PARP1 selective inhibitor yields potent and durable antitumor activity in patient-derived preclinical models

Led by investigators of the Vall d’Hebron Institute of Oncology’s (VHIO) Experimental Therapeutics Group, in collaboration with VHIO’s Hereditary Cancer Genetics Group and the Medical Oncology Department at the Vall d’Hebron University Hospital (HUVH), results of a study published in Genome Medicine show that the PARP1 selective inhibitor saruparib (AZD5305) elicited superior and durable antitumor activity in PDX BRCA1/2-associated cancer models compared to the first-generation and clinically approved PARPi olaparib.

“As a highly potent and selective PARP1 inhibitor, it is expected that saruparib could lead to a safer profile that facilitates its combination with chemotherapy or other targeted agents,” said Violeta Serra, Head of VHIO’s Experimental Therapeutics Group and co-corresponding author of this present study.

Led by Timothy Yap at the University of Texas MD Anderson Cancer Center, the phase 1/2a first-in-class, first-in-human PETRA clinical trial (NCT04644068) is assessing the safety and efficacy of this novel and selective PARP1 inhibitor in patients with advanced solid tumors harboring BRCA1/2 gene alterations.

This multi-center study, also conducted at HUVH and coordinated by Judith Balmaña, a Medical Oncologist of HUVH’s Breast Cancer Unit and Head of VHIO’s Hereditary Cancer Genetics Group, is evaluating the safety, tolerability and antitumor activity of saruparib as monotherapy, or in combination with other treatments.

The use of PARPi in tumors with alterations in DNA repair pathways

Cells have several DNA damage repair pathways, with BRCA1/2 being one of the most important. BRCA1/2-altered tumors are unable to properly repair double-stranded DNA damage and, therefore, are very sensitive to treatments that induce this type of damage, including platinum-based chemotherapy or PARP1/2 inhibitors.

First-generation PARPi, which inhibit both PARP1 and PARP2, have been shown to be effective in tumors harboring alterations in this DNA repair pathway, leading to their approval and use in the clinic for the treatment of various tumor types where alterations in the BRCA1/2 genes are prevalent, such as breast, ovarian, pancreatic, or prostate cancer.

“Despite their initial benefit, reducing primary and acquired resistance to first-generation PARPi represents a clinical challenge. More effective and durable treatments are therefore needed to expand the therapeutic arsenal for these patients,” added Serra.

“Given that PARPi inhibition is sufficient to cause synthetic lethality in tumors with alterations in BRCA1/2, and that PARP2 inhibition is associated with greater hematotoxicity, new generation PARP1 selective inhibitors, such as saruparib, are being developed. Selective PARP1 inhibition could lead to a more potent and safer profile that facilitates its combination with other agents including chemotherapy or other targeted therapies.”

This present study was designed to characterize the antitumor activity of saruparib in PDX models and compare efficacy in terms of preclinical complete response rate with the first-generation PARP1/2 inhibitor olaparib.

Potent and durable antitumor activity of PARP1 selective inhibition

For this exploratory analysis, the investigators used 13 PDX models derived from patients with breast, ovarian or pancreatic cancer with genetic alterations the DNA repair genes BRCA1 or BRCA2 and administered treatment with saruparib alone or in combination with other targeted therapies (ATR inhibitors) or platinum-based chemotherapy. They compared the antitumor activity of saruparib with that observed with olaparib, and studied the differences in mechanisms of action and resistance between the two agents.

“Saruparib showed superior antitumor activity than olaparib in terms of preclinical complete response rate, 75% versus 37%, respectively. We also observed that the preclinical median progression-free survival was significantly longer in the saruparib-treated group compared to the olaparib-treated group, 386 days versus 90 days,” said Andrea Herencia, a Postdoctoral Researcher of VHIO’s Experimental Therapeutics Group and first author of this study.

Together, these results demonstrate that saruparib yields a potent antitumor response in PDX models with alterations in the BRCA1/2-related DNA damage repair pathway—as monotherapy or in combination with other therapies—and point to the promise of PARP1 selective inhibitors as a new therapeutic option. Results from the ongoing PETRA trial will report on the safety and efficacy of saruparib in patients with advanced solid tumors harboring BRCA1/2 gene alterations.