PARP inhibitors as single agents and in combination therapy: the most promising treatment strategies in clinical trials for BRCA-mutant ovarian and triple-negative breast cancers

ABSTRACT

Introduction

Poly (ADP-ribose) polymerase inhibitors (PARPis) are an exciting class of agents that have shown efficacy, particularly for BRCA-mutant triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC). However, most patients who receive PARPi as their standard of care therapy inevitably develop resistance and this underscores the need to identify additional targets that can circumvent such resistance. Combination treatment strategies have been developed in preclinical and clinical studies to address the challenges of efficacy and resistance.

Areas covered

This review examines completed or ongoing clinical trials of PARPi mono- and combination therapies. PARPi monotherapy in HER2 negative breast (HR+ and TNBC subtypes) and ovarian cancer is a focal point. The authors propose potential strategies that might overcome resistance to PARPi and discuss key questions and future directions.

Expert Opinion

While the advent of PARPis has significantly improved the treatment of tumors with defects in DNA damage and repair pathways, careful patient selection will be essential to enhance these treatments. The identification of molecular biomarkers to predict disease response and progression is an endeavor.

KEYWORDS:

• Clinical trial
• combination therapy
• DNA damage repair (DDR)
• drug resistance
• germline BRCA-mutation
• high-grade serous ovarian cancer (HGSOC)
• homologous recombination deficiency (HRD)
• niraparib
• olaparib
• poly (ADP-ribose) polymerase (PARP) inhibitor
• preclinical study
• somatic BRCA-mutation
• triple-negative breast cancer (TNBC)
• rucaparib
• talazoparib
• veliparib
• pamiparib
• fluzoparib
• immunotherapy

Article highlights

• Several PARP inhibitors have been approved to treat advanced, relapsed patients with BRCA-mutant triple-negative breast and high-grade serous ovarian cancers.

• The use of PARP inhibitors is being expanded beyond patients with ovarian or breast cancers harboring germline or somatic BRCA1/2 mutations to those with homologous recombination deficient (HRD) tumors and other types of cancers.

• Approaches to enhance PARP inhibitor efficacy and overcome resistance are focused on combining a PARP inhibitor with other inhibitors of DNA damage repair (DDR), cell cycle checkpoints, immune checkpoints, and therapies targeting specific cell signaling pathways.

• Several clinical trials have demonstrated the benefits of PARP inhibitors as maintenance treatment in patients with BRCA mutations or HRD; however, there is a lack of clinical trials comparing PARP inhibitor treatment in the first line setting to the other first or second line of treatment options for breast cancer patients.

• Future directions include exploring the benefits of PARP inhibitors in neoadjuvant settings and broadening the significant benefits of PARP inhibitors in combination with other targets.

• Identifying molecular biomarkers to predict the response to PARP inhibitor monotherapy or combination strategies is an area of unmet need.

• This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer has received honoraria from AstraZeneca, Pfizer, GSK, Clovis and Gilead.

Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.