saruparib (AZD5305) / AstraZeneca - LARVOL DELTA

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

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) - P3 | "Clinical Trial Registration Number: NCT06120491 The abstract will be released to the public on February 10, 2025 at 2:00 PM PST"

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

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

Discovery of 6-Fluoro-5-{4-[(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (AZD9574): A CNS-Penetrant, PARP1-Selective Inhibitor. (PubMed, J Med Chem) - "PARP inhibitors have attracted considerable interest in drug discovery due to the clinical success of first-generation agents such as olaparib, niraparib, rucaparib, and talazoparib. Recently, there has been interest in central nervous system (CNS)-penetrant PARP inhibitors for CNS malignancies and other neurological conditions; however, AZD5305 is not CNS penetrant. Herein we describe the discovery and optimization of a series of CNS-penetrant, PARP1-selective inhibitors and PARP1-DNA trappers, culminating in the discovery of AZD9574, a compound that maintains the PARP1 selectivity of AZD5305 with improved permeability, reduced efflux, and increased CNS penetration."

Journal • Brain Cancer • CNS Tumor • Hematological Disorders • Oncology

AZD5305 hADME in Patients With Advanced Solid Malignancies (clinicaltrials.gov) - P1 | N=8 | Not yet recruiting | Sponsor: AstraZeneca

Metastases • New P1 trial • Oncology • Solid Tumor

AZD5305: Data from P1 ASCERTAIN trial (NCT05938270) for newly diagnosed prostate cancer post 2025 (AstraZeneca) - Q3 2024 Results

P1 data • Oncology • Prostate Cancer

Discovery of Pyrazolo[1,5,4-de]quinoxalin-2(3H)-one Derivatives as Highly Potent and Selective PARP1 Inhibitors. (PubMed, J Med Chem) - "30 achieved tumor regression in the BRCA1-mutated MDA-MB-436 xenograft model and showed synergistic efficacy in combination with carboplatin in the SUM149PT xenograft model. In the rat hematological toxicity study, 30 exhibited minimal impact on hematological parameters at 25 mg/kg, while AZD5305 at 1 mg/kg caused 56.5% reduction of reticulocyte. Taken together, we discovered compound 30 with a therapeutic index superior to that of PARP1 inhibitors AZD5305 and AZD9574 in the preclinical setting."

Journal • Hematological Disorders • Oncology • BRCA1 • HRD • PARP2

Saruparib: Data from P3 EvoPAR-Prostate01 trial (NCT06120491) for metastatic CSPC post 2025 (AstraZeneca) - Q3 2024 Results: Data from P3 EvoPAR-Breast01 trial (NCT06380751) in combination with camizestrant for HR+/HER2-negative advanced breast cancer post 2025

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

AZD5305: Data from P1/2a PETRA trial (NCT04644068) for advanced solid malignancies post 2025 (AstraZeneca) - Q3 2024 Results: Data from P1/2a PETRANHA trial (NCT05367440) for metastatic prostate cancer post 2025

P1/2 data • Oncology • Prostate Cancer • Solid Tumor

Preclinical Candidate SYN608 - a Novel PARG Inhibitor with Excellent Anti-tumor Activity (EORTC-NCI-AACR 2024) - "In HRD-enriched tumor cells, SYN608 exhibits a broader range of inhibitory effects than the second-generation PARPi AZD5305... Collectively, these findings provide compelling evidence supporting the further clinical development of SYN608 as a potential best-in-class PARG inhibitor. GMP manufacturing is currently underway, advancing SYN608 closer to clinical trials."

Preclinical • Oncology • BRCA • HRD

Structural variants of BRCA1/2 represent a novel biomarker of homologous recombination deficiency in multiple tumour types (EORTC-NCI-AACR 2024) - "Drug sensitivity testing was performed using PARPi (olaparib, saruparib (AZD5305)), cisplatin and doxorubicin.ResultsSix of the eight cell lines with BRCA1 CNL and all (n=4) with BRCA2 CNL showed low BRCA1 or BRCA2 gene expression respectively (p2>5JIMT1BreastBRCA1 28 ±60.0136 ±22>5MDAMB453BreastBRCA1 17 ±222.3 ±0.2OVKATEOvaryBRCA1 40 ±140.0840 ±32NASKBR3BreastBRCA1 12 ±22>5SKES1BoneBRCA1 9 ±22>5MDAMB134VIBreastBRCA216 ±42NAOVSAHOOvaryBRCA215 ±422.5 ±0.2CAPAN1PancreasComparator (BRCA2 mutant)24 ±12>5*compared to UWB1289+BRCA1.**RAD51+ cell defined as >5 foci.Values±SEM"

Biomarker • High Grade Serous Ovarian Cancer • Oncology • Osteosarcoma • Ovarian Cancer • Sarcoma • Solid Tumor • BRCA • BRCA1 • BRCA2 • HRD • RAD51

Addressing Project Optimus: Preclinical, modelling and clinical data to support identification of the Recommended Phase 2 Dose for saruparib (EORTC-NCI-AACR 2024) - P1/2 | "Potent and durable PARylation inhibition was observed in preclinical and clinical samples. Preclinical and modelling data predicted that clinical doses in excess of 20 mg would be required for maximal efficacy, which was confirmed from clinical data in PETRA where 60 mg demonstrated improved efficacy without additional safety concerns and thus was selected as the RP2D.This integration of preclinical data and modelling, paired with clinical PK, safety and efficacy from the PETRA trial allowed us to recommend 60 mg as the most optimal saruparib dose for subsequent phase 2 and phase 3 clinical studies which are now ongoing."

Clinical data • P2 data • Preclinical • Oncology • HRD

ASCERTAIN: A Study to Investigate the Biological Effects of Saruparib (AZD5305), Darolutamide, and in Combination in Men With Newly Diagnosed Prostate Cancer. (clinicaltrials.gov) - P1 | N=120 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Feb 2025 ➔ Nov 2025 | Trial primary completion date: Feb 2025 ➔ Nov 2025

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

FONTANA: Phase I/IIa Study of AZD5335 as Monotherapy and Combination Therapy in Participants With Solid Tumors (clinicaltrials.gov) - P1/2 | N=396 | Recruiting | Sponsor: AstraZeneca | N=150 ➔ 396

Enrollment change • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor

Defining the effects of PARP inhibition on androgen receptor function in homologous recombination- proficient prostate cancer (PCF 2024) - " We used RNA-sequencing to profile the effects of PARP inhibition on AR function in HR-proficient prostate cancer cells using the PARP1/2 inhibitors olaparib and rucaparib and the PARP1-selective inhibitor AZD-5305. We measured DNA repair and the growth effects of PARP inhibitor treatment under androgen deprivation or treatment with the AR antagonist enzalutamide... Collectively, our results indicate that while PARP inhibitors mediate AR transcriptional function, they do not synergize with androgen deprivation or AR inhibition in HR-proficient prostate cancer cells. Instead, we demonstrate that therapeutic response to PARP inhibition requires cell cycle progression in HR-proficient prostate cancer, suggesting caution in combining PARP inhibitors with cell-cycle altering drugs."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

EvoPAR-BR01: Saruparib (AZD5305) Plus Camizestrant 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=500 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Jul 2030 ➔ Oct 2030

Trial completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

TOPOISOMERASE I INHIBITING ANTIBODY-DRUG-CONJUGATES SYNERGIZE WITH POLY(ADP-RIBOSE) POLYMERASE INHIBITORS IN TRIPLE NEGATIVE BREAST CANCER (IGCS 2024) - "Two ADCs are approved for TNBC: Sacituzumab govitecan-hziy (SG) and trastuzumab deruxtecan (T-DXd). The combination of each ADC (SG and T-DXd) with PARP inhibitors (olaparib, talazoparib, saruparib) were synergistic across the TNBC panel. Further functional analysis is currently ongoing investigating apoptosis induction and DNA-damaging effects of the combinations. Conclusion/Implications: The combination of TOP1 inhibiting ADCs with DNA-damaging therapies is synergistic, enhancing target therapies for TNBC patients; providing a rationale for further investigation."

IO biomarker • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • TOP1

EvoPAR-Prostate01: Phase III, double-blind, placebo-controlled, 2-cohort, randomized study of PARPi Saruparib (AZD5305) in combination with NHAs in patients with mCSPC with and without HRRm (DGU 2024) - P1/2, P3 | "The Phase III EvoPAR-Prostate01 study (NCT06120491) is evaluating the efficacy and safety of saruparib plus physician's choice of NHA (abiraterone, darolutamide, or enzalutamide) compared with placebo plus physician's choice of NHA in participants with mCSPC. This is a 2-cohort, 2-arm, randomized, double-blind, placebo-controlled, multicenter global study. Approximately 1,800 participants (550 HRRm; 1,250 non-HRRm) will be randomized. Enrolment in Germany began in August 2024 and is ongoing."

Clinical • Combination therapy • P3 data • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • HRD • PARP2

D5330C00004: Ascending Doses of Ceralasertib in Combination With Chemotherapy and/or Novel Anti Cancer Agents (clinicaltrials.gov) - P1/2 | N=466 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Jul 2026 ➔ Mar 2025 | Trial primary completion date: Jul 2026 ➔ Mar 2025

Trial completion date • Trial primary completion date • Breast Cancer • Colorectal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal 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

The PARP1 selective inhibitor saruparib (AZD5305) elicits potent and durable antitumor activity in patient-derived BRCA1/2-associated cancer models. (PubMed, Genome Med) - "Collectively, these results show that the novel PARP1 selective inhibitor AZD5305 yields a potent antitumor response in PDX models with HRD and delays PARPi resistance alone or in combination with carboplatin or ceralasertib, which supports its use in the clinic as a new therapeutic option."

Journal • Preclinical • Breast Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • BRCA1 • BRCA2 • HRD • PALB2 • RAD51

D5330C00004: Ascending Doses of Ceralasertib in Combination With Chemotherapy and/or Novel Anti Cancer Agents (clinicaltrials.gov) - P1/2 | N=466 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Dec 2026 ➔ Jul 2026 | Trial primary completion date: Dec 2026 ➔ Jul 2026

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • Colorectal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal 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

EvoPAR-BR01: Saruparib (AZD5305) Plus Camizestrant 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=500 | Recruiting | Sponsor: AstraZeneca | Not yet recruiting ➔ Recruiting | Initiation date: Apr 2024 ➔ Aug 2024

Enrollment open • Metastases • Trial initiation date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

D5330C00004: Ascending Doses of Ceralasertib in Combination With Chemotherapy and/or Novel Anti Cancer Agents (clinicaltrials.gov) - P1/2 | N=466 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Aug 2026 ➔ Dec 2026 | Trial primary completion date: Aug 2026 ➔ Dec 2026

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • Colorectal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal 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

The PARP1 selective inhibitor saruparib elicits potent and durable antitumor activity in patient-derived BRCA1, BRCA2 and PALB2-associated cancer models (EACR 2024) - "Here, we aimed to characterize the antitumor activity of saruparib in preclinical models compared to the first generation PARP1/2 inhibitor olaparib and to identify mechanisms of resistance.Material and Methods Thirteen previously characterized patient-derived tumor xenograft (PDX) models from breast, ovarian and pancreatic cancer patients harboring germline pathogenic alterations in BRCA1, BRCA2 or PALB2 were used to evaluate the efficacy of saruparib alone or in combination with carboplatin or an ATR inhibitor (ATRi) and compared it to olaparib. Saruparib elicited profound and durable responses when combined with carboplatin or ATRi in 3/6 and 5/5 models, respectively. Conclusion Collectively, these results show that the novel PARP1 selective inhibitor saruparib yields a potent antitumor response in PDXs with HRD and delays PARPi resistance alone or in combination with carboplatin or ATRi, which supports its use in the clinic as a new therapeutic option."

Clinical • Preclinical • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatology • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Solid Tumor • BRCA1 • BRCA2 • HRD • PALB2 • RAD51

Drug-drug Interaction Study With AZD5305 and Itraconazole in Patients With Advanced Solid Malignancies (clinicaltrials.gov) - P1 | N=16 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed

Metastases • Trial completion • Oncology • Solid Tumor