PARP inhibitors in ovarian cancer

BACKGROUND: Slow progress in improving the outcome of ovarian cancer with chemotherapy over the last decade has stimulated research into molecularly targeted therapy. Poly(ADP-ribose) polymerase (PARP) inhibitors target DNA repair and are specifically active in cells that have impaired repair of DNA by the homologous recombination (HR) pathway. Cells with mutated BRCA function have HR deficiency (HRD), which is also present in a significant proportion of non-BRCA-mutated ovarian cancer. DESIGN: In the last decade, olaparib, the first and most-investigated oral PARP inhibitor, has undergone phase I-III trials as a single agent, in comparison with and in addition to chemotherapy, and as a maintenance therapy following chemotherapy. RESULTS: The greatest benefit to-date has been in the maintenance setting, prolonging the progression-free survival of high-grade serous ovarian cancer with a BRCA1/2 mutation. In this group of patients, olaparib has received approval as maintenance following chemotherapy from the EMA, and accelerated approval as a single agent in women who have had three or more lines of therapy. Olaparib can be given for a prolonged period with few significant side-effects in most patients. Similar trials with other PARP inhibitors (rucaparib, niraparib and veliparib) are in progress and include non-BRCA-mutated ovarian cancer. Second-generation studies are exploring the combination of PARP inhibitors with anti-angiogenic drugs. CONCLUSIONS: PARP inhibitors represent a step change in the management of ovarian cancer. BRCA mutations are the first genotypic predictive markers in ovarian cancer and can be used to select patients who will most likely benefit from PARP inhibitors. BRCA testing is now becoming a routine part of the evaluation of women with ovarian cancer, and tests for HRD are being used to evaluate PARP inhibitors in an extended population of non-BRCA-mutated ovarian cancer

The European Society for Medical Oncology (ESMO) Congress 2016: Highlights and summary of selected abstracts in gynecologic cancers

The 2016 ESMO Congress held in Copenhagen, Denmark (07–11th October 2016) brought together over 20,000 attendees from 127 countries. The highlight of the meeting for the gynecological track was the presentation at a Presidential session of the ENGOT-OV16/NOVA niraparib maintenance study. Other sessions included the following: 4 oral abstract presentations, 6 poster-discussion presentations and 45 general posters; an educational session on difficult decisions in gynecological oncology and a special symposium on personalized medicine in gynecological oncology. This report discusses the oral abstract sessions and selected poster presentations from the conference

The status of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in ovarian cancer, part 2: extending the scope beyond olaparib and BRCA1/2 mutations

Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have shown clinical activity in epithelial ovarian cancer, leading both the US Food and Drug Administration (FDA) and the European Medicines Agency to approve olaparib for tumors characterized by BRCA1 and BRCA2 mutations. However, it is becoming increasingly evident that tumors that share molecular features with BRCA-mutant tumors-a concept known as BRCAness-also may exhibit defective homologous recombination DNA repair, and therefore will respond to PARP inhibition. A number of strategies have been proposed to identify BRCAness, including identifying defects in other genes that modulate homologous recombination and characterizing the mutational and transcriptional signatures of BRCAness. In addition to olaparib, a number of other PARP inhibitors are in clinical development. This article reviews the development of PARP inhibitors other than olaparib, and discusses the evidence for PARP inhibitors beyond BRCA1/2-mutant ovarian cancer

The status of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in ovarian cancer, part 1: olaparib

Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have shown promising clinical activity in epithelial ovarian cancer. Following the observation in vitro that PARP inhibition is synthetically lethal in tumors with BRCA mutations, PARP inhibition has become the first genotype-directed therapy for BRCA1- and BRCA2-associated ovarian cancer. However, it is becoming clear that PARP inhibition also may have clinical utility in cancers associated with defects or aberrations in DNA repair that are unrelated to BRCA mutations. Deficient DNA repair mechanisms are present in approximately 30% to 50% of high-grade serous ovarian cancers, the most common histologic subtype. Olaparib is the best-studied PARP inhibitor to date, and a number of phase 3 trials with this agent are underway. This article reviews the development of olaparib for ovarian cancer and discusses the current evidence for its use, ongoing studies, future research directions, and the challenges ahead

Targeted Therapies for Ovarian Cancer

Epithelial ovarian cancer has the highest mortality rate of all gynaecological malignancies. Most women present with advanced disease and develop a recurrence after radical surgery and chemotherapy. Improving the results of first- or subsequent-line chemotherapy has been slow, and novel approaches to systemic treatment are needed. Ovarian cancer is a heterogeneous disease with complex molecular and genetic changes. Understanding these better will provide information on the mechanisms of resistance and opportunities to target therapy more rationally, exploiting specific changes in the tumour. Here we reviewed targeted approaches to therapy, focussing on targeting angiogenesis and inhibition of DNA repair, 2 areas that show promising activity. Additionally, we reviewed studies that are underway, targeting the cell cycle, signalling pathways and immunotherapeutic strategies. Many of these innovative approaches already demonstrate promising activity in ovarian cancer and have the potential to improve the outcome in women with ovarian cancer

Adjuvant and post-surgical treatment in high-grade epithelial ovarian cancer

Cytoreductive surgery is the mainstay of treatment for high-grade epithelial ovarian cancer. Although for early stage disease outcomes following surgery alone are good, the risk of recurrence necessitates adjuvant chemotherapy for the majority of patients. Post-operative chemotherapy in advanced-stage disease, or neoadjuvant chemotherapy followed by surgery has improved progression-free survival (PFS) and overall survival (OS). However, despite the use of chemotherapy, the rate of recurrence remains high. In recent years, there has been considerable increase in knowledge regarding the biology of ovarian cancer, which has led to a journey of drug discovery, facilitating the use of novel targeted agents such as VEGF inhibitors and, more recently, PARP inhibitors in the first-line treatment of ovarian cancer. Here, we outline the current evidence-based guidance for systemic therapies in ovarian cancer and highlight the ongoing research to improve patient outcome

Maintenance treatment for recurrent ovarian carcinoma – Evidence supporting the efficacy and safety of PARP inhibitors

While recent advances in treatment mean that women with ovarian cancer are living longer, many eventually experience disease relapse highlighting the need for new treatments that can extend progression-free survival (PFS). The PARP inhibitors olaparib, niraparib and rucaparib have been approved by the US Food and Drug Administration and the European Commission and are currently available for the maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Here, we review the efficacy and safety data from the key clinical trials supporting the approvals for these treatments as second-line maintenance therapies, including Study 19, SOLO2/ ENGOT-OV21 (olaparib), NOVA/ENGOT-OV16 (niraparib) and ARIEL3 (rucaparib). Across trials, PFS was improved with PARP inhibitor maintenance treatment versus placebo in patients with a BRCA mutation. However, evidence from some of the trials shows that a wider group of patients can benefit from PARP inhibitor maintenance treatment including those with or without homologous recombination deficient tumours. The safety profile for olaparib, niraparib and rucaparib was generally similar across trials with haematological and gastrointestinal adverse events and fatigue/asthenia being the most common. As evidenced by the significant improvements in PFS and manageable safety profiles in these trials, PARP inhibitors represent a new standard of care for recurrent ovarian cancer following platinum-based chemotherapy and delay the need for further chemotherapy

Front-line therapy of advanced ovarian cancer: new approaches

BACKGROUND: The 5-year survival of ovarian cancer has slowly increased but to date much of this has been due to the use of more lines of treatment rather than better first-line therapy. In this setting, there has been little improvement over the past 15 years. The introduction of new treatments to extend time to first progression and overall survival remains a key objective of clinical research. DESIGN: The focus of research in the previous decade has been on the incorporation of anti-angiogenic therapy or dose-dense scheduling of paclitaxel (Taxol) to improve outcome. The new trials being conducted build on the knowledge gained and are focussing on two new areas of research, the use of PARP (poly-ADP ribose polymerase) inhibitors and immunotherapy. RESULTS: Ongoing randomised trials using PARP inhibitors or immune checkpoint inhibits are reviewed and the potential benefits and challenges of using these agents are discussed. CONCLUSIONS: Improvements in outcome from some of the many open trials may present challenges; interpretation of the outcome data needs to be taken in the context of clinical benefit and a health-economic assessment. The latter is becoming ever-more important as the cost of trials with combinations of targeted therapy is very great

Latest clinical evidence and further development of PARP inhibitors in ovarian cancer

For several decades, the systemic treatment of ovarian cancer has involved chemotherapy, with the relatively recent addition of antiangiogenic strategies given with chemotherapy and in the maintenance setting. In the past decade, numerous poly(ADP-ribose) polymerase (PARP)-inhibiting agents have been assessed. We review key trials that have led to the approval of three PARP inhibitors-olaparib, niraparib and rucaparib-as maintenance therapy for platinum-sensitive recurrent ovarian cancer. We discuss the efficacy and safety of these agents in the populations studied in clinical trials. We then provide an overview of the numerous avenues of ongoing research for PARP inhibitors in different treatment settings: as treatment rather than maintenance strategies and in combination with other anticancer approaches, including antiangiogenic and immunotherapeutic agents. Three phase III trials (NOVA, SOLO2 and ARIEL3) demonstrated remarkable improvement in progression-free survival (PFS) with PARP inhibitors given as maintenance therapy in patients with complete or partial response after platinum-based therapy for platinum-sensitive ovarian cancer. Differences in trial design and patient populations influence the conclusions that can be drawn from these trials. Overall survival data are pending and there is a limited experience regarding long-term safety. PARP inhibitors have transformed the management of ovarian cancer and have changed the course of disease for many patients. Although recent approvals are irrespective of BRCA mutation or homologous repair deficiency status, genetic profiles, as well as dosing schedules, tolerability and affordability, may influence patient selection and the setting in which PARP inhibitors are used. The development and evolution of PARP inhibitors continue, with new agents, strategies, combinations and indications under intensive evaluation