Novel PARP1 Inhibitor Shows Promise in Breast Cancer

SAN DIEGO — Saruparib, an investigational selective PARP1 inhibitor, showed promising activity in patients with certain homologous recombination repair (HRR)-deficient breast cancers, while limiting toxicity, according to results from a phase I/II study presented here.

Among the 31 breast cancer patients treated at the recommended phase II dose level of 60 mg, the objective response rate was 48.4%, with a median duration of response of 7.3 months, and median progression-free survival was 9.1 months, reported Timothy Yap, MBBS, PhD, of the University of Texas MD Anderson Cancer Center in Houston, during a press briefing at the American Association for Cancer Research annual meeting.

Among a larger group of patients with different cancers, Yap pointed out that pharmacokinetic analyses showed that, at all dose levels, patients maintained higher blood concentrations of saruparib than typically observed with other PARP inhibitors, and at the molecular level, saruparib inhibited around 90% of PARP activity in tumor tissue collected from biopsies.

Moreover, Yap reported that saruparib demonstrated a favorable safety profile while achieving these therapeutic benefits, despite being used in a heavily pretreated population.

“The favorable safety profile of saruparib together with the low rate of dose reductions compared with approved PARP inhibitors may allow patients to remain on treatment longer at an optimal dose, with superior drug exposures and maximal target engagement, which could lead to improved efficacy,” Yap said. “What we have seen in this trial … is that you really get bang for your buck in terms of safety.”

He pointed out that while approved PARP inhibitors certainly benefit patients, these target both PARP1 and PARP2, “and in the patients we have been treating with approved PARP inhibitors, we know they are associated with toxicities, including myelosuppression, gastrointestinal toxicities, and also fatigue.”

However, “only PARP1 trapping is required for synthetic lethality in the homologous recombination deficiency settings,” he said, adding that this provided his team with the rationale to “dial out” PARP2 and really focus on inhibiting PARP1 with saruparib.

“Importantly, you could see the higher-fold coverage, the greater PK [pharmacokinetics] exposure versus all approved PARP inhibitors, so we were getting much higher doses of drug into the patients as well,” he said. “Thinking back to the original phase I trials that we ran, we weren’t able to get above certain dose levels because of toxicities, because of dose-limiting toxicities we were observing during dose escalation. But we were certainly able to push the doses of saruparib much, much higher and we were also able to see really robust pharmacodynamic effects, and the efficacy as demonstrated … which certainly looks very promising.”

Patricia LoRusso, DO, of the Yale School of Medicine in New Haven, Connecticut, who served as discussant when the results of the study were formally reported during a clinical trials symposium, noted that despite the “outstanding therapeutic response” seen with saruparib, patients with metastatic disease will eventually develop resistance.

“How will we delay or overcome this to enhance therapeutic benefit for our patients?” she asked. “In 2024, I still believe that combination strategies will be needed.”

Given the preclinical and clinical monotherapy toxicity profile of saruparib, the question becomes whether it will safely combine with other therapeutics — particularly chemotherapeutics, she added. “And if there is drug tolerance with chemotherapy, is simultaneous drug administration the most appropriate administration to advance forward?”

The multicenter PETRA trial evaluated the safety, tolerability, and efficacy of saruparib in 306 patients with previously treated HRR-deficient breast, ovarian, pancreatic, or prostate cancers in dose-escalation and -expansion cohorts. Patients had tumors with mutations in one of five HRR genes: BRCA1, BRCA2, PALB2, RAD51C, or RAD51D. Patients had a median age of 57 years, and a median of three prior lines of therapy.

The 31 patients in the dose-expansion cohort included those with HER2-negative breast cancer who were PARP inhibitor-naive, although there was no limit on prior chemotherapy lines in the metastatic setting.

The dose-escalation phase of the trial evaluated patients at doses ranging from 10 to 140 mg daily, with Yap and colleagues determining that dose levels up to 90 mg were well-tolerated. The dose-expansion phase of the study evaluated dose levels of 20, 60, and 90 mg, with 60 mg daily chosen as the recommended dose for further clinical development.

In the cohort of 141 patients who received the 60-mg dose across all cancer types, adverse events (AEs) were observed in 92.2% of patients, while 12.1% of patients experienced a serious AE.

Saruparib-related AEs were observed in 76.6% of patients, grade ≥3 AEs occurred in 27.7%, and 2.1% had a serious AE. Treatment was discontinued in 3.5% of patients due to AEs related to saruparib, while 14.2% had dose reductions, and 29.1% had dose interruptions.

Yap noted that hematologic and gastrointestinal toxicities were low for saruparib at dose levels up to 60 mg.

Saruparib is being further evaluated at the recommended 60-mg dose level in the phase III EvoPAR-PR01 trial.

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