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

• Published open access in Genome Medicine, results of a study led by VHIO’s Experimental Therapeutics Group further support the use of selective PARP1 inhibitors in tumors with genetic alterations in BRCA1/2.

• Findings show that the PARP1 selective inhibitor saruparib elicited superior antitumor activity in patient-derived xenograft models (PDX), compared to first-generation, clinically approved PARP inhibitor (PARPi) olaparib, which targets PARP1 and PARP2 proteins.

• The ongoing phase 1/2a PETRA multi-center clinical trial is assessing the safety and efficacy of saruparib in patients with advanced solid tumors harboring BRCA1/2 gene alterations. Also conducted at the Vall d’Hebron University Hospital, this study could open up new therapeutic avenues for patients with BRCA1/2-associated cancer.  

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.  

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Reference

*Herencia-Ropero A, Llop-Guevara A, Staniszewska AD, Domènech-Vivó J, García-Galea E, Moles-Fernández A, Pedretti F, Domènech H, Rodríguez O, Guzmán M, Arenas EJ, Verdaguer H, Calero-Nieto FJ, Talbot S, Tobalina L, Leo E, Lau A, Nuciforo P, Dienstmann R, Macarulla T, Arribas J, Díez O, Gutiérrez-Enríquez S, Forment JV, O’Connor MJ, Albertella M, Balmaña J, Serra V. The PARP1 selective inhibitor saruparib (AZD5305) elicits potent and durable antitumor activity in patient-derived BRCA1/2-associated cancer models. Genome Med. 2024 Aug 26;16(1):107. 

About VHIO

The Vall d’Hebron Institute of Oncology (VHIO), established in 2006 and located within the Vall d’Hebron Campus, is a reference comprehensive cancer center for personalized medicine in oncology. Through our purely translational and multidisciplinary research model, we aim to improve the prevention, early diagnosis and treatment of cancer by transforming the latest scientific discoveries made in the laboratory into early phase clinical trials for the development of more effective therapies to improve the quality of life and survival  of cancer patients.

VHIO forms part of the CERCA – Research Centres of Catalonia system and is accredited as a Severo Ochoa Center of Excellence.

Research at VHIO would not be possible without the support received from our patrons – Generalitat de Catalunya, Fundació Privada CELLEX, “La Caixa” Foundation, Fundación FERO, and the Fundación BBVA, the public funding it receives as well as the generous support from institutional supporters, private institutions, companies, associations, societies, and individual donors. Only with such continued support will VHIO continue to advance personalized and targeted therapies against cancer.