'Outstanding' Ovarian Cancer PFS With Olaparib Maintenance

Liam Davenport

October 21, 2018

MUNICH — A first-of-its kind phase 3 study found that patients with advanced ovarian cancer who carry a BRCA mutation have a marked increase in progression-free survival (PFS) if they are given maintenance therapy with the poly(ADP)-ribose polymerase (PARP) inhibitor olaparib (Lynparza, AstraZeneca) following successful first-line chemotherapy.

Kathleen Moore, MD

The finding comes from the SOLO1 study, presented here at the European Society of Medical Oncology 2018 annual meeting, and simultaneously published in the New England Journal of Medicine.

Kathleen Moore, MD, associate professor at the Stephenson Cancer Center, University of Oklahoma, and colleagues found that, after more than 3 years of follow-up, olaparib was associated with a 70% increase in PFS compared with placebo, while causing few toxicities and having no impact on quality of life.

Noting that the "outstanding" improvement in PFS was maintained even after stopping treatment at 2 years, Moore said that the findings "herald a new era in treatment for women diagnosed with advanced ovarian cancer who carry a BRCA mutation."

"While it is too early to say whether we have impacted the fraction of women who could be cured with their front-line therapy, the fact that it is estimated that over 50% of women in the olaparib arm were still progression free at 4 years as compared to only 11% for placebo speaks to this hope," she said in a statement.

At a press briefing, Moore said, "We believe that the SOLO1 data really promise a change in the standard of care for women with advanced ovarian cancer who harbor a BRCA mutation, and we hope that this will be available to patients relatively soon."

Jonathan A. Ledermann, MD, director of Cancer Research UK and the University College London Cancer Trials Centre, UK, commented for ESMO: "Comparing that with all the trials we've done with other cytotoxic chemotherapy and drugs like bevacizumab, we've just not seen median progression-free survivals that good at that period of time out to 3 years."

There's a real, real hope that this treatment will perhaps lead to an increase in the cure rate.    Jonathan A. Ledermann, MD

"So I think there's a real, real hope that this treatment will perhaps lead to an increase in the cure rate, which will be reflected by a reduction in the first relapse rate. We’ll need to wait longer for that, but there's no doubt that this is a big step forward for the patients with BRCA-mutated ovarian cancer."

Ledermann noted that there nevertheless remain many challenges "not least access to the drug and the cost of the drug, but also the testing of patients for BRCA mutations."

He explained that testing will need to be "done earlier in patients, at diagnosis, to know whether they will be able to qualify for olaparib maintenance after their first chemotherapy, and that produces some logistical challenges in many countries and many regions."

Clara MacKay, project director at the nonprofit organization World Ovarian Cancer Coalition, agreed.

Pointing to a survey they conducted which revealed wide variations in access to testing across the globe, she said: "The key things that strike me from a patient perspective is the absolute urgency and need to ensure that women who are diagnosed with ovarian cancer have access to genetic testing."

Isabelle Ray-Coquard, MD, PhD, from Université Claude Bernard, Lyon, France, who was not involved in the study and was commenting for ESMO, said the results of this study were "outstanding" and they "promise to change practice" in BRCA-mutated patients.

However, she said two questions nevertheless remain, the first being whether the benefit seen with olaparib can be extended to all high-grade serious carcinomas.

"Looking at existing results in relapse with PARP inhibitor maintenance in all comers, we can anticipate excellent results for all patients with high-grade serious or endometrioid ovarian carcinoma," she said.

"Also, what is the best maintenance therapy? Standard first-line therapy in many countries is chemotherapy plus bevacizumab maintenance for the majority of advanced disease, but the question remains whether maintenance with olaparib alone or in combination with bevacizumab is preferable."

This last point may be addressed by the results of the PAOLA 1 trial, expected in 2019, she noted.

Solange Peters, MD, PhD, ESMO scientific committee chair, and Oncology Department, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, told Medscape Medical News ahead of the congress that it has been "a long time" since there have been any good outcomes with novel strategies in ovarian cancer. She added that the new data could "change the landscape of BRCA1-mutated ovarian cancer."

Ovarian Cancer Has One of the Highest Mortality Rates

Susana Banerjee,

Opening the press conference, co-investigator Susana Banerjee, MD, PhD, the Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, UK, explained that ovarian cancer is not only one of the most common malignancies in women but also has one of the highest mortality rates.

She said that, since the approval in 2011 for the use of bevacizumab as first-line treatment in combination with standard carboplatin and paclitaxel chemotherapy in women with newly diagnosed advanced ovarian cancer, there have been significant advances in targeted therapy.

This includes the approval of olaparib in 2014 for the maintenance treatment of adult patients with platinum-sensitive relapsed BRCA-mutated ovarian cancers, which was reported at the time by Medscape Medical News.

Banerjee said that, currently, PARP inhibitors have been shown to be effective and are approved for use in women with BRCA-mutated recurrent ovarian cancer that has returned more than 6 months after completing platinum-based chemotherapy.

In this setting, they significantly extend the time to progression and the time to treatment failure.

The PARP inhibitors are not available, however, for newly diagnosed advanced ovarian cancer, whether or not it is associated with a BRCA mutation, and standard treatment consists of surgery and platinum-based chemotherapy with or without bevacizumab.

This is associated with a 5-year survival rate for stage III disease of just 20%, falling to 5% in patients with stage IV disease, Banerjee noted. Overall, approximately 70% of women relapse within 3 years of first-line therapy.

Taking over the podium, Moore said that SOLO1 is the first phase 3 trial to examine maintenance PARP inhibitor therapy following platinum-based chemotherapy in newly diagnosed advanced ovarian cancer with a BRCA mutation.

She said that the vast majority of the 400 patients in the trial had undergone cytoreductive surgery and all had shown at least a partial response to platinum-based chemotherapy.

They were randomized in a 2:1 fashion to olaparib 300 mg twice daily or placebo, with treatment continued until disease progression. Patients with no evidence of disease at 2 years stopped treatment, while those with a partial response could continue.

In all, 260 patients assigned to the olaparib group and 130 assigned to placebo received the trial intervention. The two groups were well balanced in terms of baseline characteristics.

The patients had a good ECOG performance status, with approximately 78% able to undertake normal activities, the vast majority (approximately 95%) had a CA-125 level in the normal range, and 82% had a complete response to chemotherapy.

The most common BRCA mutation was BRCA1, which was seen in approximately 71% of patients overall, while BRCA2 was seen in around 27%, and both mutations were seen in 1% of olaparib patients.

"This is the group of patients where if anyone's going to be cured with frontline therapy alone, you would have seen it in this group of patients," Moore noted, pointing out that they "are unlike any other group of patients who are currently being enrolled in clinical trials."

She explained, "There's a whole bunch of clinical trials that are launching right now in ovarian cancer and they're great trials, but only in high-risk patients."

The median follow-up in SOLO1 was 40.7 months for olaparib patients and 41.2 months for placebo patients. After 2 years, just 26 (10%) olaparib patients and three (2%) of those given placebo continued with treatment, dropping to 13 and one patient, respectively, at data cutoff.

At 3 years, substantially fewer patients treated with olaparib than those given placebo had progressed, with 60.4% and 26.9% of patients, respectively, remaining progression-free.

This translated into a hazard ratio for progression with olaparib versus placebo at 3 years of 0.30 (P < .0001). The median PFS with placebo was 13.8 months, but was not reached for olaparib.

The researchers also found, albeit on an interim analysis, that olaparib was associated with a significant delay in time to second progression, at a hazard ratio for second disease progression or death at 3 years of 0.50, and time to first subsequent therapy or death, at a hazard ratio of 0.30.

Patients treated with olaparib did not experience a change in health-related quality of life scores relative to baseline.

Moore said that the majority of adverse events seen in the trial were low grade, with the most common grade ≥ 3 toxicities in olaparib-treated patients being anemia and neutropenia in 22% and 8% of patients, respectively.

She also noted that 28% of olaparib patients had dose reductions during treatment, while 52% had dose interruptions and 12% discontinued treatment because of toxicity.

Continued Benefit After Stopping Olaparib

At the press conference, Moore said that "the second most important thing about this trial, apart from the remarkable results," was the information they gained on how BRCA-mutated ovarian cancers behave when followed prospectively.

Referring to the continued benefit with olaparib even after stopping treatment, she asked, "What's going on there at the 2-year mark?"

"It's hard to say at this point...We hope that it means that we've converted a larger fraction of patients to cure, and that that's what you're seeing with the flattening of the survival curve, but it took us 3 years to get to this point, so how long is it going to take us to comment on an overall survival?" she commented. "It's a good problem to have," she added.

Asked whether patents will be convinced to stop taking therapy after 2 years, Moore said, "I will tell you that when we designed this study, and we were moving forward with it, I did not want to stop at 2 years."

"If you'd had asked me to redesign the study I would have said we should have just done olaparib forever, because we know that patients are going to recur in large numbers, and our patients on the study actually were mad when they had to stop."

"But...now when I see the data and I see that the curve doesn't change at 2 years...I feel as a physician, and I want my patients to live, much more comfortable stopping at 2 years, and I wondered if we could have stopped earlier," she commented.

Moore added, "This is why you do trials, and you follow the rules of trials, because this says that my bias was wrong originally and our patients, when they see this, are going to be much more comfortable as well."

"Patients who still have evidence of disease at 2 years are going to be allowed to continue on the drug. I think that will be in the label because that's how the trial was written and we don't see any difference in outcomes for those patients," she said.

The study was funded by AstraZeneca and Merck. Moore has received fees for advisory boards from AstraZeneca, Advaxis, Clovis, Tesaro, Genentech/Roche, Immunogen, VBL Therapeutics, and Janssen. Banerjee has received research funding from AstraZeneca and fees for advisory boards from AstraZeneca, Tesaro, and Clovis. Disclosures for the other authors are listed in the article. The World Ovarian Cancer Coalition is sponsored by Merck and AstraZeneca, among other companies.

European Society for Medical Oncology (ESMO) 2018 Congress. Presented October 21, 2018. Abstract LBA7.

N Engl J Med. Published online October 21, 2018. Abstract

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