PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions

Abstract

Poly(ADP-ribose) polymerase (PARP) inhibitors cause targeted tumour cell death in homologous recombination (HR)-deficient cancers, including BRCA-mutated tumours, by exploiting synthetic lethality. PARP inhibitors are being evaluated in late-stage clinical trials of ovarian cancer (OC). Recently, olaparib was the first PARP inhibitor approved in the European Union and United States for the treatment of advanced BRCA-mutated OC. This paper reviews the role of BRCA mutations for tumorigenesis and PARP inhibitor sensitivity, and summarises the clinical development of PARP inhibitors for the treatment of patients diagnosed with OC. Among the five key PARP inhibitors currently in clinical development, olaparib has undergone the most extensive clinical investigation. PARP inhibitors have demonstrated durable antitumour activity in BRCA-mutated advanced OC as a single agent in the treatment and maintenance setting, particularly in platinum-sensitive disease. PARP inhibitors are well tolerated; however, further careful assessment of moderate and late-onset toxicity is mandatory in the maintenance and adjuvant setting, respectively. PARP inhibitors are also being evaluated in combination with chemotherapeutic and novel targeted agents to potentiate antitumour activities. Current research is extending the use of PARP inhibitors beyond BRCA mutations to other sensitising molecular defects that result in HR-deficient cancer, and is defining an HR-deficiency signature. Trials are underway to determine whether such a signature will predict sensitivity to PARP inhibitors in women with sporadic OC.

A Review of Mirvetuximab Soravtansine in the Treatment of Platinum-Resistant Ovarian Cancer

“…In this regard, two new classes of targeted agents have been approved for EOC therapy in the last 5 years -angiogenesis inhibitors (bevacizumab) and PARP inhibitors (olaparib, rucaparib and niraparib) [23] -each of which selectively impact oncogenic pathways linked to ovarian tumorigenesis [24,25]. One strategy designed to improve patient outcomes involves combining targeted agents, which possess distinct mechanisms of action and favorable tolerability, with established chemotherapeutics [26].…”

Germline mutation contribution to chromosomal instability

“…The lack of a functional HR repair mechanism in BRCA1/2-deficient cells renders vulnerability to cell death upon PARPi administration (Bryant et al 2005). Clinical trials using PARPi, namely olaparib and rucaparib, in BRCAassociated cancers such as breast and ovarian cancers have been encouraging (Kaufman et al 2015, Konecny & Kristeleit 2016. In particular, ovarian cancer patients with germline BRCA mutations or BRCA-like LOH demonstrated a more favorable response to rucaparib compared to those with wild-type BRCA (Konecny & Kristeleit 2016).…”

“…Clinical trials using PARPi, namely olaparib and rucaparib, in BRCAassociated cancers such as breast and ovarian cancers have been encouraging (Kaufman et al 2015, Konecny & Kristeleit 2016. In particular, ovarian cancer patients with germline BRCA mutations or BRCA-like LOH demonstrated a more favorable response to rucaparib compared to those with wild-type BRCA (Konecny & Kristeleit 2016). The promising progress of PARPi trials in HR-deficient cancers suggests that synthetic lethality may be a feasible therapeutic strategy for cancer patients with germline mutations in DNA damage response due to the sensitization of tumor to the catastrophic consequences of failed DNA damage repair.…”

DNA Mismatch Repair in Advanced Metastatic Prostate Carcinoma: Clinical Perspective

“…Some of these genetic aberrations have been associated with sensitivity to platinum and PARP inhibitors in preclinical studies [29]. As PARP is involved in multiple aspects of DNA repair, PARPi, olaparib has been approved for treating ovarian cancers with BRCA1/2 mutations [30]. PARP inhibition exhibited significant antitumor activity in men with advanced metastatic CRPC, and deleterious germline mutations in BRCA2.…”