAR accumulation, mitochondrial damage, nuclear translocation of AIF and MIF. These findings establish the microbiota-isoalloLCA-PARP1-parthanatos axis in CaOx nephrolithiasis and identify PARP1 as a promising therapeutic target for kidney stone management."

Journal • Nephrology • Renal Calculi • Transplantation • PARP1

A highly sensitive and specific PARylation assay confirms significant and durable target engagement by AZD5305 in patients (AACR 2023) - P1/2 | "Table. Residual PARylation levels by dose in the PETRA study20 mg 60 mgTime post-dose1 hour4 hours1 hour4 hoursPatients with >90% PARylation inhibition, n (%)9/15 (60.0)10/15 (66.7)11/13 (84.6)10/13 (76.9)Median residual PARylation levels (residual PARylation), %5.35.04.03.7"

Clinical • Oncology • Solid Tumor

Phase III, randomized, double-blind, placebo-controlled study of adjuvant saruparib (AZD5305) in patients with BRCAm localized high-risk prostate cancer who are receiving radiotherapy and androgen deprivation therapy (EvoPAR-Prostate02). (ASCO-GU 2026) - P1/2, P3 | "In both Cohort A (ADT alone) and Cohort B (ADT plus abiraterone/prednisone), randomization is 1:1 to saruparib or placebo. Approximately 700 patients will be randomized. Recruitment began in July 2025 and is ongoing."

Clinical • P3 data • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor • BRCA1 • BRCA2

TiP: Randomized, double-blind, placebo-controlled phase III trial of adjuvant treatment with saruparib (AZD5305) in patients with localized BRCA1/BRCA2m high-risk prostate cancer receiving radiotherapy and ADT (EvoPAR-Prostate02) | NCT0695280 (NORDKONGRESS 2026) - P1/2, P3 | "Randomization to saruparib or placebo is 1:1 in both cohort A (ADT alone) and cohort B (ADT plus abiraterone/prednisone). Approximately 700 patients will be randomized. Recruitment began in July 2025 and is ongoing."

Clinical • P3 data • Acute Myelogenous Leukemia • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor • BRCA1

Selective PARP1 inhibitors (2021-2025): patent landscape, structural evolution, and future therapeutic opportunities. (PubMed, Expert Opin Ther Pat) - "Particular emphasis is placed on the structural evolution of AZD5305-derived compounds and emerging quinazolinone- and isoquinolinone-based chemotypes...Despite significant progress, the disclosed chemical space remains relatively limited, highlighting opportunities for further scaffold diversification and differentiated patent strategies. These advances are expected to facilitate the development of next-generation PARP1-targeted therapeutics with improved safety profiles and broader clinical potential."

Journal • Review • Hematological Disorders • Oncology • HRD

From dual inhibition to precision selectivity: the molecular rationale and clinical evolution of next-generation PARP1-selective inhibitors in solid tumors. (PubMed, Front Oncol) - "Standard PARP inhibitors such as olaparib, rucaparib, niraparib, and talazoparib have been shown to inhibit both PARP1 and PARP2, and have shown significant clinical efficacy in breast, ovarian, prostate, and pancreatic cancers...These limitations led to the use of next-generation selective PARP1 inhibitors, such as saruparib (AZD5305), with approximately 500-fold higher selectivity for PARP1 over PARP2 with potent antitumor activity and reduced hematological toxicity...Collectively PARP1 inhibitors have demonstrated clinically impactful advancement that exhibits anticancer effect without causing significant hematological toxicity. They have potential of treating patients who benefit from PARP1 inhibitor-based precision oncology."

Journal • Review • Hematological Disorders • Neutropenia • Oncology • Pancreatic Cancer • Solid Tumor • Thrombocytopenia • BRCA • BRCA1 • BRCA2 • HRD • PARP2

Modular Clinical Pharmacology Study to Evaluate the Drug-drug Interaction Potential and Relative Bioavailability of Saruparib (clinicaltrials.gov) - P1 | N=41 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Apr 2026 ➔ May 2028

Trial completion date • Oncology • Solid Tumor

EvoPAR-Breast01: Saruparib (AZD5305) Plus Camizestrant or Plus Endocrine Therapy, Compared With CDK4/6 Inhibitor Plus Endocrine Therapy or Plus Camizestrant in HR-Positive, HER2-Negative (IHC 0, 1+, 2+/ ISH Non-amplified), BRCA1, BRCA2, or PALB2m Advanced Breast Cancer (clinicaltrials.gov) - P3 | N=788 | Recruiting | Sponsor: AstraZeneca | N=500 ➔ 788 | Trial completion date: Oct 2030 ➔ Dec 2031 | Trial primary completion date: Mar 2029 ➔ Dec 2029

Enrollment change • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • BRCA1 • BRCA2 • HER-2