Olaparib (LYNPARZAO) Ovarian cancer: spare patients who are in remission.

Abstract

Standard post-surgical (adjuvant) chemotherapy for ovarian cancer is based on a platinum salt, and may be repeated if relapse occurs more than six months after the end of chemo- therapy. Olaparib inhibits enzymes involved in DNA repair. It is claimed to have an antitumour effect, especially in the presence of deleterious BRCA muta- tions. Olaparib has been authorised in the EU for continuous single-agent therapy after the end of platinum-based chemotherapy in patients with "plati- num-sensitive" BRCA-positive ovarian cancer who have already received at least two lines of platinum-based che- motherapy and entered complete or partial remission after the last course of treatment. Clinical evaluation of olaparib is based on a randomised, double-blind, placebo-controlled trial in 265 patients who were recruited regardless of their BRCA status. After a median follow-up of 37 months, patients treated with olaparib showed no survival advan- tage, whether or not their tumour harboured BRCA mutations. The time to radiological progression was pro- longed by several months. An inher- ently unreliable post hoc analysis suggested that olaparib delayed the need for further chemotherapy. Olaparib exposes these patients in remission to frequent adverse effects, including nausea, vomiting, and impaired haematopoiesis. Olaparib can also cause life-threatening myelo- dysplastic syndrome, acute myeloid leukaemia, and haemorrhage. Olaparib is metabolised in the liver, mainly by cytochrome P450 isoenzymes CYP3A4 and CYP3A5. It is also a P-glycoprotein substrate and is likely to inhibit CYP3A4, P-glycopro- tein and other carrier proteins. Multiple pharmacokinetic interactions are also likely. Treatment with olaparib requires patients to take eight capsules twice a day, between meals. In practice, in early 2016, expectations of patients with ovarian cancer who have received at least two lines of chemotherapy are high, as they have short life expectancy and no sat- isfactory treatment options. Yet treat- ment with olaparib after the end of platinum-based chemotherapy still has an unfavourable harm-benefit bal- ance: patients derive no proven ben- efit, but adverse effects are frequent and sometimes fatal.