Ovarian cancer is a leading cause of cancer death in women worldwide, with almost 300,000 cases diagnosed in 2018.1 If diagnosed and treated at stage I, the 5-year relative survival rate is 92%. However, only about 15% of ovarian cancers are diagnosed at this stage, and the prognosis for advanced ovarian cancer is bleak: 5-year survival rates at stage III and IV are 39% and 17%, respectively.2 The standard of care for advanced ovarian cancer is cytoreductive surgery followed by chemotherapy,3 but the majority of patients relapse within 24 months.4
In recent years, however, a new class of drugs, poly (ADP-ribose) polymerase (PARP) inhibitors, has provided new hope for a subgroup of patients with ovarian cancer. The PARP protein is involved in single-stranded DNA repair.5 The BRCA1/2 genes, together with several other genes, code for this protein. If the ability of a cell to repair single-strand breaks (SSBs) is impaired, they become double-strand breaks (DSBs), which are lethal unless repaired. PARP inhibitors inhibit the repair of DNA SSBs, thus transforming them into DNA DSBs. This process is called synthetic lethality and is a selective therapeutic approach that is very specific for cells that have homologous recombination deficiency (HRD), such as ovarian cancer.6 An estimated 11–15% of patients with ovarian cancer have germline BRCA1 or BRCA2 mutations.7,8 In addition, loss of BRCA function can occur through somatic mutations, potentially expanding the number of patients who may benefit from PARP inhibition.9
The most extensively studied PARP inhibitor is olaparib (Lynparza®; AstraZeneca, Cambridge, UK ), which was approved in 2014 by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) as the first-in-class PARP inhibitor for the treatment of patients with germline BRCA-mutated ovarian cancer following previous chamotherapy.6 In 2017, the phase III SOLO-2 showed that maintenance treatment with olaparib provided a significant progression-free survival (PFS) improvement in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. The most common adverse event of severity grade 3 or worse was anaemia in 19%; other adverse events were generally low-grade and manageable.10
Following these promising findings, the phase III SOLO-1 study evaluated the efficacy and safety of olaparib as a maintenance treatment for patients with newly-diagnosed, advanced BRCA-mutated ovarian cancer who were in complete or partial response following first-line standard platinum-based chemotherapy.11 Detailed results of the SOLO-1 study were presented at the European Society for Medical Oncology (ESMO) meeting in October 2018 in Munich, Germany. These results showed statistically significant and clinically meaningful improvements in PFS with olaparib compared to placebo, with a reduction in the risk of disease progression or death of 70% (hazard ratio 0.30 [95% confidence interval 0.23–0.41], p<0.001). After 41 months follow-up, the median PFS for patients treated with olaparib was not reached compared with 13.8 months for women in the placebo arm. Among patients receiving olaparib, 60% remained progression-free at 36 months compared with 27% of women treated with placebo. Safety findings were consistent with those in previous studies.11
Kathleen Moore, Co-Principal Investigator of the SOLO-1 trial and Associate Director for Clinical Research at the Stephenson Cancer Centre at the University of Oklahoma, Oklahoma City, US, said: ‘Women with ovarian cancer are often diagnosed with advanced disease, which unfortunately is associated with poor long-term survival rates. The newly-diagnosed setting is our best opportunity to achieve a sustained remission, since once a patient’s ovarian cancer recurs, it is typically incurable. The SOLO-1 results demonstrate the potential of Lynparza maintenance therapy earlier in the treatment pathway and reinforce the importance of identifying a patient’s BRCA mutation status at the time of diagnosis – these results could change the way we treat women with advanced BRCA-mutated ovarian cancer.’11
It is easy to understand the excitement in the medical community around PARP inhibitors. They are administered orally, which is convenient for patients. Biomarkers such as sequencing BRCA1/2, panel sequencing, or HRD assays, can identify the patients who will benefit the most from this therapy. Two other drugs in this class have received marketing approval in the treatment of ovarian cancer: rucaparib (Rubraca®; Clovis Oncology, Boulder, CO, US) and niraparib (MK-4827, Zejula®; Tesaro, Waltham, MA, US).
Further clinical investigation of PARP inhibitors is underway. A number of clinical trials are investigating the combination of PARP inhibitors and immune checkpoint inhibitors. Recent data from the phase II MEDIOLA trial (ClinicalTrials.gov Identifier: NCT02734004)12 showed that combination therapy with olaparib and the PD-L1 inhibitor durvalumab (Imfinzi®; AstraZeneca, Cambridge, UK) induced objective responses in more than 70% of patients with relapsed, platinum-sensitive, BRCA-mutated ovarian cancer.13 The combination of PARP inhibitors and angiogenesis inhibitors is also being explored; the ongoing phase III trial, PAOLA-1 (ClinicalTrials.gov Identifier: NCT02477644),14 is evaluating the combination of olaparib and bevacizumab (Avastin®; Genentech, South San Francisco, CA, US) as a maintenance treatment for patients with newly-diagnosed advanced ovarian cancer, regardless of their BRCA status. A phase II study is evaluating the combination of niraparib and bevacizumab in the maintenance setting for patients with advanced ovarian cancer following response on frontline platinum-based chemotherapy (NCT03326193).15 In addition, a phase III study of combined cediranib and olaparib (NCT02446600)16 is ongoing after the combination demonstrated impressive efficacy in a phase II study.13 Other ongoing phase I/II studies include olaparib in combination with PI3K pathway inhibitors (< a href=”https://clinicaltrials.gov/ct2/show/NCT01623349″>NCT01623349),17 AKT inhibitors (NCT02338622),18 and mTORC1/2 inhibitors (NCT02208375),19 and an inhibitor of the tyrosine kinase WEE1 (a href=”https://clinicaltrials.gov/ct2/show/NCT02511795″>NCT02511795). 20
One potential concern of olaparib therapy is an increased risk of myelodysplastic syndromes (MDL)/acute myeloid leukaemia (AML), both of which have been reported in clinical use of olaparib and are associated with increasing dose and duration of platinum therapy.21 However, an analysis of SOLO-2 data concluded that olaparib did not increase the risk of MDS/AML compared with placebo.22 Many patients having received more than 5 years of continuous olaparib therapy without serious adverse events, and positive data continues to accumulate. However, with treatment durations anticipated to become even longer, greater numbers of patients receiving this therapy, and the ongoing investigation of novel combination strategies employing PARP inhibitors, ongoing monitoring will be essential.
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