^
    9d
    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
    |
    ATM (ATM serine/threonine kinase) • HRD (Homologous Recombination Deficiency) • CHEK1 (Checkpoint kinase 1)
    |
    Lynparza (olaparib) • saruparib (AZD5305)
    11d
    CERTIS1: Study of AZD9574 as Monotherapy and in Combination With Anti-cancer Agents in Participants With Advanced Solid Malignancies (clinicaltrials.gov)
    P1/2, N=695, Recruiting, AstraZeneca | Trial completion date: Apr 2027 --> Aug 2027 | Trial primary completion date: Apr 2027 --> Aug 2027
    Trial completion date • Trial primary completion date
    |
    HER-2 (Human epidermal growth factor receptor 2) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • HRD (Homologous Recombination Deficiency) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D)
    |
    HER-2 negative • PALB2 mutation • RAD51C mutation • RAD51D mutation
    |
    temozolomide • Enhertu (fam-trastuzumab deruxtecan-nxki) • Datroway (datopotamab deruxtecan-dlnk) • AZD9574
    11d
    A novel 18 F-labeled brain penetrant PET ligand for imaging poly(ADP-ribose) polymerase-1. (PubMed, bioRxiv)
    In 22Rv1 xenograft mouse models, the tracer demonstrated significant tumor accumulation that was specific to PARP-1, and ex vivo biodistribution confirmed organ uptake consistent with specific tumor binding and PARP-1 expression. Together, these findings establish [ 18 F]AZD9574 as a promising PARP-1-targeted imaging agent with strong potential for advancing cancer research and therapeutic monitoring.
    Journal • PARP Biomarker
    |
    HRD (Homologous Recombination Deficiency) • PARP1 (Poly(ADP-Ribose) Polymerase 1)
    |
    AZD9574
    14d
    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, AstraZeneca | Recruiting --> Active, not recruiting
    Enrollment closed
    |
    saruparib (AZD5305)
    1m
    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
    |
    PARP2 (Poly(ADP-Ribose) Polymerase 2)
    |
    saruparib (AZD5305)
    2ms
    CERTIS1: Study of AZD9574 as Monotherapy and in Combination With Anti-cancer Agents in Participants With Advanced Solid Malignancies (clinicaltrials.gov)
    P1/2, N=695, Recruiting, AstraZeneca | Trial completion date: Feb 2027 --> Jun 2027 | Trial primary completion date: Feb 2027 --> Jun 2027
    Trial completion date • Trial primary completion date
    |
    HER-2 (Human epidermal growth factor receptor 2) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • HRD (Homologous Recombination Deficiency) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D)
    |
    HER-2 negative • PALB2 mutation • RAD51C mutation • RAD51D mutation
    |
    temozolomide • Enhertu (fam-trastuzumab deruxtecan-nxki) • Datroway (datopotamab deruxtecan-dlnk) • AZD9574
    2ms
    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, AstraZeneca | Not yet recruiting --> Recruiting
    Enrollment open
    |
    saruparib (AZD5305)
    2ms
    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, AstraZeneca | Trial completion date: Apr 2026 --> Apr 2031 | Trial primary completion date: Apr 2026 --> Apr 2031
    Trial completion date • Trial primary completion date
    |
    Xtandi (enzalutamide) • abiraterone acetate • Nubeqa (darolutamide) • apalutamide • saruparib (AZD5305)
    3ms
    Discovery of a novel benzofuran-7-carboxamide-based PARP1/c-Met dual inhibitor for addressing c-Met amplification-mediated PARP1i acquired-resistance. (PubMed, Eur J Med Chem)
    In this study, we report the development of a novel PARP1/c-Met dual inhibitor derived from the benzofuran-7-carboxamide moiety of the PARP1 inhibitor Mefuparib. Compared with compound 16 obtained in the previous study, compound S12 was identified as a highly potent dual inhibitor with lower molecule weight and better solubility, demonstrating robust inhibitory activity against both PARP1 (IC50 = 21.8 nM) and c-Met (IC50 = 30.2 nM). Importantly, S12 exhibited remarkable anti-tumor efficacy in the HCT116OR xenograft models, suggesting that targeting both PARP1 and c-Met represents an effective therapeutic strategy to overcome PARP1 inhibitor resistance mediated by c-Met amplification.
    Preclinical • Journal
    |
    MET (MET proto-oncogene, receptor tyrosine kinase)
    |
    MET amplification
    3ms
    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, AstraZeneca | Not yet recruiting --> Recruiting
    Enrollment open
    |
    BRCA (Breast cancer early onset)
    |
    abiraterone acetate • prednisone • saruparib (AZD5305)
    3ms
    Study of NMS-03305293 in Adult Patient With Relapsed Small Cell Lung Cancer (clinicaltrials.gov)
    P1, N=10, Recruiting, Nerviano Medical Sciences | Not yet recruiting --> Recruiting
    Enrollment open
    |
    temozolomide • NMS-293