“Huge breakthrough” in advanced ovarian cancer

UPDATED June 4, 2023 // Editor’s note: This story has been updated with additional comments from Dr. Christina Fotopoulou.

CHICAGO New results in the treatment of advanced ovarian cancer were welcomed by an expert not involved in the study, even though the study showed an improvement in progression-free survival (PFS) and not yet in overall survival.

Findings are from the DUO-O trial, in which PARP inhibitor olaparib (Lynparza) and anti-PD-L1 antibody immunotherapy durvalumab (Imfinzi) were added to standard of care paclitaxel/carboplatin chemotherapy and bevacizumab (Avastin). in newly diagnosed patientsBRCA extension mutated advanced ovarian cancer.

A planned interim analysis revealed that adding durvalumab and olaparib was associated with a 37% improvement in PFS compared with standard of care chemotherapy plus bevacizumab alone.

This improvement increased to 51% in patients with homologous recombination deficiency (HRD)-positive tumors, which indicates an inability to effectively repair double-stranded DNA breaks, a defect found in approximately 70% of ovarian cancers.

Co-principal investigator Carol Aghajanian, MD, chief of the Gynecologic Medical Oncology Service at Memorial Sloan Kettering Cancer Center in New York City, described the benefits seen with the new combination therapy as “statistically significant and clinically significant.”

He was speaking at a press conference held before the American Society of Clinical Oncology annual meeting, where the findings will be presented (abstract LBA5506) Today.

Commenting for ASCO, Merry Jennifer Markham, MD, professor of medicine and chief of the division of hematology and oncology at the University of Florida Health, Gainesville, said the findings represent a “huge step forward.”

He added that the rate of progress it represents may not be “fast enough for our patients with advanced ovarian cancer, but every little integral improvement we can find in major studies, like this one, really means a lot to that single patient in that classroom.” ‘examination”.

Markham pointed out that about 80% of women with epithelial ovarian cancer are diagnosed at an advanced stage and “know what they are dealing with”, which is that “the vast majority” of them will have a recurrence “at some point”.

“So while progression-free survival may not necessarily mean their overall survival, there will be hope that it does. And I’m very excited to see where this study heads in that direction.” Markham added that PFS is “very important to our patients” and the study represents progress. “We are working to improve outcomes for advanced ovarian cancer.”

Also, “women are often disappointed when their cancer doesn’t have a BRCA extension mutation because they know it may limit some of their treatment options,” and so the current study suggests that there are “options for everyone” and “there is still hope.”

Access to treatment and testing

Asked by Medscape Medical News While there could be issues accessing patients clinically eligible for the new combination, Aghajanian said all drugs have been approved by the US Food and Drug Administration for indications that cover this use.

They are also covered by medical insurance and, for those patients with financial toxicity, “there is access to paid assistance programs and the like.”

He said patients can then “be advised about their expected benefits,” based on their own BRCA extension and HRD testing.

Markham, on the other hand, said she was “a little less optimistic” about access, explaining that it exists in the southern US, and “our populations [and] insurance coverage is a little different.”

She noted that, at her Florida institution, “a fair number of patients are underinsured,” and they “encountered a lot of problems with people who couldn’t afford their co-pays,” which can be “prohibitive.”

“Much of my counseling has been and will continue to be about the benefit, but also the financial toxicity, that that individual patient might experience and the need for co-pay assistance programs or other support mechanisms,” Markham said.

Aghajanian added that “the financial toxicity and access issue comes even before treatment, in getting those BRCA extension1/2 tests and HRD tests performed, so patients have the information they need to make informed decisions.”

“We have disparities with genetic testing and genomic testing that needs to be fixed,” she said.

Study details

Previous studies, including SOLO1 and PAOLA-1, have demonstrated that maintenance therapy with olaparib and bevacizumab improves outcomes in the first-line treatment of advanced ovarian cancer.

“However, an unmet need still remains, especially in some subgroups of patients without a BRCA extension mutation,” Aghajanian said.

While adding immunotherapy to standard of care has yet to show clinical benefit in this setting in Phase 3 studies, the Phase 2 MEDIOLA study indicated that the combination of durvalumab, bevacizumab, and olaparib was active in the non-germline BRCA extension-mutated, platinum-sensitive cancer relapsed.

The Phase 3 DUO-O study therefore set out to determine whether this combination would be beneficial as maintenance therapy in 1130 patients with newly diagnosed stage III or IV high-grade ovarian cancer without cancer BRCA extension1/2 mutation.

Patients had to have received no prior systemic therapy for ovarian cancer and were naïve to both PARP inhibition and immunotherapy. They also had to have completed primary debulking surgery beforehand or be scheduled to have the procedure.

After an initial course of paclitaxel/carboplatin chemotherapy, patients were randomly assigned to one of three regimens:

  • Standard of care treatment, including chemotherapy plus bevacizumab and durvalumab-placebo, followed by maintenance therapy with bevacizumab, durvalumab-placebo, and olaparib-placebo (arm 1)

  • Chemotherapy plus bevacizumab and durvalumab, followed by maintenance therapy with bevacizumab, durvalumab and olaparib-placebo (arm 2)

  • Chemotherapy plus bevacizumab and durvalumab, followed by maintenance therapy with bevacizumab, durvalumab and olaparib (arm 3)

In the maintenance phase, bevacizumab was to be administered for a total of 15 months, while durvalumab and olaparib, or their placebo equivalents, were prescribed for 24 months. Treatment was continued until disease progression, study completion, or other discontinuation criteria were met.

Aghajanian presented the results of a planned interim analysis, with a cut-off date of December 5, 2022.

Among HRD-positive patients, those in arm 3 had significantly longer PFS than those in arm 1, with a median of 37.3 months vs 23 months, or an hazard ratio of 0.49 (P < .0001).

In the intention-to-treat analysis, arm 3 was also associated with a significant improvement in median PFS compared with arm 1, at 24.2 months vs 19.3 months, or an hazard ratio of 0.63 (P < .0001), indicating that the study met both of its primary endpoints.

While there was a numerical difference in median PFS between Arm 2 and Arm 1, at a median of 20.6 months versus 19.3 months, this was not significant. This means the relative contribution of adding durvalumab alone is unclear, Aghajanian commented, and said this comparison “will be reevaluated at the time of the final PFS analysis.”

It added that “a ‘PFS effect was observed in all subgroups for the comparison of arm 3 and arm 1’, including in the HRD negative subgroup, with a median of 20.9 months versus 17.4 months or hazard ratio by 0.68.

The safety and tolerability of the regimens were generally consistent with what is known for individual agents, he commented.

Serious adverse events were reported in 34%, 43% and 39% of patients in arms 1, 2 and 3, respectively.

The most common grade 3 or higher adverse events were neutropenia (in 26% of arm 1 patients, 28% of arm 2 patients, and 31% of arm 3 patients) followed by anemia (8% , 8% and 24%, respectively).

Dose modifications were required in 72% of patients in arm 1, 80% of patients in arm 2 and 85% of patients in arm 3. Treatment discontinuation was reported in 20%, 26%, respectively and 35%.

Addressing underprivileged patient populations

Discussing the findings, Christina Fotopoulou, MD, PhD, professor of gynecological cancer surgery in the Department of Surgery and Cancer, Imperial College London, UK, said that while the regimen may appear new, the treatments involved are “old-timers.” and yet are addressing previously underprivileged patient populations.

Fotopoulou, who was not involved in the study, noted that the results were highly anticipated and the study produced a “breakthrough in ovarian cancer.” However, he questioned the choice of control arm and stressed that the hazard ratio in favor of the combination therapy is “relatively modest” considering that there are three drugs.

Fotopoulou pointed out, however, that one of the more important findings was in patients with negative HRDs, which he characterized as the equivalent of doctors going to the “dark side of the moon.” She said that “for the first time, we have a positive study in this patient population,” although she emphasized that the results are from an interim analysis.

The key question that remains, Fotopoulou said, is, “Why? What’s making the difference?” He noted that, unfortunately, the study design did not allow identification of the relative contributions of olaparib and durvalumab.

The study was sponsored by AstraZeneca and conducted in collaboration with the European Network of Gynecological Oncological Trial Groups (ENGOT), GOG Foundation, Inc. and Myriad Genetic Laboratories, Inc.

Harter discloses relationships with AstraZeneca, Clovis Oncology, Eisai, GlaxoSmithKline, Lilly, MSD Oncology, Roche, Sotio, Stryker, Zai Lab, Immunogen, Merck, Roche, Tesaro and Genmab (Inst). Aghajanian discloses relationships with AstraZeneca, Merck, Eisai, Repare Therapeutics, AbbVie (Inst), Clovis Oncology (Inst), and Genentech/Roche (Inst). Markham discloses relationships with Pfizer, GlaxoSmithKline, Aduro Biotech (Inst), Lilly (Inst), Tesaro (Inst), Novartis (Inst), VBL Therapeutics (Inst), AstraZeneca (Inst) and Merck (Inst).

American Society of Clinical Oncology Annual Meeting 2023: Abstract LBA5506. To be submitted on June 3, 2023.

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