saruparib (AZD5305)

P2, N=531, Recruiting, AstraZeneca | Trial completion date: Mar 2025 --> Aug 2026 | Trial primary completion date: Mar 2025 --> Aug 2026

P3, N=500, Not yet recruiting, AstraZeneca

P1, N=200, Recruiting, University of Leeds | Trial completion date: May 2027 --> Mar 2028 | Trial primary completion date: Mar 2023 --> Apr 2025

P3, N=1800, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting

The Phase 3 PROpel study showed that first-line combination treatment with olaparib and abiraterone significantly improved radiographic progression-free survival (rPFS) over abiraterone alone in pts with metastatic castration-resistant PC (mCRPC) (hazard ratio [HR], 0.66; 95% CI, 0.54 to 0.81; p<0.001). Similarly, the Phase 3 TALAPRO-2 study showed that first-line talazoparib with enzalutamide resulted in statistically significant improvement in rPFS over enzalutamide alone in pts with mCRPC (HR, 0.63; 95% CI, 0.51 to 0.78; p<0.0001)...Enrollment began in September 2023; sites across North America, Europe and Australia will enroll up to 120 patients. Clinical trial information: NCT05938270.

PETRANHA, an open-label nonrandomized study, is evaluating the safety and DDIs of AZD5305 with physician’s choice of NHA (enzalutamide [enza], abiraterone acetate [abi] or darolutamide [daro]) in pts with metastatic prostate cancer...Key exclusion criteria were previous PARPi, platinum chemotherapy, or targeted radioligand therapy for pts with mCRPC or mCSPC; and previous NHA or docetaxel in pts with mCSPC... Initial safety, tolerability, and DDI data from the PETRANHA study indicates that AZD5305 can be safely combined with three individual NHAs with low rates of dose interruptions or reductions. The study is ongoing in Australia, Italy, UK, and USA. Clinical trial information: NCT05367440.*Includes AZD5305 in combination with any NHA.

P1/2, N=804, Recruiting, AstraZeneca | N=604 --> 804

P3, N=1800, Not yet recruiting, AstraZeneca

P1/2, N=466, Recruiting, AstraZeneca | Trial completion date: Feb 2026 --> Jun 2026 | Trial primary completion date: Feb 2026 --> Jun 2026

While responses were seen in patients with EWS, the combination of the PARP1/2 inhibitor talazoparib with irinotecan and/or temozolomide did have a narrow therapeutic window with concern for hematologic toxicity. DNA damaging agents combined with PARPi have shown effect both preclinically and clinically in EWS; however, the narrow therapeutic window represents a significant challenge in treating patients. The combination of nal-IRI with talazoparib is currently being tested in early phase pediatric trials as one strategy to improve tolerability as nal-IRI combinations were shown in adult studies to have less grade 3/4 dose-limiting toxicities. The development of PARP1 selective agents such as AZD5305 may further mitigate toxicity and allow for dose escalation and potentially improved therapeutic benefit in this patient population.

Cerala, a selective and potent ATR inhibitor, in combination with olaparib, has demonstrated activity in pts with homologous recombination deficiency-positive, PARPi-resistant OC (CAPRI; NCT03462342). Secondary objectives include assessment of antitumour activity, pharmacokinetics and pharmacodynamic biomarkers. Recruitment started in April 2023 and sites across North America, Europe and Asia Pacific will enrol up to 150 pts in total.

The study will evaluate AZD5335 as monotherapy in patients with ovarian cancer or lung adenocarcinoma (Module 1), or AZD5335 in combination with AZD5305, a selective poly(ADP-ribose) polymerase 1 inhibitor, in patients with ovarian cancer (Module 2). Secondary objectives include assessment of objective response rate, duration of response, disease control rate, and progression-free survival by RECIST v1.1, and overall survival; characterising the pharmacokinetics of AZD5335 when given as monotherapy or in combination; and assessing immunogenicity. The study will be open to recruitment by 25 May 2023.

P1/2, N=150, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting

P1/2, N=604, Recruiting, AstraZeneca | Trial completion date: Jan 2026 --> Jul 2026 | Trial primary completion date: Jan 2026 --> Jul 2026

P1, N=120, Not yet recruiting, AstraZeneca

P1/2, N=466, Recruiting, AstraZeneca | N=330 --> 466

P1/2, N=172, Recruiting, AstraZeneca | Trial completion date: Mar 2029 --> Jun 2030 | Trial primary completion date: Mar 2029 --> Jun 2030

Our work demonstrates the value of identifying HRD for therapeutic targeting by PARPi and platinum in individuals with the aggressive rare malignancy, uLMS and suggests that individuals with HRD uLMS should be included in trials of PARP1-specific PARPi.

P1/2, N=150, Not yet recruiting, AstraZeneca

AZD5305 alone or in combination with platinum delayed visceral metastasis, ultimately extending the lifespan of OC-PDX-bearing mice. These preclinical models mimic the progression of the disease occurring in patients after debulking surgery, and are translationally relevant.

The first-generation PARP inhibitors (PARPi) olaparib, niraparib, talazoparib and rucaparib have been clinically approved for several cancers, like breast, ovarian and prostate, especially in BRCA-mutant tumors which are of homologous recombination repair (HRR)-deficiency. We identify the gene AUNIP (Aurora Kinase A and Ninein Interacting Protein), in the top hit from AZD5305 screen but not in olaparib screen, suggesting that AUNIP may be an additional target for synthetic lethality with PARP1 loss. Taken together, this screen reveals the potential molecular genes related with PARP1 inhibitor that can be further explored targeted and combined cancer therapy.

To further exploit the DNA damage elicited by the specific delivery of the TOP1i warhead, the combination of AZD8205 with a novel poly-ADP ribose polymerase 1 (PARP1) selective inhibitor, AZD5305, was investigated. These data demonstrate that AZD8205 is a promising therapeutic candidate for the treatment of B7-H4 positive solid tumors. A first in human phase I/IIa study in patients with advanced solid tumors is currently ongoing (NCT05123482).

In preclinical models, we previously demonstrated that KSQ-4279 shows therapeutic potential in combination with olaparib for treating patients who are either intrinsically resistant, or have developed acquired resistance to PARP inhibitors...Second generation PARP1 selective inhibitors such as AZD5305 are currently in clinical development and may provide a safety and efficacy advantage for patients...We observed significantly greater and more durable anti-tumor activity, including regressions, with the combination therapy compared to single agents. Our data supports the clinical testing of KSQ-4279 in combination with PARP inhibitors.

P2, N=531, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting

P2, N=451, Not yet recruiting, AstraZeneca

Findings from the phase I/IIa trial of AZD5305, a next-generation, highly selective PARP1 inhibitor, indicate that the drug is better tolerated in patients with ovarian, HER2-negative breast, pancreatic, and prostate cancers with BRCA1/2, PALB2, and RAD51C mutations compared with first-generation PARP inhibitors. In addition, 25% of 40 evaluable patients had a partial response.

AZD5305 also showed profound and durable regressions when combined with carboplatin or AZD6738 in a PDX with primary resistance to olaparib (PDX127), but not in 2 others with preclinical/clinical acquired-resistance to PARPi (PDX474.2OR and PDX474.7). Conclusion The novel PARP1 inhibitor AZD5305 yields a potent antitumor response in g BRCA mutated breast and ovarian cancer PDX in terms of tumor regression and preventing tumor regrowth.

These results suggest that T-DXd combined with the next generation PARP1 inhibitor AZD5305 is a potentially active combination, with preclinical activity demonstrated in HRD and HR proficient models. Further, the dose and scheduling may warrant exploration clinically to optimize therapeutic index.

AZD5305 is a highly selective PARP1 inhibitor and trapper with excellent physiochemical properties and a wide therapeutic index. It led to maximal target engagement and showed promising clinical activity with favorable tolerability at exposures surpassing those of 1st generation PARPi. >

Recently there have been numerous activities exploring the use of PARP inhibitors in the CNS, which could have benefits in a number of indications such as: 1) BRCAm tumors with a high propensity for brain metastasis, such as breast cancer, 2) glioblastoma and other CNS malignancies with elevated baseline replication stress and constitutive DNA damage response pathway (DDR) activation, and 3) neurological conditions.AstraZeneca has previously described the discovery of a next generation PARP1 selective inhibitor and PARP1-DNA trapper, AZD5305, which was not designed for CNS penetration...This profile makes it an ideal candidate for treating CNS malignancies or brain metastases that have a dependence on PARP inhibition either as single agent or in combination with other therapies. AZD9574 will soon enter clinical trials.

Since the approval of olaparib in 2014 for BRCA mutated (BRCAm) ovarian cancer, many PARP inhibitors have been developed and have seen widespread success...The publication of NMS-P118 in 2015 by Nerviano Medical Sciences showed that a highly selective PARP1 inhibitor could be found...The secondary pharmacology of AZD5305 is remarkably clean, with hERG activity >40 µM. AZD5305 has a very favorable pre-clinical PK profile, low predicted human dose, and has shown efficacy in an MDA-MB-436 mouse xenograft model.

AZD5305 dosed at 0.1mg/kg QD or higher for 35 days delivered about 90% regression, compared with 83% regression caused by treatment with 100mg/kg QD olaparib...Hence, we investigated the anti-tumour effects of AZD5305 in combination with carboplatin or paclitaxel in a BRCA1m TNBC xenograft, SUM149PT, and BRCA WT TNBC PDX model, HBCx-9. In both models, combination of AZD5305 with carboplatin was well tolerated and demonstrated clear benefit compared to each monotherapy treatment. The effects of adjusted dosing and scheduling of the combination on the anti-tumour efficacy will be presented.