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    DRUG:

    saruparib (AZD5305)

    i
    Other names: AZD5305, AZD-5305, AZD 5305
    Company:
    AstraZeneca
    Drug class:
    PARP1 inhibitor
    Related drugs:
    17d
    Discovery of selective PARP1/CDK6 dual target inhibitors modulating Wnt signaling pathway for the treatment of TNBC. (PubMed, Bioorg Chem)
    Herein, we report the rational design and synthesis of a series of second-generation selective PARP1/CDK6 dual inhibitors, based on the structural features of the latest selective PARP1 inhibitor AZD5305...Furthermore, compared with first-generation inhibitors, PC8 displays improved metabolic stability in liver microsomes. As a novel selective PARP1/CDK6 dual inhibitor with improved pharmacological properties, PC8 represents a promising lead structure for further optimization of second-generation PARP1/CDK6 dual inhibitors for the treatment of TNBC.
    Journal
    |
    CDK6 (Cyclin-dependent kinase 6) • PARP2 (Poly(ADP-Ribose) Polymerase 2)
    |
    saruparib (AZD5305)
    22d
    PARTHENON: Study of AZD4956 as Monotherapy and in Combination With Anti-Cancer Agents in Participants With Advanced/Metastatic Homologous Recombination Deficient Solid Tumours (clinicaltrials.gov)
    P1/2, N=180, Not yet recruiting, AstraZeneca
    New P1/2 trial
    |
    saruparib (AZD5305)
    22d
    Modular Clinical Pharmacology Study to Evaluate the Drug-drug Interaction Potential and Relative Bioavailability of Saruparib (clinicaltrials.gov)
    P1, N=41, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting | Trial completion date: Nov 2026 --> Apr 2026 | Trial primary completion date: Jul 2026 --> Feb 2026
    Enrollment closed • Trial completion date • Trial primary completion date
    |
    metformin • saruparib (AZD5305)
    1m
    D5330C00004: Ascending Doses of Ceralasertib in Combination With Chemotherapy and/or Novel Anti Cancer Agents (clinicaltrials.gov)
    P1/2, N=357, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2025 --> Jun 2026
    Trial completion date
    |
    HER-2 (Human epidermal growth factor receptor 2) • ATM (ATM serine/threonine kinase) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D)
    |
    HER-2 negative • HRD • PALB2 mutation • RAD51C mutation • BRCA mutation
    |
    Lynparza (olaparib) • carboplatin • Imfinzi (durvalumab) • ceralasertib (AZD6738) • saruparib (AZD5305)
    1m
    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=0, Withdrawn, AstraZeneca | N=30 --> 0 | Trial completion date: Mar 2029 --> Dec 2025 | Active, not recruiting --> Withdrawn | Trial primary completion date: Mar 2029 --> Dec 2025
    Enrollment change • Trial completion date • Trial withdrawal • Trial primary completion date
    |
    BRCA1 (Breast cancer 1, early onset)
    |
    saruparib (AZD5305)
    1m
    D9727C00001: A study to evaluate the impact on metastases-free survival with the addition of saruparib vs placebo to a standard radiotherapy androgen deprivation regimen in men with high-risk prostate cancer with a BRCA mutation. (2024-513586-39-00)
    P2/3, N=253, Recruiting, AstraZeneca AB
    New P2/3 trial
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • BRCA (Breast cancer early onset)
    |
    BRCA2 mutation • BRCA1 mutation
    |
    abiraterone acetate • saruparib (AZD5305)
    1m
    SARUPANC/ET24-201: Trial assessing the efficacy of suraparib as first line therapy for patients with metastatic homologous repair-deficient pancreatic cancer (2024-516558-24-00)
    P1/2, N=700, Completed, Centre Leon Berard
    New P1/2 trial
    |
    BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • BRCA (Breast cancer early onset)
    |
    PALB2 mutation • BRCA mutation
    |
    saruparib (AZD5305)
    2ms
    ANDROMEDA: A Trial to Learn How Safe AZD9750 is and How Well it Works in People With Metastatic Prostate Cancer When Given With or Without Other Anticancer Drugs (clinicaltrials.gov)
    P1/2, N=300, Not yet recruiting, AstraZeneca
    New P1/2 trial • First-in-human
    |
    saruparib (AZD5305)
    3ms
    Genetic evidence for PARP1 trapping as a driver of PARP inhibitor efficacy in BRCA mutant cancer cells. (PubMed, Nucleic Acids Res)
    We also identified and characterised a PARP1 mutation resulting in loss of the enzymatic inhibition and trapping activity of the PARP1-selective inhibitor, saruparib. However, the same mutation increased the trapping ability of other PARPi, namely veliparib and olaparib, without enhancing their enzymatic inhibition activity, a change that led to an increase in efficacy in this BRCA1m model. Together, these data suggest that PARP1 trapping, and not only its enzymatic inhibition, is a key driver for PARPi effectiveness in BRCA1m cancer cells.
    Journal • BRCA Biomarker • PARP Biomarker
    |
    BRCA1 (Breast cancer 1, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)
    |
    BRCA mutation
    |
    Lynparza (olaparib) • veliparib (ABT-888) • saruparib (AZD5305)
    3ms
    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, AstraZeneca | Trial completion date: Feb 2026 --> Aug 2026 | Trial primary completion date: Feb 2026 --> Aug 2026
    Trial completion date • Trial primary completion date
    |
    Nubeqa (darolutamide) • saruparib (AZD5305)
    4ms
    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, AstraZeneca | Recruiting --> Active, not recruiting
    Enrollment closed
    |
    Xtandi (enzalutamide) • abiraterone acetate • Nubeqa (darolutamide) • apalutamide • saruparib (AZD5305)
    4ms
    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)