Next-generation PARP Inhibitor Demonstrates Clinical Benefit in Patients with Homologous Recombination Repair-deficient Breast Cancer

Drug has higher selectivity for PARP1, improving safety and tolerability

SAN DIEGO – Saruparib, a selective inhibitor of poly-ADP ribose polymerase 1 (PARP1), demonstrated a promising objective response rate and progression-free survival in patients with certain homologous recombination repair (HRR)-deficient breast cancers, according to results from the phase I/II PETRA trial presented at the American Association for Cancer Research (AACR) Annual Meeting 2024, held April 5-10.

Although blocking the enzyme PARP1 may be sufficient to prevent DNA repair in HRR-deficient tumors, all PARP inhibitors currently approved by the U.S. Food and Drug Administration (FDA) block both PARP1 and PARP2, which can limit utility because of toxicity, explained Timothy A. Yap, MBBS, PhD, professor of Investigational Cancer Therapeutics and vice president and head of clinical development in the Therapeutics Discovery Division at The University of Texas MD Anderson Cancer Center, who presented the study.

“When we were developing first-generation PARP inhibitors, we weren’t able to increase the doses above a certain threshold because of toxicity,” Yap said. “By designing selective PARP1 inhibitors, we have a great opportunity to improve safety, tolerability, pharmacokinetics, pharmacodynamics, efficacy, and combinability with other therapies.”

Saruparib, a PARP1-specific inhibitor, showed promising tumor growth inhibition in preclinical models of breast, ovarian, pancreatic, and prostate cancer harboring HRR deficiency mutations. Because saruparib was less toxic than other PARP inhibitors, it could be given at higher doses.

“The properties of saruparib enable patients to reach high drug pharmacokinetic exposure levels and pharmacodynamic target engagement,” Yap said. “This means that patients may be able to stay on the optimal dose for a longer duration due to fewer dose interruptions and reductions, which may ultimately improve efficacy.”

PETRA is a multicenter phase I/II clinical trial evaluating the safety, tolerability, and efficacy of saruparib in 306 patients with previously treated (including ≤1 prior PARP inhibitor in the dose escalation phase and PARP inhibitor-naive breast cancer patients in the dose expansion phase) HRR-deficient breast, ovarian, pancreatic, or prostate cancer. Patients had tumors with mutations in one of five HRR genes: BRCA1, BRCA2, PALB2, RAD51C, or RAD51D.

Patients were treated at doses ranging from 10 to 140 mg saruparib daily; 60 mg daily was chosen as the recommended dose for further clinical development. Among the 31 breast cancer patients treated with 60 mg saruparib, the objective response rate was 48.4%, the median duration of response was 7.3 months, and the median progression-free survival was 9.1 months.

In the cohort of 141 patients who received the 60 mg dose across all cancer types, adverse events were observed in 92.2% of patients and 12.1% of patients experienced a serious adverse event. Adverse events related to saruparib were observed in 76.6% of patients, and 2.1% of patients had a serious adverse event related to the drug; 3.5% of patients discontinued treatment due to adverse events related to saruparib.

Yap noted that the adverse events profile from this phase I/II trial of heavily pretreated patients compared favorably to those from phase III trials testing other PARP inhibitors in treatment-naïve patients. “The low rate of dose reductions observed with saruparib suggests a very manageable safety profile that we believe will enable patients to stay longer at the optimal dose and therefore maximize the opportunity for long-term benefit,” Yap said.

Pharmacokinetic analyses showed that, at all dose levels, patients maintained higher blood concentrations of saruparib than typically observed with other PARP inhibitors. At the molecular level, saruparib inhibited around 90% of PARP activity in tumor tissue collected from biopsies.

“The excellent safety and tolerability profile, along with the favorable pharmacokinetic and pharmacodynamic properties, may enable patients to remain on saruparib treatment with sustained maximal target engagement and limited dose reductions or discontinuation,” Yap said.

Limitations of this study include its single-arm design and small sample size.

This study was funded by AstraZeneca. Yap is head of clinical development in the Therapeutics Discovery Division at The University of Texas MD Anderson Cancer Center, which has licensed therapeutics to Artios Pharma. He serves or has served as a consultant for 858 Therapeutics, Inc., AbbVie, Acrivon Therapeutics, Adagene, Aduro Biotech, Inc., Almac,  Amgen, Amphista Therapeutics, Artios Pharma, Astex Pharmaceuticals, AstraZeneca, Athena Therapeutics, Atrin Pharmaceuticals, Avenzo Therapeutics, Avoro Capital Advisors, Axiom Real-Time Metrics, Baptist Health System, Bayer, BeiGene, BioCity Biopharma, Blueprint Medicines, Boxer Capital, BridGene Biosciences, Bristol Myers Squibb, C4 Therapeutics, Inc., Calithera Biosciences, Cancer Research UK, Carrick Therapeutics, Circle Pharma, Inc., Clovis Oncology, Cybrexa Therapeutics, Daiichi Sankyo, Dark Blue Therapeutics Ltd., Debiopharm, Diffusion Pharmaceuticals, Duke Street Bio Ltd., EcoR1 Capital Fund, Ellipses Pharma, EMD Serono, Inc., Entos Pharmaceuticals, FoRx Therapeutics AG, F-star Therapeutics, Genesis Therapeutics, Genmab, Glenmark Pharmaceuticals, GLG Pharma, Globe Life Sciences, Grey Wolf Therapeutics, GSK, Guidepoint, IDEAYA Biosciences, Idience, Ignyta, Inc., I-Mab, ImmuneSensor Therapeutics, Inc., IMPACT Therapeutics, Institut Gustave Roussy, Intellisphere LLC, Janssen, Joint Scientific Committee for Phase I Clinical Trials (Hong Kong), Kyn Therapeutics, Kyowa Kirin, MEI pharma, Mereo BioPharma Group plc, Merck, Merit, Monte Rosa Therapeutics, Natera, Nested Therapeutics, Nexys Therapeutics, Inc., Nimbus Therapeutics, LLC, Novocure, Odyssey Therapeutics, Oregon Health & Science University, OncoSec, Ono Pharmaceutical Co. Ltd., Onxeo, PanAngium Therapeutics, PEGASCY-Group, PER, Pfizer, Piper Sandler Companies, Pliant Therapeutics, Prelude Therapeutics, ProLynx Inc., Protai Bio, Ltd., Radiopharm Theranostics, Repare Therapeutics, resTORbio, Inc., Roche, Ryvu Therapeutics SA, Sanofi, Schrödinger, Inc., Servier Pharmaceuticals, the Swiss Group for Clinical Cancer Research, Synnovation Therapeutics, Synthis Therapeutics, Inc., Tango Biosciences, Inc., TCG Crossover, Terns Pharmaceuticals, Terremoto Biosciences, Tessellate BIO, Theragnostics, Thryv Therapeutics Inc., TOLREMO therapeutics, AG, Tome Biosciences, Translational Drug Development (TD2), Trevarx Biomedical, Varian, Veeva Systems, Versant Ventures, Vibliome Therapeutics, LLC, Voronoi Inc., XinThera Inc., Zai Lab, and ZielBio; receives or has received research support from Artios Pharma, AstraZeneca, Bayer, BeiGene, BioNTech, Blueprint Medicines, Bristol Myers Squibb, Boundless Bio, the Cancer Prevention and Research Institute of Texas, Clovis Oncology, Constellation Pharmaceuticals, Cyteir Therapeutics, Eli Lilly and Company, EMD Serono, Exelixis, Forbius, F-star Therapeutics, GSK, Genentech, Gilead Sciences, Golfers Against Cancer, Haihe Biopharma, IDEAYA Biosciences, ImmuneSensor Therapeutics, Inc., Insilico Medicine, Ionis Pharmaceuticals, Ipsen, Jounce Therapeutics, Inc., Karyopharm Therapeutics, KSQ Therapeutics, Inc., Kyowa Kirin, Merck, Mirati Therapeutics, the National Cancer Institute of the National Institutes of Health, Novartis, Pfizer, Pliant Therapeutics, Prelude Therapeutics, Regeneron Pharmaceuticals, Repare Therapeutics, Ribon Therapeutics, Inc., Roche, Rubius Therapeutics, Sanofi, Scholar Rock, Seagen, Synnovation Therapeutics, Inc., Tango Biosciences Inc., Tesaro, the U.S. Department of Defense, V Foundation for Cancer Research, Vivace Therapeutics, Zenith Epigenetics, and Zentalis Pharmaceuticals; and holds stock in Seagen.

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