Worse PFS Seen with Nivolumab-Rucaparib in Ovarian Cancer

The addition of nivolumab to rucaparib did not lead to better progression-free survival than rucaparib monotherapy in patients with newly diagnosed, advanced, high-grade ovarian cancer (AHGOC), a new study has found.
Bradley J. Monk, MD, presented this finding and other results of the ATHENA-COMBO study, at the European Society for Medical Oncology Congress 2024. 
The phase 3, randomized trial compared the efficacy of rucaparib (Rubraca) plus nivolumab (Opdivo) combination therapy vs rucaparib monotherapy as maintenance treatment in patients with AHGOC who had responded to first-line platinum-based chemotherapy. The study showed the combination therapy was associated with numerically shorter median PFS compared with rucaparib monotherapy in the intent-to-treat (ITT) population (15.0 months vs. 20.2 months; hazard ratio [HR], 1.3; 95% CI, 1.1 – 1.5). This trend was consistent across various subgroups, including those based on homologous recombination deficiency (HRD) status and programmed death-ligand 1 (PD-L1) expression levels.
During his talk, Monk, of the Florida Cancer Specialists & Research Institute, West Palm Beach, Florida, explained the rationale for conducting ATHENA-COMBO.
“PARP inhibitors, bevacizumab, and their combination are good options, but they’re not enough. There is extreme rationale and reason to add immune therapy to PARP inhibitors,” he said. Monk also outlined three key mechanisms supporting this approach: PARP inhibitors’ interference with DNA repair leading to increased neoantigens, activation of the STING (stimulator of interferon gene) pathway, and increased PD-L1 expression.
Study Design and Patient Population 
The trial enrolled 863 patients with FIGO stage III-IV AHGOC across 294 sites in 24 countries. Patients were randomly assigned 1:1 to receive either oral rucaparib 600 mg twice daily plus IV nivolumab 480 mg every 4 weeks or rucaparib plus placebo. The primary endpoint was investigator-assessed, progression-free survival (PFS) in the ITT population. The investigators also performed exploratory analyses to assess PFS in homologous recombination deficiency (HRD) subgroups and PD-L1 subgroups.
Combination Therapy Is Not Superior to Monotherapy
During his talk, Monk said he was surprised that the PARP inhibitor and the immune checkpoint agent didn’t provide synergistic effects translating into a low hazard ratio, because of the modes of action of the drugs. 
“PARP inhibitors lead to increased neoantigens, which means more immunogenicity. We had hoped that we could improve PFS. We were ambitious in trying to target a hazard ratio of 0.75 and increase the median PFS to 28 months,” he said.
These findings fell short of the researchers’ high expectations, according to Philipp Harter, MD, PhD, of Kliniken Essen-Mitte in Essen, Germany.
“We wanted to see comparable results like in melanoma, cervical cancer, and endometrial cancer.” Although the results were disappointing, they should be viewed in context, Harter continued.
“We cannot say that this is a detrimental trial. We have to think that back when this trial started in 2018, the standard of care was carboplatin and paclitaxel without any maintenance therapy,” said Harter, who was not involved in the ATHENA-COMBO trial and served as a discussant of the findings presented at the meeting.
During his discussion session, Harter raised the following question about the study design and optimal combination strategies in ovarian cancer treatment: “Would the results look different if bevacizumab was used in addition?”
He added that, in the MEDIOLA study assessing triplet vs doublet therapy in relapsed ovarian cancer, the addition of bevacizumab to olaparib and durvalumab improved objective response rates from 34.4% to 87.1%. 
Long-Term Follow-up and Safety Considerations 
The trial provided additional follow-up data for the rucaparib monotherapy group, confirming its efficacy in this setting. Monk highlighted, “At 4 years, 33% of the patients on rucaparib alone are progression-free and hopefully even cured.”
However, the study raised safety considerations. The combination group had a higher rate of treatment discontinuation due to adverse events than the monotherapy group (21% vs. 12.7%). Moreover, grade 3 or higher treatment-related adverse events were more common in the combination group, particularly neutropenia (25.4% vs 15.4%) and elevated liver enzymes (21.2% vs 10.0%). The rates of grade 3 or higher treatment-related anemia were similar between the two groups (27.1% in the combination treatment group vs 28.6% in the monotherapy group).
Monk suggested that increased toxicity and treatment discontinuation rates might have played a role in the inferior outcomes of the combination therapy. He noted that the combination group had more adverse events, more grade 3 events, more interruptions, and more dose discontinuations. Monk explained that the higher rate of treatment discontinuation could have led to reduced exposure to rucaparib in the combination group, potentially compromising its efficacy. 
While acknowledging the higher discontinuation rate, Harter questioned whether this alone could explain the findings. During the discussion session, he noted that the discontinuation rate of 25% is high, but only approximately 10% higher than the rates reported in other PARP inhibitor trials in primary ovarian cancer. 
Implications for Future Research
During the discussion session, Harter emphasized that the ATHENA-COMBO trial results add to a growing body of evidence regarding immunotherapy in ovarian cancer. He added that, even though the combination of rucaparib and nivolumab did not improve outcomes compared to rucaparib alone, the study provides valuable insights that will inform future research initiatives. 
Harter also speculated whether the choice of nivolumab as the checkpoint inhibitor, rather than another agent, could have played a role in the unexpected results, hinting at potential differences in efficacy or tolerability among various immunotherapy drugs in this setting. 
He added that there are currently two trials investigating the role of checkpoint inhibitors in primary ovarian cancers: the FIRST trial, investigating the combination of dostarlimab with rucaparib, and the KEYLINK trial, assessing the combination of olaparib with pembrolizumab.
Monk reported financial relationships with Regeneron, Verastem Oncology, and Zentalis (honoraria); Acrivon, Adaptimmune, Agenus, Alkermes, Amgen, AstraZeneca, Bayer, BioNTech, Clovis Oncology, Corcept, Duality, Eisai, Elevar Therapeutics, EMD Merck, Genelux, Genmab/Seattle Genetics, GOG Foundation, Gradalis, Immunogen, Karyopharm Therapeutics, Laekna, Merck, Mersana, Myriad Pharmaceuticals, Novartis, Novocure, OncoC4, Panavance, Pfizer, Profound Bio, Regeneron, Roche/Genentech, Sarah Cannon Research Institute, Tesaro/GSK, Tubulis, Verastem, and Zentalis (consulting role); Aadi, Adaptimmune, AstraZeneca, Clovis Oncology, Eisai, Merck, Myriad Pharmaceuticals, Roche/Genentech, and Tesaro/GSK (speakers bureaus); and Aadi, Acrivon, Adaptimmune, Agenus, Alkermes, Amgen, AstraZeneca, Bayer, BioNTech, Clovis Oncology, Corcept, Duality, Eisai, Elevar Therapeutics, EMD Merck, Genalux, Genmab/Seattle Genetics, GOG Foundation, Gradalis, Immunogen, Karyopharm Therapeutics, Laekna, Merck, Mersana, Myriad Pharmaceuticals, Novartis, Novocure, OncoC4, Panavance, Pfizer, Profound Bio, Regeneron, Roche/Genentech, Sarah Cannon Research Institute, Tesaro/GSK, Tubulis, Verastem Oncology, and Zentalis (personal or other financial interests). 
Harter reported financial relationships with Amgen, AstraZeneca, GSK, Roche, Immunogen, Sotio, Stryker, Zai Lab, MSD, Clovis, Miltenyi, Eisai, Mersana, Exscientia, Daiichi Sankyo, Karyopharm, and AbbVie (honoraria); AstraZeneca, Roche, GSK, Clovis, Immunogen, MSD, Miltenyi, Novartis, Eisai, Corcept, and BioNTech (advisory board); and AstraZeneca, Roche, GSK, Genmab, DFG, European Union, DKH, Immunogen, Seagen, Clovis, and Novartis (institutional research funding). 
 
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