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Key Updates in Cervical and Ovarian Cancers: IGCS 2022 Annual Meeting

Susana Banerjee, MBBS, MA, PhD, FRCP

Consultant Medical Oncologist
Research Lead,
Gynaecology Unit
Royal Marsden NHS Foundation Trust
London, United Kingdom

Susana Banerjee, MBBS, MA, PhD, FRCP: consultant/advisor/speaker: Amgen, AstraZeneca, Clovis, EMD Serono, Epsilogen, GlaxoSmithKline, ImmunoGen, Merck Sharp & Dohme Corp, Mersana Therapeutics, Novartis, OncXerna, Pfizer, Regeneron, Roche, Seagen, Shattuck Lans, Takeda; researcher: AstraZeneca, GlaxoSmithKline.

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Mansoor Raza Mirza, MD

Medical Director
Department of Oncology
Chief Oncologist
The Finsen Centre
Copenhagen University Hospital
Copenhagen, Denmark

Mansoor Raza Mirza, MD: advisor/speaker: AstraZeneca, BioCad, Boehringer Ingelheim, GlaxoSmithKline, Karyopharm, Merck, Roche, Zailab; member of board of directors: Karyopharm; stock/stock options: Karyopharm.

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Released: November 3, 2022

Key Takeaways

  • In the CALLA study, durvalumab in combination with and following chemoradiation did not significantly improve PFS or OS compared with chemoradiation alone in patients with locally advanced cervix cancer
  • Topotecan, paclitaxel, and bevacizumab may be a promising option for the management of high-grade neuroendocrine cervical cancer, based on results from the retrospective NeCTuR trial
  • In the SOLO3 study, maintenance olaparib after 3 or more previous lines of chemotherapy had a detrimental effect on OS in patients with high-grade serous ovarian cancer with a germline BRCA1/2 mutation
  • In ARIEL3, maintenance rucaparib compared with placebo yielded a robust PFS benefit; however, an OS benefit was not observed

In this commentary, Susana Banerjee, MBBS, MA, PhD, FRCP, from the Royal Marsden NHS Foundation Trust in London and Mansoor Raza Mirza, MD, from Copenhagen University Hospital in Denmark discuss the recent results presented at the International Gynecologic Cancer Society (IGCS) 2022 Annual Global Meeting in New York City, including new findings from clinical trials in cervical cancer and ovarian cancer, and the potential for influence on clinical practice.

CALLA: Chemoradiotherapy With or Without Durvalumab in Cervical Cancer

Susana Banerjee, MBBS, MA, PhD, FRCP:
Chemoradiation has been the standard of care for cervical cancer for more than 20 years. In recent years, PD-1 inhibitors have shown activity in advanced and recurrent cervical cancer alone and in combination with chemotherapy. Thus, it seems a logical step to combine immunotherapy and chemoradiation in early-stage disease. The phase III CALLA trial is a global study comparing immune checkpoint inhibition vs placebo, both in combination with and following chemoradiotherapy, in locally advanced cervical cancer (stage IB/II to IVA). In CALLA, 770 women from 15 countries with newly diagnosed disease were randomized to receive durvalumab (1500 mg IV) or placebo every 4 weeks for 24 cycles. All patients also received external beam radiotherapy with cisplatin (40 mg/m2) or carboplatin (AUC 2) once weekly for 5 weeks, followed by image-guided brachytherapy.

Disappointingly, CALLA was a negative trial: Adding durvalumab to or following chemoradiation did not significantly improve progression-free survival (PFS). At 2 years, the PFS rate was 66% with durvalumab vs 62% with placebo (HR: 0.84; P = .174). The overall survival (OS) data also were similar between arms (HR: 0.78; P = .156), with the caveat that these data are immature and not formally tested in the report presented at IGCS 2022. Now, so far, there is no detriment to overall survival, but the data is immature and not formally tested. It will be important to consider these data in context with other ongoing studies evaluated in this setting, such as the phase III KEYNOTE-826 trial, which is evaluating pembrolizumab plus chemotherapy vs placebo plus chemotherapy in advanced cervical cancer (NCT03635567). I hope that continuing to study combinations with immunotherapy combinations or other novel agents in the future.

Mansoor Raza Mirza, MD:
But why was this trial negative when similar trials with combinations using different checkpoint inhibitors have been positive? One reason could be the inappropriate definition of high-risk disease in CALLA, which required patients with IB-IIB cervical cancer to also be node positive; the problem is that a single node on a scan qualified the patient as node positive, but that may not actually be accurate. Also, the sample size for high-risk disease is relatively small, and therefore a subgroup analysis of the high-risk node-positive patients wouldn’t be feasible. Another setback is that patients were given durvalumab both concomitantly with chemoradiotherapy and as maintenance treatment when it is unclear whether chemoradiotherapy enhances or inhibits the efficacy of checkpoint inhibition. A maintenance therapy–only arm would have helped clarify this question. The phase III KEYNOTE-A18/GOG 3047 study is currently comparing chemoradiotherapy with or without the PD-1 antibody pembrolizumab in locally advanced cervical cancer, with both PFS and OS as endpoints, but results won’t be available until 2024 (NCT0422194)].

NeCTuR: TPB in High-grade Neuroendocrine Cervical Cancer

Susana Banerjee, MBBS, MA, PhD, FRCP:
At IGCS 2022, Frumovitz and colleagues presented the results from a retrospective NeCTuR registry study of topotecan, paclitaxel, and bevacizumab (TPB) in patients with neuroendocrine cervical cancer, a very rare and difficult-to-treat subtype. Standard-of-care options are limited, as few trials have assessed a cohort with this cancer. This analysis included 62 women who had received TPB and 56 who had non–TPB-based treatments, with the caveat that some patients had received those drugs individually. Results presented at IGCS showed that the median PFS with TPB was 8.7 months vs 3.7 months without TPB (HR: 0.27), and at 1 year, 26% of patients remained on TPB regimens vs 9% with non-TPB regimens. However, no significant OS difference was seen between the TPB vs non-TPB groups (median OS: ~15 months; HR: 0.87). Nevertheless, the authors concluded that TPB should be considered an option for recurrent, high-grade neuroendocrine cervical cancer.

These are interesting results that may open the door to prospective studies in this rare tumor type. Of note, it can be hard to recruit sufficient numbers of patients for clinical trials for rare gynecologic cancers, but through international gynecology community collaborations, it may be possible. So, I am very hopeful.

SOLO3 Post hoc Analysis: OS by Number of Previous Lines of Chemotherapy in Ovarian Cancer

Susana Banerjee, MBBS, MA, PhD, FRCP:
At IGCS 2022, Leath and colleagues presented a post-hoc subgroup analysis from the phase III SOLO-3 study of olaparib vs chemotherapy in BRCA-mutated, platinum-sensitive, relapsed ovarian cancer with at least 2 previous lines of platinum-based chemotherapy. Olaparib had previously been approved as maintenance therapy for patients with BRCA-mutated ovarian cancer in response to first-line platinum chemotherapy in this setting. Primary results from this study had shown no significant OS benefit despite clinically relevant improvements in PFS and responses. In the results from SOLO3 presented at IGCS, the OS was numerically favorable for olaparib vs chemotherapy (HR: 0.83) in patients with 2 previous lines of therapy, but there was a detrimental effect for OS (HR: 1.33) seen in those who had received 3 or more previous lines of chemotherapy. By contrast, PFS remained favorable with olaparib regardless of number of previous lines. How can this be? What potential mechanisms could result in a detrimental effect on OS? The answer might be secondary BRCA reversion mutations, which are a mechanism of resistance to both PARP inhibitors and platinum-based chemotherapy. Reversion mutations were indeed detected in 22% of olaparib-treated patients in SOLO3 upon disease progression. More work is needed to determine if acquired BRCA reversion mutations in patients receiving olaparib or other PARP inhibitors might affect clinical outcomes on subsequent treatment, as this could affect OS.

The long-term effect of PARP inhibition on survival in ovarian cancer is being investigated in other trials as well. One such trial is ARIEL3. Dr. Mirza, would you please discuss the ARIEL3 study of rucaparib?

ARIEL3: Maintenance Rucaparib vs Placebo in Ovarian Cancer Following Chemotherapy

Mansoor Raza Mirza, MD:
The phase III ARIEL3 trial was designed to measure the impact of rucaparib as maintenance therapy in recurrent ovarian cancer after platinum chemotherapy. In this trial, patients with platinum-sensitive recurrent disease who responded to at least 2 previous lines of platinum-based therapy were randomized 2:1 to receive rucaparib 600 mg twice daily or placebo until disease progression. In the original analysis, rucaparib maintenance therapy significantly improved the primary endpoint of PFS compared with placebo in the overall population and in subpopulations, including those with homologous recombination repair defects such as BRCA1/2 mutations and loss of heterozygosity.

In the current analysis from IGCS 2022, OS data are reported, with the caveat that the trial was not powered for OS, so these results are hypothesis-generating only and should not be used to influence practice. In all 3 cohorts—BRCA mutated, homologous recombination deficient, and intention to treat—the median OS was similar with rucaparib and with placebo (36.0 vs 43.2 months, respectively). Of note, a high percentage (45.8%) of patients in the placebo group had crossed over to receive rucaparib and could have confounded the OS data. Because these data are not conclusive, with HRs approaching or crossing 1 in all 3 groups, I do not plan to change my practice and will continue using PARP inhibitors as maintenance therapy in patients with platinum-sensitive ovarian cancer.

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