Development of poly(ADP-ribose) polymerase inhibitor and immunotherapy combinations: progress, pitfalls, and promises

Highlights

• Poly(ADP-ribose) polymerase inhibitors (PARPi) are approved by the FDA as monotherapy for ovarian, breast, and pancreatic tumors harboring BRCA1/2 mutations, as well as castration-resistant prostate cancers with homologous recombination repair (HRR) mutations.

• Immune checkpoint blockade (ICB) – through the use of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitors – has demonstrated durable responses in different solid tumors. Several PD-1/PD-L1 inhibitors are FDA approved for non-small cell lung cancer, metastatic urothelial carcinoma, and metastatic cutaneous squamous cell carcinoma.

• Preclinical data support a synergistic relationship between PARPi and ICB; PARPi-mediated DNA damage modulates the tumor immune microenvironment though different molecular and cellular mechanisms, such as increasing genomic instability, immune pathway activation, and PD-L1 expression on cancer cells; all of which may increase responsiveness to ICB.

• Early data from a Phase I trial suggested that the combination of PARPi and anti-PD-1/PD-L1 may be beneficial in patients regardless of mutational status or even in the case of platinum sensitivity. Thus far, it has been shown that combining PARPi with ICB may be a safe and well tolerated strategy, with the potential to improve survival outcomes in a broad population of patients with BRCA1/2 mutations.

The efficacy of poly(ADP-ribose) polymerase inhibitors (PARPi) is restricted by inevitable drug resistance, while their use in combination with chemotherapy and targeted agents is commonly associated with dose-limiting toxicities. Immune checkpoint blockade (ICB) has demonstrated durable responses in different solid tumors and is well-established across multiple cancers. Despite this, single agent activity is limited to a minority of patients and drug resistance remains an issue. Building on the monotherapy success of both drug classes, combining PARPi with ICB may be a safe and well-tolerated strategy with the potential to improve survival outcomes. In this review, we present the preclinical, translational, and clinical data supporting the combination of DNA damage response (DDR) and ICB as well as consider important questions to be addressed with future research.

Introduction

The field of oncology drug development has seen substantial progress in the treatment of different cancers over the past decade. Inhibitors of key DDR mechanisms, specifically against PARP, have proven to be effective and are now approved as single-agent therapies in breast, ovarian, pancreatic, and castration-resistant prostate cancers (CRPC) [1]. ICB agents targeting cytotoxic T lymphocyte antigen (CTLA)-4 and programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) have also emerged as effective strategies to improve survival outcomes in various solid tumors [2]. However, clinical benefit for both classes of drugs is limited by innate and acquired resistance and/or drug-related toxicities. Preclinical studies have supported the mechanistic rationale for the combination of PARPi and ICB as a therapeutic strategy for patients with different solid tumors [3].

In this review, we discuss the preclinical, translational, and clinical studies supporting the combination of PARPi and ICB therapies as well as consider important questions to be addressed with future research.