AZD9574 / AstraZeneca - LARVOL DELTA

KBD111 is a highly selective, long-acting and brain-penetrant PARP1 inhibitor (ESMO 2025) - "Background Currently, several pan-PARP inhibitors such as olaparib, niraparib, and rucaparib are approved for the treatment of cancers with homologous recombination deficiency (HRD)...Results KBD111 exhibited over 5,000-fold selectivity for PARP2 by DNA-trapping assays, demonstrated potent anti-proliferative activity against BRCA-mutant cancer cell lines, while showing markedly reduced cytotoxicity toward normal CD34 + hematopoietic stem cells (IC 50 >10,000 nM) compared to talazoparib (IC 50 = 27 nM)...Furthermore, KBD111 achieved superior tumor growth inhibition compared to AZD5305 in DLD-1 BRCA2 - / - xenograft models following once-weekly oral dosing. In an intracranial MDA-MB-436-luc model, KBD111 also demonstrated enhanced efficacy relative to AZD9574 under QW oral dosing...A phase 1 trial is planned for 2026. Legal entity responsible for the study The authors."

Oncology • BRCA • BRCA2 • CD34 • HRD • PARP2

Imaging poly(ADP-ribose) polymerase-1 (PARP1) in vivo with 18F-labeled brain penetrant positron emission tomography (PET) ligand. (PubMed, Acta Pharm Sin B) - "Our comprehensive approach, encompassing pharmacological, cellular, autoradiographic, and in vivo PET imaging evaluations in non-human primates, demonstrates the capacity of [18F]AZD9574 to specifically bind to PARP1 and to successfully penetrate the BBB. These findings position [18F]AZD9574 as a viable molecular imaging tool, poised to facilitate the exploration of pathophysiological changes in PARP1 tissue abundance across various diseases."

Journal • Preclinical • PARP1

Discovery of novel radioligand [18F]AZD9574 for selective imaging of PARP1 in the CNS. (PubMed, Acta Pharm Sin B) - No abstract available

Journal • CNS Disorders • Oncology • PARP1

SEACLIFF: Study of AZD0516 as Monotherapy and in Combination in Participants With Metastatic Prostate Cancer (clinicaltrials.gov) - P1/2 | N=177 | Recruiting | Sponsor: AstraZeneca | Not yet recruiting ➔ Recruiting

Enrollment open • Monotherapy • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • STEAP1

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 | Sponsor: AstraZeneca | Trial completion date: Feb 2027 ➔ Jun 2027 | Trial primary completion date: Feb 2027 ➔ Jun 2027

Monotherapy • Trial completion date • Trial primary completion date • Brain Cancer • Breast Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Solid Tumor • BRCA1 • BRCA2 • HER-2 • HRD • IDH1 • IDH2 • RAD51C • RAD51D

SEACLIFF: Study of AZD0516 as Monotherapy and in Combination in Participants With Metastatic Prostate Cancer (clinicaltrials.gov) - P1/2 | N=177 | Not yet recruiting | Sponsor: AstraZeneca

Monotherapy • New P1/2 trial • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • STEAP1

Discovery of PARP1- and CDK2-selective inhibitors for targeted therapy in cancer (ACS-Fall 2025) - "The first program targeted homologous recombination repair deficient tumors, such as those harboring a BRCA mutation (BRCAm), through PARP1 inhibition, structure-based drug design campaign that led to the discovery of new generation, selective PARP1 inhibitor and DNA trapper Saruparib (AZD5305) and CNS-penetrant PARP1-selective inhibitor and DNA trapper AZD9574. The second campaign targeted cyclin E (CCNE)-amplified or overexpressed tumors through inhibition of CDK2 activity, which led to the discovery of CDK2-selective inhibitor AZD8421. AZD8421 is highly selective for CDK2 over other members of the CDK family as well as the broader kinome and demonstrated efficacy in CCNE-amplified ovarian PDX models."

Oncology • BRCA • HRD

A novel 18F-labeled brain penetrant PET ligand for imaging poly(ADP-ribose) polymerase-1 (SNMMI 2025) - "Blocking studies with AZD9574, Olaparib, Rucaparib, Veliparib, and Pamiparib significantly reduced intracellular radiotracer uptake, while no significant reduction was observed with UPF-1035, a PARP2-specific inhibitor (Fig. The radiotracer 18F-AZD9574 was synthesized following a previously established protocol (Fig. 1A). Western blot analysis confirmed substantial PARP1 expression in the U87-MG (glioblastoma), 22Rv1 (prostate), PSN-1 (pancreatic), MDA-MB-436 (breast), and MDA-MB-231 (breast) cancer cell lines (Fig."

Brain Cancer • Breast Cancer • Glioblastoma • Oncology • Pancreatic Cancer • Solid Tumor • PARP1 • PARP2

HSK46256, a highly selective and brain penetrable PARP1 inhibitor for the treatment of HRD cancers (AACR 2025) - "The CNS penetration of HSK46256 in rodent showed an unbound partition coefficient (Kpuu) of 0.32, indicating good CNS penetration compared to Kpuu of 0.25 of AZD9574. HSK46256 may offer a more efficacious and less toxic cancer treatment compared with currently approved PARPi especially when used in combination with other anti-cancer agents. Furthermore, owing to its CNS penetration capability HSK46256 may provide a new treatment option for patients with CNS malignancies or patients with brain metastases, where HRR suppression or HRD exists or for cancers with high rates of brain metastases."

Late-breaking abstract • Brain Cancer • CNS Tumor • Oncology • Solid Tumor • BRCA • HRD • PARP2

H3K27M diffuse midline glioma is homologous recombination defective and sensitized to radiotherapy and NK cell-mediated antitumor immunity by PARP inhibition. (PubMed, Neuro Oncol) - "The HRR deficiency in H3K27M DMG can be therapeutically leveraged with PARP inhibitors to radiosensitize and induce an NK cell-mediated antitumor immune response selectively in H3K27M DMG, supporting the clinical investigation of PARP1 inhibitors with RT in DMG patients."

Journal • Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • Targeted Protein Degradation • HRD • NKG2D

CERTIS1: Study of AZD9574 as Monotherapy and in Combination With Anti-cancer Agents in Participants With Advanced Solid Malignancies (clinicaltrials.gov) - P1/2 | N=490 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Aug 2026 ➔ Feb 2027 | Trial primary completion date: Aug 2026 ➔ Feb 2027

Monotherapy • Trial completion date • Trial primary completion date • Brain Cancer • Breast Cancer • HER2 Breast Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Solid Tumor • BRCA • BRCA1 • BRCA2 • HER-2 • HRD • IDH1 • IDH2 • RAD51C • RAD51D

CERTIS1: Study of AZD9574 as Monotherapy and in Combination With Anti-cancer Agents in Participants With Advanced Solid Malignancies (clinicaltrials.gov) - P1/2 | N=490 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Jan 2026 ➔ Aug 2026 | Trial primary completion date: Jan 2026 ➔ Aug 2026

Monotherapy • Trial completion date • Trial primary completion date • Brain Cancer • Breast Cancer • HER2 Breast Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Solid Tumor • BRCA • BRCA1 • BRCA2 • HER-2 • HRD • IDH1 • IDH2 • RAD51C • RAD51D

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

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

H3K27M diffuse midline glioma is homologous recombination defective and sensitized to radiotherapy and NK cell-mediated antitumor immunity by PARP inhibition. (PubMed, bioRxiv) - "We also show that the novel brain penetrant, PARP1-selective inhibitor AZD9574 compares favorably to olaparib when combined with RT, prolonging survival in a syngeneic orthotopic model of H3K27M DMG. This study highlights the ability of PARP1 inhibition to radiosensitize and induce an NK cell-mediated antitumor immunity in H3K27M DMG and supports future clinical investigation."

Journal • Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • Targeted Protein Degradation • BRCA1 • NKG2D • RAD51 • RNF168

A novel 18F-labeled brain penetrant PET ligand for imaging poly(ADP-ribose) polymerase-1 (SNMMI 2024) - "Further blockade experiments, as evidenced by substantially decreased brain uptake in the presence of Olaparib, Pamiparib and Veliparib, along with no effect with UPF-1035 blocking, confirmed high specific binding to PARP1 (Fig1G, I). We have successfully validated 18F-AZD9574 as a potent and selective PARP1 PET ligand through cellular uptake, ARG and PET imaging studies. The preclinical data presented in this work suggests that 18F-AZD9574 may serve as a novel molecular imaging tool for selective and specific imaging of PARP1 in vivo. This holds great promise for identifying PARP1-related pathologies within the human brain."

Oncology • PARP1 • PARP2

Further evaluation of the brain penetrant PARP1 PET imaging probe [11C]PyBic (SNMMI 2024) - "Commercially available PARP1/2 non-selective (veliparib and pamiparib) and PARP-1 selective (AZD9574) inhibitors were used in blocking experiments to determine the binding specificity and selectivity of [11C]PyBic. Data from the present study suggest that [11C]PyBic is brain permeable, is not a P-gp substrate, and binds specifically and selectively to PARP1 in the NHP brain with high levels of specific binding signals. Further, [11C]PyBic is shown to effectively image brain tumors in animals with intact BBB. Taken together, [11C]PyBic exhibits favorable kinetic and binding characteristics for imaging and quantification of PARP1 in the brain and glioma."

Brain Cancer • CNS Disorders • CNS Tumor • Glioma • Oncology • Solid Tumor • PARP1

Activity of PARP1-selective inhibitor SNV-001 in models of HRD cancers as monotherapy and in combination (AACR 2024) - "SNV-001 showed greater efficacy at lower doses compared to olaparib at 100 mg/kg or at equivalent doses of AZD9574...SNV-001 enhanced cytotoxicity of the DNA-damaging agent topotecan or carboplatin in Capan-1 (BRCA2mut) and HCC1395 (BRCA1mut) cells. Synergy was seen between SNV-001 and cell cycle check point inhibitors camonsertib (ATRi) or adavosertib (WEE1i) in DLD1 (BRCA2 -/-) and UWB1.289 (BRCA1mut) cells, as DNA damage induced by PARP1 trapping relies on cell cycle modulation for repair. Combination of SNV-001 with polymerase theta inhibitor ART558 or USP1 inhibitor KSQ4279 exhibited synergistic effects in DLD1 (BRCA2 -/-) or UWB1.289 (BRCA1mut) cells...Current data highlight a potential strategy for improving treatment efficacy and overcoming resistance. Further clinical investigations are warranted to validate this combination strategy."

Monotherapy • Oncology • BRCA1 • BRCA2 • HRD • PARP2 • USP1

HH102007 is a highly selective and potent PARP1 inhibitor and trapper (AACR 2024) - "HH102007 achieved tumor regression in MDA-MB-436 xenografts at a lower dose than AZD9574, and showed synergistic efficacy in combination with carboplatin in SUM149PT, which was insensitive to AZD9574. As for hematological toxicity, HH102007 up to 25 mg/kg did not reduce reticulocyte in rat while AZD5305 at 1 mg/kg caused reticulocyte reduction in a head-to-head comparison. In summary, HH102007 is a potent PARP1 inhibitor and trapper, with better selectivity and therapeutic window than both AZ compounds."

Late-breaking abstract • Oncology • DRD • PARP2

CERTIS1: Study of AZD9574 as Monotherapy and in Combination With Anti-cancer Agents in Participants With Advanced Solid Malignancies (clinicaltrials.gov) - P1/2 | N=490 | Recruiting | Sponsor: AstraZeneca | Trial primary completion date: Apr 2025 ➔ Jan 2026

Combination therapy • Metastases • Monotherapy • Trial primary completion date • Brain Cancer • Breast Cancer • Gastrointestinal Cancer • HER2 Breast Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Solid Tumor • BRCA • BRCA1 • BRCA2 • HER-2 • HRD • IDH1 • IDH2 • RAD51C • RAD51D

Investigating PARP1/2 activity of piperazine ring surrogates and adenine-binding pocket motifs in AZD-9574 | Poster Board #1606 (ACS-Sp 2024) - "Once considerable PARP1 inhibition and selectivity were attained, novelty in the scaffold was the next goal. Consequently, we focused on the optimization of novel ABP motifs leading to the synthesis and biochemical characterization of potent and selective PARP1 inhibitors."

Oncology • Solid Tumor

From serendipity to intention: development of brain penetrant PARP1 selective inhibitors. (PubMed, Clin Cancer Res) - "Primary and secondary brain tumors cause significant mortality and constitute an important unmet need. The development of AZD9574, a brain-penetrant, PARP1 selective inhibitor, with favorable pharmacologic properties and intriguing preclinical activity, has led to an ongoing clinical trial evaluating it alone and in combination with temozolomide or antibody drug conjugates."

Journal • Brain Cancer • Oncology • Solid Tumor

CERTIS1: Study of AZD9574 as Monotherapy and in Combination With Anti-cancer Agents in Participants With Advanced Solid Malignancies (clinicaltrials.gov) - P1/2 | N=490 | Recruiting | Sponsor: AstraZeneca | N=270 ➔ 490 | Trial primary completion date: Sep 2024 ➔ Apr 2025

Combination therapy • Enrollment change • Metastases • Monotherapy • Trial primary completion date • Brain Cancer • Breast Cancer • Gastrointestinal Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • BRCA • BRCA1 • BRCA2 • HER-2 • HRD • IDH1 • IDH2 • RAD51C • RAD51D

Preclinical Characterization of AZD9574, a Blood-Brain Barrier Penetrant Inhibitor of PARP1. (PubMed, Clin Cancer Res) - P1/2 | "The combination of three key features - PARP1 selectivity, PARP1 trapping profile, and high CNS penetration in a single molecule, supports the development of AZD9574 as the best-in-class PARP inhibitor for the treatment of primary and secondary brain tumors. As documented by in vitro and in vivo studies, AZD9574 shows robust anti-cancer efficacy both as a single agent as well as in combination with TMZ. AZD9574 is currently in a phase I trial (NCT05417594)."

Journal • Preclinical • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • MGMT

Preclinical Characterization of AZD9574, a Blood-Brain Barrier Penetrant Inhibitor of PARP1 (Clin Cancer Res) - "AZD9574 showed potent single agent efficacy in preclinical models with HRR-deficiency (HRD) in vitro and in vivo. In an O⁶-methylguanine-DNA methyltransferase (MGMT)-methylated orthotopic glioma model, AZD9574 in combination with TMZ was superior in extending the survival of tumor-bearing mice compared to TMZ alone."

Preclinical • Glioma