AZD9574 / AstraZeneca - LARVOL DELTA

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

CERTIS1: Study of AZD9574 as Monotherapy and in Combination With Anti-cancer Agents in Participants With Advanced Solid Malignancies (clinicaltrials.gov) - P1/2 | N=270 | Recruiting | Sponsor: AstraZeneca | N=195 ➔ 270

Combination therapy • Enrollment change • Metastases • Monotherapy • Brain Cancer • Breast Cancer • Gastrointestinal Cancer • HER2 Breast Cancer • Oncology • Solid Tumor • BRCA • BRCA1 • BRCA2 • HER-2 • HRD • IDH1 • IDH2 • PARP1 • RAD51C • RAD51D

A phase I/IIa, open-label study of the brain-penetrant PARP1-selective inhibitor AZD9574 as monotherapy and in combination in patients with advanced solid malignancies (CERTIS1) (SNO 2022) - "Module 1 will enrol patients with advanced breast, ovarian, pancreatic or prostate tumours harbouring homologous recombination deficiencies. Module 2 will enrol patients with isocitrate dehydrogenase (IDH)1/2 mutated glioma."

Clinical • Monotherapy • P1/2 data • Brain Cancer • CNS Tumor • Glioma • Hematological Disorders • Oncology • Pancreatic Cancer • Prostate Cancer • Solid Tumor • HRD • 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=195 | Recruiting | Sponsor: AstraZeneca | Trial completion date: Jun 2025 ➔ Dec 2025 | Trial primary completion date: Apr 2024 ➔ Sep 2024

Combination therapy • Metastases • Monotherapy • Trial completion date • 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

CERTIS1: Study of AZD9574 as Monotherapy and in Combination With Anti-cancer Agents in Participants With Advanced Solid Malignancies (clinicaltrials.gov) - P1/2 | N=195 | Recruiting | Sponsor: AstraZeneca | N=135 ➔ 195

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

AZD9574 is a novel, brain penetrant PARP-1 selective inhibitor with activity in an intracranial xenograft model of triple negative breast carcinoma with homologous recombination repair deficiency (SNO 2022) - "Treatment of animals with established intracranial lesions showed sustained tumour growth suppression resulting in a significantly extended survival of tumour-bearing mice. Collectively, we believe that our data support the development of AZD9574 as a potential therapy for patients with HRD+ breast cancer whose disease has spread to the brain.This abstract was previously presented at AACR 2022 (Hamerlik et al, AACR 2022, Abs #3880)"

Preclinical • Breast Cancer • Immunology • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA1 • HRD • 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=135 | Recruiting | Sponsor: AstraZeneca | N=195 ➔ 135

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

Study of AZD9574 as monotherapy and in combination with anti-cancer agents in participants with advanced solid malignancies Estudio de AZD9574 en monoterapia y en combinación con agentes antineoplásicos, en pacientes con tumores sólidos avanzados (clinicaltrialsregister.eu) - P1/2 | N=255 | Ongoing | Sponsor: AstraZeneca AB

Combination therapy • Monotherapy • New P1/2 trial • Brain Cancer • Genito-urinary Cancer • Glioma • Oncology • Pancreatic Cancer • Prostate Cancer • Solid Tumor