Saruparib, a first-in-class PARP1-selective inhibitor, was reported to have favorable safety and anticancer activity in heavily pretreated patients with breast cancer harboring homologous recombination–repair (HRR) mutations, according to the results of the phase I/II PETRA study presented at the American Association for Cancer Research (AACR) Annual Meeting 2024.1 Moreover, the safety profile of this new drug appears to allow patients with advanced solid tumors to stay on treatment longer with increased drug exposure, compared with currently approved PARP inhibitors, which target both PARP1 and PARP2.
Getting in more drug with better efficacy looks promising, and saruparib will be studied in combination with camizestrant in phase III breast cancer trials.— Timothy A. Yap, MBBS, PhD, FRCP
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“Saruparib at 60 mg [once daily] demonstrated deep and durable responses with a high response rate and tumor reduction, as well as a prolonged progression-free survival in a heavily pretreated population of patients, including those with breast cancer, harboring different HRR mutations,” said presenting author Timothy A. Yap, MBBS, PhD, FRCP. Dr. Yap is Professor of Investigational Cancer Therapeutics and Vice President and Head of Clinical Development in the Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston.
Background and Study Rationale
PARP inhibitors approved in the United States currently target PARP1 and PARP2, although “we know PARP1 is what we need to target,” Dr. Yap explained. Currently available PARP inhibitors—which are the standard of care in certain cancer types—have limited use and combinability with other agents because toxicity related to the dual blockade of PARP1 and PARP2.
In the original dose-escalation trials, he continued, the dose levels of approved PARP inhibitors were limited to a certain threshold because of toxicity. “By designing PARP1-selective inhibitors, we have a great opportunity to improve safety, tolerability, pharmacokinetics, pharmacodynamics, efficacy, and the ability to use them in combinations with other therapies,” Dr. Yap noted. “The favorable safety profile of saruparib together with the low dose-reduction rate compared with approved PARP inhibitors may allow patients to remain on treatment longer at an optimal dose, offering maximal pharmacokinetic exposure and pharmacodynamic engagement, which could lead to improved efficacy.”
Study Details
PETRA is a multicenter phase I/II clinical trial that included 306 heavily pretreated patients with up to one PARP inhibitor during dose escalation and PARP inhibitor–naive patients in the dose-expansion phase. Patients had advanced breast, ovarian, pancreatic, or prostate tumors harboring mutations in one of five HRR genes—BRCA1, BRCA2, PALB2, RAD51C, or RAD51D—with previous treatment for HRR-deficiency mutations.
The investigators first evaluated saruparib monotherapy at doses ranging from 10 mg once daily to 140 mg once daily in part A. This dose-escalation portion primarily included those with advanced or metastatic HER2-negative breast cancer (40.8%), ovarian cancer (19.3%), and pancreatic cancer (9.8%). The median number of prior lines of treatment in part A was three, and 45% of patients previously received PARP inhibitors and/or platinum-containing chemotherapy.
Part B of the trial included those with HER2-negative breast cancer who received no prior treatment with PARP inhibitors. Most patients in this phase had BRCA mutations, and there was no restriction on the number of prior lines of chemotherapy in the metastatic setting.
Key Results
Based on results from phase IA, the recommended dose going forward (in patients heavily pretreated with a median of three lines of therapy) was identified as 60 mg/d. Among 31 patients with breast cancer treated at the 60 mg/d dose, 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.
Across all cancer types treated at the 60 mg dose (n = 141), adverse events were seen among 92.2% of patients; serious adverse events were reported in 12.1%. Treatment-related adverse events were reported in 76.6% of patients; 2.1% had a serious treatment-related adverse event. Discontinuation of saruparib as a result of treatment-related adverse events was reported in 3.5% of patients.
Responses were seen in HER2-negative breast cancer and with HRR mutations. “At 60 mg/d, deep and durable responses were seen in patients with HER2-negative disease.
Pharmacokinetics and pharmacodynamics were more favorable with saruparib than with previously approved PARP inhibitors. According to Dr. Yap, this led to better pharmacokinetic coverage and target engagement, in spite of the improved safety and tolerability profile.
An exploratory analysis conducted at the recommended phase II dose of 60 mg/d of saruparib found that circulating tumor DNA kinetics may prove to be an early biomarker for improved progression-free survival.
Closing Comments
Development of saruparib in patients with HRR mutations is ongoing. Saruparib at the recommended phase II dose of 60 mg/d is currently being studied in the phase III EvoPAR-Prostate01 trial.
During the discussion following his presentation at a press conference, Dr. Yap shared these closing comments: “The approved dual-targeted PARP inhibitors have associated toxicity, including myelosuppression, gastrointestinal effects, and fatigue. For efficacy, what you really need is to target PARP1. The opportunity to dial out PARP2, gives you a real bang for your buck in terms of minimizing toxicity and achieving much higher-fold pharmacokinetic coverage. Getting in more drug with better efficacy looks promising, and saruparib will be studied in combination with camizestrant in phase III breast cancer trials.”
Expert Point of View
Ryan B. Corcoran, MD, PhD
Ryan B. Corcoran, MD, PhD, moderated a press conference where the PETRA data on saruparib were presented. “There are key advantages of selective targeting to PARP1, including less toxicity, compared with the approved PARP inhibitors that target PARP1 and PARP2,” he stated. Dr. Corcoran is Co-Chair of the American Association for Cancer Research (AACR) Clinical Trials Program and Director of the Gastrointestinal Cancer Center Program and Scientific Director of the Termeer Center for Targeted Therapy at the Mass General Cancer Center.
“These are early data, but they are very promising,” Dr. Corcoran continued. “There could be differentiation of saruparib from other PARP inhibitors by selectively inhibiting PARP1 and sparing PARP2. We need more data from prospective phase III trials, and we will need to see if the pharmacokinetic and pharmacodynamic properties will translate to better efficacy and tolerability in phase III.”
However, Dr. Corcoran was optimistic, considering experience with other selective targeted agents. “The trend has been if you hit only what you have to hit, you can spare toxicity and improve efficacy. We hope this class of agents pans out.”
DISCLOSURE: The PETRA trial was funded by AstraZeneca. Dr. Yap has served as a consultant to AbbVie Acrivon Adagene, Adura, Almac, Amgen, Amphista Artios, AstraZeneca, Atrin Avenzo Axion, Baptist Health Systems, Bayer BeiGene, BioCity, Blueprint, Boxer, BridGene Biosciences, Bristol Myers Squibb, C4 Therapeutics, Calithera, Cancer Research UK, Carrick Therapeutics, Circle Phava, Clovis, Cybrexa, Daiichi Sankyo, Dark Blue Therapeutics, Debiopharm Diffusion, Duke Street Bio, EcoR1 Capital, Elipses Pharma, EMD Serono, Entos, FoRx Therapeutics AD, F-Star, Genesis Therapeutics, Genmab, GlaxoSmithKline, Glenmark Pharmaceuticals, Globe Life Sciences, Grey Wolf Therapeutics, Guidepoint, Ideaya Biosciences, Idience, Ignyta, I-Mab, ImmuneSensor, Impact Therapeutics, Institut Gustave Roussy, Intellisphere, Janssen, Kyn Therapeutics, Kyowa Kirin, MEI Pharma, Merck, Mereo BioPharma, Merit, Monte Rosa Therapeutics, Natera, Nested Therapeutics, Nexys, Nimbus, Novocure, Odyssey Therapeutics, OncoSec, Ono Pharma, Onxeo, PanAngium Therapeutics, Peace Pharmaceuticals, Pfizer, Sandler, Pilani Therapeutics, Prelude Therapeutics, Protynx, Protal Bio, Radiopharma Theranostics, resTORbio, Roche Ryvu Therapeutics, SAKK, Sanofi, Schrodinger, Servier, Synnovation, Synthia Therapeutics, Tango, TCG Crossover, TD2, Terremoto Biosciences, Tessellate B8o, Theragnostics, Terns Pharmaceuticals, Thryv Therapeutics, Toiremo, Tome, Trevarx Biomedical, Varian, Veeva, Versant, Viblime, Voroni Inc, XinThera, Zai Labs, and ZielBio; has received gran and rResearch support from Artios, AstraZeneca, Bayer, BeiGene, BioNTech, Blueprint, BMS, Boundless Bio, Clovis, Ideaya, ImmuneSensor, Insilico Medicine, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, Merck, Novartis, Pfizer, Pliant, Prelude, Regeneron, Repare, Ribon Therapeutics, Roche Rubius, Sanofi, Scholar Rock, Seattle Genetics, Synnovation, Tango, Tesaro, V Foundation, Vivace, Zenith, and Zentalis; and also owns stock in Seagen. Dr. Corcoran has served as a consultant for Alterome Therapeutics, Asana BioSciences, C4 Therapeutics, Coget Biosciences, Erasca, FogPharma, Guardant Health, Interline Therapeutics, Kinnate Biopharma, Mirati Therapeutics, Nested Therapeutics, Pfizer, Qiagen, Remix Therapeutics, Revolution Medicines, Sidewinder Therapeutics, Taiho Pharmaceutical, and Theonys; has received grants from Eli Lilly and Co, Novartis, and Pfizer; and owns stock in Alterome Therapeutics, Avidity Bioscience, Erasca, Interline Therapeutics, Kinnate Biopharma, Nested Therapeutics, Remix Therapeutics, Revolution Medicine, Sidewinder Therapeutics, and Theonys.
REFERENCE
1. Yap TA, Schram AM, Balmaña J, et al: PETRA: First-in-human phase 1/2a trial of the first-in-class new generation poly (ADP-ribose) polymerase-1 selective inhibitor saruparib (AZD5305) in patients with advanced solid tumor with BRCA1/2, PALB2, or RAD51C/D mutations. AACR Annual Meeting 2024. Abstract CT007. Presented April 8, 2024.
