Saruparib Shows Favorable Activity, Safety in Mutant Advanced Solid Tumors

“Saruparib at 60 mg [once daily] demonstrated deep and durable responses with a high response rate and tumor reduction in the majority of patients and a prolonged PFS in a heavily pretreated population of patients, including those with breast cancer, harboring different HRR mutations,” according to presenting author Timothy A. Yap, MD.

Treatment with saruparib (AZD5305) demonstrated encouraging efficacy, favorable safety, a wide therapeutic index, and improved pharmacokinetic properties compared with currently approved PARP inhibitors in patients with advanced solid tumors harboring BRCA1/2, PALB2, or RAD51C/D mutations, according to findings from the phase 1/2a PETRA study (NCT04644068) presented at the American Association for Cancer Research (AACR) 2024 Annual Meeting.

In part B1 of the trial, which included patients with heavily pretreated HER2-negative breast cancer, saruparib produced tumor responses across different dose levels, including at 20 mg, 60 mg, and 90 mg once daily. Additionally, responses occurred in patients with both hormone receptor–positive and triple-negative breast cancer. Investigators also reported responses across different zygosity-defined subgroups, including biallelic, monoallelic, suspected biallelic, and unknown zygosity.

Saruparib at 20 mg once daily yielded a median best change in tumor size of –22.1% (range, –91.2% to 133.3%), an overall response rate (ORR) of 35.7% (80% CI, 23.5%-49.6%), and a median progression-free survival (PFS) of 4.6 months (80% CI, 3.7-5.4) among those with HER2-negative breast cancer. The corresponding values observed in the 60 mg dosing cohort were –34.6% (range, –100% to 43.2%), 48.4% (80% CI, 35.7%-61.3%), and 9.1 months (80% CI, 5.7-9.3).

In the 20 mg and 60 mg once-daily cohorts, respectively, the median duration of response (DOR) was 6.1 months (80% CI, 3.8-7.4) and 7.3 months (80% CI, 5.6-7.6), and the median time to response following the first dose was 1.9 months (80% CI, 1.7-1.9) and 3.5 months (80% CI, 1.9-3.6). Six patients in the 60 mg cohort remained on study treatment at the time of data cutoff; assessments for PFS in this cohort are ongoing. Those who received the agent at 90 mg once daily had a shorter follow-up duration, and immature data did not indicate improvements in ORR and DOR compared with other doses. Based on these results, investigators established a recommended phase 2 dose (RP2D) of 60 mg once daily.

“Saruparib at 60 mg [once daily] demonstrated deep and durable responses with a high response rate and tumor reduction in the majority of patients and a prolonged PFS in a heavily pretreated population of patients, including those with breast cancer, harboring different HRR mutations,” presenting author Timothy A. Yap, MD, a medical oncologist and professor in the Department of Investigational Cancer Therapeutics of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, said.

In the phase 1/2a PETRA study, 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 HER-negative breast cancer (40.8%), ovarian cancer (19.3%), pancreatic cancer (9.8%), and prostate cancer. The median number of prior lines of treatment in part A was 3, 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.

The trial’s primary end point was safety and tolerability. Secondary end points included pharmacokinetics, pharmacodynamics, preliminary efficacy, and circulating tumor DNA (ctDNA) analysis. Patients needed to have an ECOG performance status of 0 to 2 and adequate hemoglobin, platelet, and absolute neutrophil counts to enroll on the trial.

Of note, most dose levels were well tolerated among patients, with no dose-limiting toxicities reported in the 90 mg once-daily cohort; investigators determined this to be the maximum tolerated dose. Additionally, the rates of hematological and gastrointestinal toxicities were generally low across the 10 mg, 20 mg, 40 mg, and 60 mg once-daily groups. There was 1 dose-limiting toxicity at the 140 mg once daily dose, and 4 of 6 evaluable patients in this cohort experienced dose interruptions or reductions.

Across each dosing level cohort, rates of dose reductions ranged from 5.9% to 25.0%. Additionally, dose interruptions occurred in anywhere from 5.9% to 53.7% of patients.

Overall, saruparib demonstrated favorable safety among a heavily pretreated patient population. Compared with other PARP inhibitors, treatment with saruparib demonstrated selectivity for PARP1 vs PARP2. Additionally, the experimental agent elicited an improvement in fold coverage over target effective concentration (31.71) compared with other agents in this drug class such as niraparib (Zejula; 0.36), talazoparib (Talzenna; 0.50), rucaparib (Rubraca; 2.44), and olaparib (Lynparza).

Pharmacokinetics appeared to be linear with a dose-proportional increase exposure across each dosing cohort, and saruparib demonstrated an optimal pharmacological profile with no food interactions. Investigators reported PARylation inhibition of at least 90% in 5 of 6 tumor biopsies available among patients who received saruparib at day 15 of cycle 1.

In an exploratory ctDNA analysis, molecular responses or an approximately 50% or higher reduction in mean variant allele frequency was achieved in 64% (n = 16/25) of evaluable patients. ctDNA molecular responses also demonstrated an association with improvements in PFS (P = .033).

According to Yap, the favorable safety profile and low incidence of dose reductions associated with saruparib compared with approved PARP inhibitors may allow patients to remain on treatment for a longer duration with maximal target engagement, which may produce improved efficacy. Additionally, investigators plan to further assess treatment with saruparib at the RP2D of 60 mg once daily as part of the phase 3 EvoPAR-Prostate01 trial (NCT06120491).

Reference

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 (PARP1i) saruparib (AZD5305) in patients with advanced solid tumors with BRCA1/2, PALB2 or RAD51C/D mutations. Presented at the American Association for Cancer Research (AACR) 2024 Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT014.