Successful Dose Optimization and Recommended Phase III Dose Determination of Saruparib (PARP1 Selective Inhibitor) Through MIDD and Comprehensive Quantitative Clinical Pharmacology
Authors: Lanke Shankar , Amezcua Victor , Cosulich Sabina , Gibbs Megan , Lukacs Edit , Mondal Hasi , Moorthy Ganesh , Olabode Damilola , Phipps Alex , Vishwanathan Karthick , Yang Jincheng , Zhou Diansong 
Published: February 2025

Objectives: Saruparib (AZD5305) was developed through rational design to be highly selective for poly(ADP-ribose) polymerase-1 (PARP1), with increased potency & improved physicochemical properties versus approved PARP inhibitors. Multiple dose expansion cohorts were evaluated at 20, 60, & 90 mg QD to characterize the exposure-safety & -efficacy relationships to aid in dose optimization (Project Optimus). Here we present model informed drug development (MIDD) using comprehensive quantitative exposure response (ER) analysis to support selection of recommended phase III dose of saruparib. Methods: Clinical data (PK, PD, safety & efficacy) was generated in the PETRA Study (NCT04644068), exploring saruparib monotherapy dose escalation (10 to 140 mg QD) & dose expansions (20, 60 & 90 mg QD,) in PARP inhibitor naïve, advanced/metastatic breast, ovarian, castration resistant prostate cancer or pancreatic cancer harboring mutations in homologous recombination repair (HRR) genes BRCA1, BRCA2, PALB2, or RAD51C/D. Population PK (PopPK) was developed enabling an assessment of covariate impact on PK variability. Comprehensive exposure-safety analysis, using logistic regression, assessed 282 participants, linking saruparib exposure (AUCss, Cmaxss) with adverse events (AEs). A preliminary exposure efficacy (ORR, PFS) analysis was performed on 89 breast cohort patients (20, 60, 90 mg) from module 1, part B1. Results: PopPK analysis described saruparib PK across the dose range & identified body weight as a statistically significant but not a clinically significant covariate impacting saruparib PK. Investigation into the exposure-safety relationship, encompassing all AEs & dose interruptions/reductions, logistic regression & cumulative incidence analysis indicates a significant association between saruparib exposures (90 mg) & the occurrence of anemia, neutropenia & dose interruptions (p < 0.05). Exposure-efficacy analysis reveals a trend of increasing efficacy (ORR, PFS) with escalating doses & exposure levels Kaplan-Meier analysis illustrates enhanced progression-free survival (PFS) with higher doses (60, 90 mg) & exposure. In the exposure-safety/efficacy analysis, no statistically significant covariate relationships were detected. Overall, these findings suggest improved clinical benefit & associated risks with higher doses & exposure levels of saruparib in the PETRA monotherapy study, with 60 mg was identified as an optimal dose.Conclusions: Saruparib PK was linear across all doses. Saruparib demonstrated a favorable safety & tolerability profile with no unexpected safety findings & delivered promising efficacy in patients with advanced breast cancer harboring HRR mutations. Comprehensive quantitative ER analysis has established saruparib 60 mg QD as the optimal recommended monotherapy dose which provides a favorable benefit-risk profile for further evaluation in Phase III studies.Citations: NA