More Options for Ovarian cancer
March 17, 2020 | Disease
One in 78 women will suffer from ovarian cancer during their lifetime. The condition accounts for more deaths than any other cancer of the reproductive system – and ranks fifth in overall cancer deaths among women.
The good news is that the range of available treatments is expanding. Precision medicine continues to generate therapies that are more targeted to particular genetic mutations, and more treatment combinations are being tested. If the disease is picked up early, five-year survival rates are very good – up to 80% or more. That has led some to consider ovarian cancer a chronic disease, as is the case for some breast cancers that are diagnosed promptly.
But about three quarters of women suffering with ovarian cancer – over half of whom are in their mid-sixties or older – are diagnosed only when the disease has advanced to stage 3 or 4. Standard treatment is surgery to remove tumors, followed by chemotherapy with or without the VEGF-inhibitor Avastin (bevacizumab). This has not changed much in the last decade, although the disease will recur in most women.
That’s why scientists are investigating the merits of using more targeted treatments – notably, PARP inhibitors – both earlier and later in the treatment pathway. PARP inhibitors block the body’s attempts to repair mutated DNA found in many cancers. They include Lynparza (olaparib), sold by Merck and AstraZeneca, Zejula (niraparib), sold by GSK, and Clovis Oncology’s Rubraca (rucaparib).
PARP inhibitors have for several years used in women whose cancer has returned after several rounds of chemotherapy. Lynparza was initially approved in 2014 for heavily pre-treated patients with advanced disease who had defective BRCA genes – mutations that occur in an estimated one in three ovarian cancer patients. Three years later, approval was expanded to maintenance therapy for all patients with recurrent disease – as Zejula, too, reached the market.
As scientists work out which combinations and treatment sequences work best – not an easy task, given ethical and competitive hurdles – the PARP inhibitors are becoming more widely available. In late 2018, Lynparza got a green light as first line maintenance therapy for BRCA-mutated advanced ovarian cancer, meaning it can be used after a round of chemotherapy, not only after recurrence. Approval was based on a trial showing a 70% reduction in the risk of disease progression or death, compared to placebo.
Last year, Zejula was approved as a late-line monotherapy, in patients with advanced disease that had had three or more prior chemotherapy rounds. Eligible women must have either a BRCA gene mutation, or genomic instability – as defined by a molecular test. Such patients are said to be “HRD positive” – homologous recombination deficient. They may not specifically have a BRCA gene mutation.
GSK is testing Zejula as a maintenance therapy in newly-diagnosed ovarian cancer patients, while Lynparza is combined with Avastin to determine whether these two therapies work better together for some patients. Trials are not limited to patients with HRD mutations, but those groups did tend to show the greatest benefit. As yet, though, data is inconclusive over whether to exclude non-HRD patients; researchers are still trying to work out where, and whether, to genetically segregate. There are also questions around whether early use of PARP inhibition may impact the effectiveness of chemotherapy, if it is required.
There may be more PARPs to come: AbbVie has a late-stage candidate that has shown some promise in ovarian disease, though earlier trials in breast and lung cancers failed.
Meanwhile, immuno-therapy (I-O), which works by harnessing the body’s immune system to fight cancer, may yet have a role in ovarian cancer. So far, checkpoint inhibitors such as Merck’s Keytruda have had little success fighting ovarian tumors, due to their particular immunogenic profile. But there too, combinations are under investigation – of different I-O approaches, and of I-O drugs with PARP inhibitors or Avastin. So are personalized vaccines, tailored to individual womens’ tumors.
Determining which treatment combination and sequence will benefit which patients is a work in progress, as is it across most other cancer types. Yet as the therapy armamentarium grows and as genetic testing becomes more widespread, ovarian cancer patients today unquestionably have more options.
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