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Pricey Drug Combo Boosts PFS in First-Line Advanced Ovarian Cancer

— Questions about anti-PD-L1 contribution, cost, and access to durvalumab, bevacizumab, olaparib

MedpageToday

CHICAGO -- A three-drug combination significantly improved progression-free survival (PFS) in newly diagnosed non-BRCA advanced ovarian cancer but raised questions about the cost of the regimen, according to a study reported here.

Upfront durvalumab (Imfinzi), chemotherapy, and bevacizumab (Avastin), followed by durvalumab, bevacizumab, and olaparib (Lynparza), led to a median investigator-assessed PFS of 37.3 months versus 23 months with chemotherapy plus bevacizumab followed by bevacizumab and placebo in homologous recombination-deficient (HRD)-positive tumors. An intention-to-treat (ITT) analysis produced median PFS values of 24.2 months for the three-drug combination and 19.3 months for the control group, which also achieved statistical significance.

A subgroup analysis showed that the three-drug combination significantly improved PFS in patients with HRD-positive and HRD-negative tumors, reported Carol Aghajanian, MD, of Memorial Sloan Kettering Cancer Center in New York City, at the American Society of Clinical Oncology (ASCO) annual meeting.

"The relative contribution of durvalumab [to the three-drug regimen] requires further investigation," she acknowledged during a press briefing that preceded the ASCO meeting. "The safety and tolerability of the combination was generally consistent with known profiles of the individual agents. Data at the time of this planned PFS interim analysis are important, and the trial is ongoing. Final PFS, OS [overall survival] and other key secondary endpoints will be reported when available."

'Huge Step Forward'

The study represents a "huge step forward" and is clinically meaningful at the level of the individual patient, said invited discussant Merry Jennifer Markham, MD, of the University of Florida in Gainesville. She noted that about 80% of ovarian cancers are advanced-stage at diagnosis, and most of the patients will have a recurrence after initial response to treatment.

"Progress probably has not been quick enough for our patients with advanced ovarian cancer but every little integral improvement that we can find in studies like this one really means so much to the patient in the exam room," said Markham.

"While progression-free survival may not necessarily mean overall survival, though we hope it does, and I'm very excited to see whether this study heads in that direction," she added. "Even progression-free survival is very important to our patients. For the woman who wants to be able to not be on chemotherapy for recurrent disease shortly after her initial diagnosis, or even in the next 3 to 5 years, this does represent progress. I think we are chipping away at improving outcomes for women with advanced ovarian cancer."

The activity in non-BRCA and HRD-negative tumors offers another reason for optimism, as absence of mutation, in particular, may limit treatment options, Markham continued.

Maintenance therapy with bevacizumab and olaparib has improved outcomes in first-line advanced ovarian cancer and has become standard of care. However, the non-BRCA patient population remains an unmet need, Aghajanian noted. Phase III clinical trials evaluating the addition of immuno-oncology agents to standard of care have yet to show a benefit in first-line advanced ovarian cancer. A did show promising clinical activity with the combination of durvalumab, bevacizumab, and olaparib.

Trial Design, Key Findings

Aghajanian reported findings from an interim analysis of the international, randomized DUO-O/ENGOT-ov46/AGO-OVAR 23/GOG-3025 trial. Investigators enrolled patients with stage III/IV epithelial ovarian cancer without BRCA mutations and with or without HRD. Patients were randomized to three regimens:

  • Arm 1: Paclitaxel-carboplatin chemotherapy, bevacizumab and durvalumab placebo, followed by maintenance with bevacizumab, durvalumab placebo, and olaparib placebo
  • Arm 2: Chemotherapy plus bevacizumab and durvalumab followed by bevacizumab, durvalumab, and olaparib placebo
  • Arm 3: Chemotherapy, bevacizumab, and durvalumab, followed by bevacizumab, durvalumab, and olaparib

The primary endpoints were PFS for arm 3 vs arm 1 in the non-BRCA, HRD-positive subgroup and in the ITT population. Secondary endpoints included PFS for arm 2 vs arm 1 in the ITT population, OS, and safety.

Investigators randomized 1,130 patients, including 531 patients with HRD-positive tumors. After a median follow-up of about 2 years, the results showed that arm 3 reduced the hazard for disease progression or death by 51% versus arm 1 (95% CI 0.35-0.69, P<0.0001) in the HRD-positive patients and by 37% in the ITT analysis (95% CI 0.52-0.76, P<0.0001). Arm 2 resulted in a median PFS of 20.6 months in the ITT analysis, which did not achieve significance versus arm 1.

Separate analyses by HRD status showed arm 3 demonstrated superiority versus arm 1 in HRD-negative patients (20.9 vs 17.4 months, HR 0.68, 95% CI 0.54-0.96), as well as the HRD-positive subgroup. Arm 2 did not achieve statistical superiority in either subgroup versus arm 1 and had a numerically lower median PFS in the HRD-negative group (15.4 vs 17.4 months).

Adverse events (AEs) in the chemotherapy and maintenance phases combined occurred more often with arm 3, particularly nausea and anemia. The most common grade ≥3 AEs were neutropenia (28-31% across all groups) and anemia (24% arm 3 vs 8% for arms 1 and 2).

Financial Toxicity

During a discussion that followed the presentation, ASCO chief medical officer Julie Gralow, MD, raised the issue of cost with Markham.

"These are expensive drugs. What do you think about access and payers in the United States approving use of all these drugs, especially in the broader intention-to-treat group?" asked Gralow, who moderated the press briefing.

Markham said she might be "a little less optimistic about what this looks like from an access perspective," noting that patients and insurers in the southern U.S. are different.

"At my institution, for example, a fair number of patients are underinsured," she said. "We run into a lot of issues with people not being able to afford their copays. If insurance is able to cover it, the cost of the copay can be prohibitive. For some of my patients, a large portion of my counseling has been and will continue to be around the benefit, but also the financial toxicity that the individual patient may experience."

Aghajanian said her experience with insurers has been more positive.

"These drugs are covered by insurance. Obviously, there are patients who do have some financial toxicity related to copays and other issues that come up, but there is also access to copay assistance programs," she said.

In response to another question, Aghajanian said investigators could not comment on the contributions of durvalumab to the outcomes in the trial. Preclinical studies had suggested synergy with olaparib, but that was not specifically evaluated in the trial.

"This trial was initiated at a time when olaparib wasn't standard of care for the non-BRCA group, something we learned about in the interim," said Aghajanian. "Certainly, if we had it to do over again, we would have a fourth arm that had bevacizumab and olaparib maintenance so that we could do a comparison [with three-drug maintenance]."

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined 鶹ý in 2007.

Disclosures

The study was supported by AstraZeneca.

Aghajanian disclosed relationships with AstraZeneca, Merck, Eisai, Repare Therapeutics, AbbVie, Clovis Oncology, and Genentech/Roche.

Markham disclosed relationships with Pfizer, GlaxoSmithKline, Aduro Biotech, AstraZeneca, Lilly, Merck, Novartis, Tesaro, and VBL Therapeutics.

Primary Source

American Society of Clinical Oncology

Harter P, et al "Durvalumab with paclitaxel/carboplatin and bevacizumab followed by maintenance durvalumab, bevacizumab, and olaparib in patients with newly diagnosed advanced ovarian cancer without a tumor BRCA1/BRCA2 mutation: Results form the randomized, placebo controlled phase III DUO-O/ENGOT-ov46/AGO-OVAR 23/GOG-3025 trial" ASCO 2023; Abstract LBA5506.