1. Goodwin, Peter M.

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MUNICH-The role of PARP inhibitors for treating newly diagnosed advanced ovarian cancer was under review at the 2018 ESMO Annual Congress in the light of findings from the SOLO-1 randomized phase III trial in which there was more than a doubling of the numbers of patients surviving 3 years without disease recurrence.

Jonathan Ledermann, ... - Click to enlarge in new windowJonathan Ledermann, MD, FRCP. Jonathan Ledermann, MD, FRCP

Commenting on the findings, Jonathan Ledermann, MD, FRCP, Professor of Medical Oncology at the UCL Cancer Trials Centre, Director of Cancer Research UK and UCL Cancer Trials Centre, and Clinical Director at the UCL Cancer Institute in University College London, said the study had been a first.


"We know that olaparib and other PARP inhibitors are very successful in delaying disease progression in patients with recurrent disease. But this trial tested maintenance olaparib in the front-line setting after surgery and chemotherapy-and that was unique," he said.


Study Details

In SOLO-1, the PARP inhibitor olaparib had been compared with placebo as first-line therapy after chemotherapy in patients with stage III or IV newly diagnosed high-grade serous or endometrioid ovarian or primary peritoneal or fallopian tube cancer who tested positive for the BRCA1/2 gene mutation. Results were reported at a packed ESMO session by Kathleen Moore, MD, Associate Director for Clinical Research at the Stephenson Cancer Center, University of Oklahoma in Oklahoma City.


SOLO-1 had been conducted in patients with BRCA mutations because they were ones most likely to derive the greatest benefit. But Ledermann said there were hopes, too, that this class of anti-cancer drug might well find applications in ovarian cancer beyond this subgroup.


"Patients with a BRCA mutation tend to have a better outcome than other patients and so it took a while for the progression events to come through," Ledermann noted. But after a minimum of 3 years there had been a result. "At that point 60 percent of patients on olaparib remained free of progression, whereas 26 percent (which is what one might expect) in the placebo arm [did]."


Patients Without BRCA Mutation

When asked about the potential role of first-line PARP inhibition for patients with ovarian cancer who did not have mutated BRCA, Ledermann said he hoped benefits might be found among these patients, too.


"Certainly in the recurrent disease setting it's been quite clear that PARP inhibitors are effective in patients who don't have a BRCA mutation. The magnitude of benefit is less." He was awaiting findings from ongoing studies of first-line treatment investigating PARP inhibitor maintenance therapy in the non-BRCA setting to show whether these drugs could be used in a broader population.


But the findings from SOLO-1 signaled the need for therapy changes, according to Ledermann. "This is a landmark study. And I think that olaparib now will become treatment of choice for first-line treatment of patients with a BRCA mutation."


Points of Discussion

But there were challenges ahead. The first was to make sure patients were tested for mutated BRCA at diagnosis. "The importance of that is that often patients are treated first-line with a combination of chemotherapy and bevacizumab. [But] if a patient has a BRCA mutation, it is likely that the clinician will advise the patient not to have bevacizumab but to have olaparib at the end of chemotherapy," Ledermann said. Clinicians needed to know the results of the BRCA test before patients started chemotherapy.


Ledermann described the side effect profile of PARP inhibition in the SOLO-1 study as similar to studies with olaparib in recurrent disease-in terms of the percentage of patients requiring dose reduction or discontinuation of therapy because of toxicity. At around 12 percent, the discontinuation rate was "a relatively small number," he said.


When asked if longer than the per-protocol regimen of 2 years olaparib could have been beneficial, Ledermann said that, although around 10 percent of the patients on the trial had indeed continued the treatment beyond 2 years (allowed under the protocol on the grounds that they had visible disease at the end of chemotherapy), for the remaining patients 2 years of PARP inhibition had seemed to be optimal. "The progression-free survival curves don't seem to have come together after that time point," he said.


The continued separation of the PFS curves tempted Ledermann to speculate about cure. "It's intriguing to think that these patients might actually be cured," he said. There was a need to investigate whether olaparib had eradicated tumor cells or whether another process-such as an immune response-had taken over and kept patients free of progression.


When discussing the potential extension of OS in patients treated with olaparib, he said the SOLO-1 data gave indications that this had been happening. "One of the ways of trying to get at early data for overall survival is to measure an endpoint called the PFS2-the time to the second progression," he explained, since it was important that when patients received a drug that improved their PFS they were still able to tolerate further lines of therapy with other drugs and not to lose any advantage later on. "And that was seen in this SOLO-1 study. The hazard ratio for PFS2 was 0.5," said Ledermann.


The European Medicines Agency had indeed accepted PFS2 "as a co-regulatory endpoint in situations where the OS data were going to be a long time coming," he noted. "What's clear now is that-certainly for patients with a BRCA mutation-olaparib maintenance in the first-line setting will become a new standard of care for treatment of ovarian cancer. And we are just going to have to wait for further trials to know whether that is applicable to a wider group of patients."


But Ledermann's immediate call for action was to urge clinicians to test patients newly diagnosed with advanced ovarian cancer for BRCA mutations at diagnosis to make sure to identify those who are suitable for olaparib.


Peter M. Goodwin is a contributing writer.


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