saruparib (AZD5305) / AstraZeneca - LARVOL DELTA

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) - No abstract available

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 • PALB2

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

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

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 mutation (EvoPAR-Prostate01). (ASCO 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. 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 • Acute Myelogenous Leukemia • Genito-urinary Cancer • Hematological Malignancies • Leukemia • Metastatic Castration-Resistant Prostate Cancer • Myelodysplastic Syndrome • Oncology • Prostate Cancer • Solid Tumor • ATM • BARD1 • BRCA1 • BRCA2 • CDK12 • HRD • PALB2 • PARP2 • RAD51B • RAD51C • RAD51D

Defining The Effects Of PARP Inhibition On Androgen Receptor Function In Homologous Recombination-Proficient Prostate Cancer (ENDO 2024) - "In pursuit of this goal, we conducted experiments using HR-proficient prostate cancer cell lines, including LNCaP, 22RV1, VCaP, LN95, and LNCaP-abl, and assessed the effects of the PARP1/2 inhibitors olaparib, rucaparib, talazoparib, and the PARP1-selective inhibitor AZD-5305...However, despite these PARP inhibitor-mediated effects on AR function, our testing of the combination of PARP inhibitors and enzalutamide showed no evidence of synergy or enhanced growth-inhibitory effects at physiologically relevant doses of these inhibitors...Finally, our analysis comparing PARP1/2 with PARP1-selective inhibitors suggests that these drugs exhibit similar biological effects, both in terms of their growth-inhibitory effects and in modulating AR activity. Collectively, our results indicate that while PARP inhibitors influence AR transcriptional function, they do not synergize with androgen deprivation or AR inhibition in HR-proficient prostate cancer cells."

Late-breaking abstract • 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 | Not yet recruiting | Sponsor: AstraZeneca

Metastases • New P3 trial • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

Selective Targeting of PARP1 in Early-Phase Study Shows Activity in Breast Cancer (THE ASCO POST) - "Ryan B. Corcoran, MD, PhD...'There are key advantages of selective targeting to PARP1, including less toxicity, compared with the approved PARP inhibitors that target PARP1 and PARP2,' he stated...'These are early data, but they are very promising,' Dr. Corcoran continued. 'There could be differentiation of saruparib from other PARP inhibitors by selectively inhibiting PARP1 and sparing PARP2. We need more data from prospective phase III trials, and we will need to see if the pharmacokinetic and pharmacodynamic properties will translate to better efficacy and tolerability in phase III.'"

Media quote

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 MUTATION(EvoPAR-Prostate01) (AUA 2024) - P1/2, P3 | "The Phase III EvoPAR-Prostate01 study (NCT06120491) is evaluatingthe efficacy and safety of saruparib plus physician's choice of NHA(abiraterone, darolutamide, or enzalutamide) compared with placeboplus physician's choice of NHA in participants with mCSPC. Approximately 1,800 participants (550 HRRm; 1,250 non-HRRm) will be randomized. Enrollment began in November2023 and is ongoing."

Clinical • Combination therapy • Metastases • P3 data • Acute Myelogenous Leukemia • Genito-urinary Cancer • Hematological Malignancies • Leukemia • Metastatic Castration-Resistant Prostate Cancer • Myelodysplastic Syndrome • Oncology • Prostate Cancer • Solid Tumor • ATM • BARD1 • BRCA1 • BRCA2 • CDK12 • HRD • PALB2 • PARP2 • RAD51B • RAD51C • RAD51D

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

Study of Dato-Dxd as Monotherapy and in Combination With Anti-cancer Agents in Patients With Advanced Solid Tumours (TROPION-PanTumor03) (clinicaltrials.gov) - P2 | N=531 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Mar 2025 ➔ Aug 2026 | Trial primary completion date: Mar 2025 ➔ Aug 2026

Combination therapy • Metastases • Monotherapy • Pan tumor • Trial completion date • Trial primary completion date • Biliary Cancer • Colorectal Cancer • Endometrial Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Hepatology • Metastatic Castration-Resistant Prostate Cancer • Oncology • Ovarian Cancer • Prostate Cancer • Solid Tumor • Urothelial Cancer