At the 2019 Congress of the European Society of Medical Oncology, PARP inhibitors continued their victory march. With the success of the PAOLA-1 trial, reported in Friday's plenary session, as well as the PRIMA and VELIA/GOG-3005 trials, "we've got new front-line data that really introduces a paradigm shift into the way we're going to treat ovarian cancer in the coming years," Jonathan Ledermann, professor of medical oncology at University College London, told the audience at a session on new options on ovarian cancer.

One of the pressing questions is how to tell which patients can benefit from that paradigm shift.

PARP inhibitors got their start when it became clear that such drugs were synthetic lethal to cells with BRCA mutations, which were unable to cope with having two of their DNA repair mechanisms blocked.

BRCA mutation status is still the "best predictor" of whether a patient will respond to PARP inhibitors, Charlie Gourley told the audience at ESMO.

But their predictive capacity is far from perfect.

Gourley, who is the chair of medical oncology at the University of Edinburgh, pointed out that with the exception of PAOLA-1, every trial testing front-line PARP inhibition in ovarian cancer has provided evidence that PARP inhibitors improved the outcome for some patients with no obvious reason to be especially sensitive to DNA repair inhibition.

Sensitivity to platinum chemotherapy, which also works by inhibiting DNA repair, has been used as a criterion in a number of trials.

In the first-line setting, though, that criterion is much more difficult to use because it is the first-line setting – "you don't have an opportunity to see what a platinum-sensitive interval would be," Gourley said.

DNA repair is not the sole province of BRCA genes by any stretch, and a previous clinical trial by Ledermann, Study 19, showed that many patients who responded to Lynparza (olaparib, Astrazeneca plc and Merck & Co. Inc.) had homologous recombination deficiencies.

Another possibility is that BRCA genes may not have a mutation, but nevertheless be silenced.

Epigenetic silencing of BRCA has been tested as a possible predictor of PARP inhibitor sensitivity. While initial results were disappointing, Gourley said that recent studies suggest that testing whether both alleles of BRCA were silenced may be more useful.

Epigenetic silencing – as well as, more rarely, mutations – can be reversed, but even temporary dysfunction of BRCA leaves "DNA scarring" that can be tested for, and may predict PARP inhibitor responsiveness.

For whatever reason, for now, PAOLA-1 is the only trial where women who had neither BRCA mutations nor homologous recombination deficits (HRD) appeared to derive no benefit from adding a PARP inhibitor to the tested treatment. In that case of PAOLA-1, the specific drugs were Lynparza and Avastin (bevacizumab, Roche Holding AG). But why women without BRCA mutations or HRD derived no benefit in PAOLA, but did do better than controls in other trials, remains a mystery for now.

"If anyone knows," Gourley said, "send me a postcard."

PAOLA-1/ENGOT-ov25 enrolled 806 patients with stage III/IV ovarian cancer and partial or complete response to standard platinum-based chemotherapy and bevacizumab. After completing first-line chemotherapy, patients were randomly allocated 2-to-1 to 15 months Avastin plus 24 months of either Lynparza or placebo. Median progression-free interval (PFI) was 22.1 months in the olaparib group and 16.6 months in the placebo group (hazard ratio [HR] 0.59, p<0.0001).

In the PRIMA trial, Zejula (niraparib, Glaxosmithkline plc) administered after completion of first-line chemotherapy significantly improved PFI. In the VELIA/GOG-3005 trial, veliparib (Abbvie Inc.) given with first-line chemotherapy and then continued as maintenance treatment significantly extended PFI to 23.5 months, compared to 17.3 months in the placebo arm (HR, 0.68; p<0.001). The benefit was more pronounced for patients with BRCA mutations, whose median PFI was 34.7 months for veliparib compared to 22 months with placebo (HR, 0.44, p<0.001).

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