CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: January 23, 2023
Expiration: January 22, 2024
Susana Banerjee, MBBS, MA, PhD, FRCP:
Chemoradiation has been the standard of care for cervical cancer for more than 20 years.24 In recent years, PD-1 inhibitors have shown activity in advanced and recurrent cervical cancer alone and in combination with CT.12,13,25 Thus, it seems a logical step to combine immunotherapy and chemoradiation in early-stage disease. The phase III CALLA trial is a global study designed to compare immune checkpoint inhibition vs placebo, both in combination with and following chemoradiotherapy, in locally advanced cervical cancer (stage IB/II to IVA).26 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.
At the 2022 IGCS annual global meeting, Monk and colleagues presented the highly anticipated results from the CALLA trial.
Susana Banerjee, MBBS, MA, PhD, FRCP:
Disappointingly, CALLA was a negative trial. Adding durvalumab to or following chemoradiation did not significantly improve PFS.26 At 2 years, the PFS rate was 66% with durvalumab vs 62% with placebo (HR: 0.84; P = .174). The 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. If any OS benefit were to exist, more events will be needed to identify that signal. It will be important to consider these data in context with other ongoing studies investigating immunotherapy in this setting, such as the phase III KEYNOTE-826 trial, which is evaluating pembrolizumab plus CT vs placebo plus CT in advanced cervical cancer (NCT03635567). I hope that we continue to study combinations with immunotherapy 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 may not be available until 2024 (NCT0422194).
Susana Banerjee, MBBS, MA, PhD, FRCP:
At IGCS 2022, Frumovitz and colleagues presented the results from the retrospective NeCTuR registry study of topotecan, paclitaxel, and bevacizumab (TPB) in patients with neuroendocrine cervical cancer, a very rare and difficult-to-treat subtype.27 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.
Susana Banerjee, MBBS, MA, PhD, FRCP:
Results presented at IGCS showed that the median PFS with TPB was 8.7 months vs 3.7 months without TPB (HR: 0.27; P <.0001), 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.
Susana Banerjee, MBBS, MA, PhD, FRCP:
At IGCS 2022, Leath and colleagues presented a post-hoc subgroup analysis from the phase III SOLO3 study of olaparib vs CT in BRCA-mutated, platinum-sensitive, relapsed ovarian cancer with at least 2 previous lines of platinum-based CT.28 Olaparib had previously been approved as maintenance therapy for patients with BRCA-mutated ovarian cancer in response to first-line platinum CT in this setting. The primary results from this study showed clinically relevant improvements in PFS and responses.29
Susana Banerjee, MBBS, MA, PhD, FRCP:
In the results from SOLO3 presented at IGCS, the OS was numerically favorable for olaparib vs CT (HR: 0.83) in patients with 2 previous lines of therapy, but there was a detrimental effect for OS seen in those who had received 3 (HR: 1.20), or more than 3 (HR: 1.33-1.58) previous lines of CT.
By contrast, PFS remained favorable with olaparib up to 3 (HR: 0.87) but not after 4 previous lines of CT (HR: 2.92). How can this be? What potential mechanisms could result in a detrimental effect on OS? A hypothesis might be secondary BRCA reversion mutations, which are proposed as a mechanism of resistance to both PARP inhibitors and platinum-based CT. 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.
Susana Banerjee, MBBS, MA, PhD, FRCP:
The long-term effect of PARP inhibition on survival in ovarian cancer is being investigated in various clinical trials. One such trial is ARIEL3. Dr Mirza, would you please discuss the ARIEL3 study of rucaparib?
Mansoor Raza Mirza, MD:
At IGCS 2022, we also saw data presented for the OS results from ARIEL3. As you may remember, this phase III study was designed to measure the impact of rucaparib as maintenance therapy in recurrent ovarian cancer after response to most recent platinum CT.30 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 ITT and in patient subgroups, including those with homologous recombination repair (HRR) defects such as BRCA1/2 mutations and loss of heterozygosity.
Mansoor Raza Mirza, MD:
OS data are reported for ARIEL3 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, HRD, and ITT—the median OS was similar with rucaparib and with placebo (36.0 vs 43.2 months, respectively; HR: 0.995). 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. These data are not conclusive, with HRs approaching or crossing 1 in all 3 groups.
As a result, I do not plan to change my practice based on the presented OS data for ARIEL3, and I will continue using PARP inhibitors as maintenance therapy in patients with platinum-sensitive ovarian cancer in the recurrent setting.
Ignace Vergote, MD, PhD:
HRD testing is increasingly required to guide the use of PARP inhibitors in treating patients with ovarian cancer, especially in the first-line setting. However, current testing modalities are plagued by high failure rates and limited accessibility. The ENGOT HRD European Initiative is developing new HRD tests based on samples from the phase III PAOLA-1 trial, which randomized patients with advanced ovarian cancer to receive frontline therapy with bevacizumab plus either the PARP inhibitor olaparib or a placebo. In this study, a genomic instability score (GIS) was generated for all patients using the Myriad myChoice next-generation sequencing assay for HRD. Remaining samples were sufficient to develop additional academic-developed HRD tests, and 2 of these tests were presented at the 2022 ESGO Congress.
Ignace Vergote, MD, PhD:
At the 2022 ESGO Congress, Christinat and colleagues presented results from a study of the Geneva HRD test, which used samples and the Geneva University Hospitals OncoScan assay to determine copy number variation.31 This test does not use loss of heterozygosity (LOH) or telomeric allelic imbalance like the Myriad myChoice assay and instead focuses solely on large-scale state transitions in chromosomes. The Geneva test is far less costly than Myriad myChoice (~€350 vs ~€5000), but it does not detect BRCA mutations or other HRR mutations. In addition, there was a higher positivity rate and lower failure rate for the Geneva test, particularly in BRCA wild-type tumors.
Ignace Vergote, MD, PhD:
In this presentation, there was quite good concordance for both positivity and negativity for PFS and OS outcomes compared with the Myriad myChoice GIS, including similar PFS HRs for olaparib vs placebo (HR: 0.41). Of note, even after patients with BRCA mutations were excluded, the HR for HRD positive vs negative in the BRCA wild-type group remained very similar to the Myriad myChoice results. A caveat is that although these are very promising data, further clinical testing is warranted to fully validate this assay.
Ignace Vergote, MD, PhD:
The second new academic HRD test based on PAOLA-1 samples is the NOGGO-GIS assay.32 Unlike the Geneva test, the NOGGO-GIS HRD assay uses next-generation sequencing to detect HRR genes (eg, RAD51, PALB) and relevant mutations for patients who are HRD positive (eg, HER2 amplification, mutations in KRAS, BRAF, PIK3C, EGFR) and can evaluate LOH. Also, this HRD test is robust with a low failure rate. As discussed, the Myriad myChoice assay determines the HRD phenotype using LOH, telomeric allelic imbalance, and large-scale transitions to generate a GIS, whereas the NOGGO-GIS test generates a score based on partial LOH and proliferating cell nuclear antigen.
Ignace Vergote, MD, PhD:
Like the Geneva test, the OS curves and HRs with NOGGO-GIS (HR: 0.37) were similar to those seen with the Myriad myChoice test (HR: 0.50) in both the HRD-positive and HRD-unknown groups.
Ignace Vergote, MD, PhD:
A third new HRD test is the “Leuven” test, which also was developed as part of the ENGOT HRD initiative.33 This assay uses capture-based targeted resequencing of approximately 90,000 genome-wide small nucleotide polymorphisms and coding exons of BRCA1, BRCA2, RAD51C, RAD51D, PALB2, BLM, BARD1, BRIP1, and TP53. Like the Geneva and NOGGO-GIS assays, results are similar to those with Myriad myChoice and less expensive. I am encouraged that there are now multiple tests available that can predict PFS and OS with PARP inhibitors in first-line ovarian cancer like the Myriad myChoice test.
Isabelle Ray-Coquard, MD, PhD:
In PAOLA-1, olaparib was given in combination with bevacizumab as maintenance treatment. Do you think that in the future we should determine if these tests also are useful to guide ovarian cancer maintenance/treatment with PARP inhibitor monotherapy?
Ignace Vergote, MD, PhD:
Yes. In other trials, such as PRIMA, VELIA, and ATHENA, there was a clear benefit for maintenance with PARP inhibitor monotherapy in patients with HRD-positive ovarian cancer vs HRD-negative cancer, regardless of whether a BRCA mutation was present. As demonstrated in PAOLA-1 at the 2022 ESMO Congress, the late OS survival data make me concerned about giving patients who are HRD negative a PARP inhibitor. I feel it is important to know a patient’s current HRD status, both at diagnosis and then during first-line treatment. One question I encounter is whether to use a first-line PARP inhibitor in patients with HRD-negative ovarian cancer who do not require bevacizumab. Going forward, it will be important to improve all 3 of these newer tests. We know that not all patients who are HRD positive will respond to PARP inhibition and that some patients who are HRD negative will respond to PARP inhibition. Through academic collaboration, we can improve these tests to better identify these patients.
Isabelle Ray-Coquard, MD, PhD:
Other important data presented at the 2022 ESGO Congress included the phase III ARIEL3 trial.34 As presented at IGCS, and discussed by others earlier, no OS benefit was seen in the HRD-positive cohort, where the placebo arm had slightly longer median OS (HR: 1.005). However, PFS on the subsequent line of therapy (PFS2) was improved with rucaparib across the ITT population (HR: 0.70), including patients with a BRCA mutation (HR: 0.67) and patients with HRD (HR: 0.72).
Ignace Vergote, MD, PhD:
These are intriguing results. In your opinion, should PARP inhibitors be used in patients with HRD-negative ovarian cancer in platinum-sensitive relapse?
Isabelle Ray-Coquard, MD, PhD:
Currently, I think this is an option that could be considered. However, ARIEL3 was not powered to detect an OS difference, and the patients who progressed on the rucaparib and placebo arm had differences. As others have alluded to, HRD testing is best used in the first-line setting, where it is unclear whether a patient with platinum sensitivity should receive a PARP inhibitor. In general, I do favor PARP inhibitor maintenance in patients with ovarian cancer who responded to first-line platinum CT and have not yet received a PARP inhibitor.
Isabelle Ray-Coquard, MD, PhD:
Nonepithelial ovarian cancers are rare and include germ-cell tumors and sex cord–stromal tumors.35 In the retrospective GINECO VIVROVAIRE tumor study, 144 patients with germ-cell tumor or sex cord–stromal tumor ovarian cancer received treatment with surgery plus CT (bleomycin, etoposide, and platinum BEP).36 After at least 2 years of follow-up, they were age matched with a control group of 144 women without cancer, and all patients were given questionnaires to capture fatigue, QoL, and long-term AEs (neurotoxicity, cognition, day-to-day life, anxiety/depression, and insomnia).
Isabelle Ray-Coquard, MD, PhD:
Results showed that these measures were largely similar between groups, with the exception of social well-being scores, which were higher in patients with cancer vs the control group (5.5% vs 4.9%, respectively; P <.01). Of note, significantly more patients with cancer had entered menopause (mean: 38.6 years) vs the control group (mean: 50.4 years); also, a BMI >30 kg/m2 was seen in 17% of patients with cancer vs 5% in the control group (P <.001). More individuals in the control group had a high level of education (78% vs 55% of patients with cancer; P <.001). Likewise, sexual worries and concerns were significantly more common in patients with cancer.
Isabelle Ray-Coquard, MD, PhD:
Moreover, patients with cancer saw a much worse impact of their health condition on daily life, including daily activities, leisure activities, and sports. Severe neuropathy was reported in 23% of patients with cancer vs 5% of the control group, and cognitive complaints were noted in 31% vs 14%, respectively. Overall, it is clear that although CT can cure patients with rare nonepithelial ovarian cancers, it comes at a price of substantial toxicity and long-term sequelae that must be managed.
Ignace Vergote, MD, PhD:
There have been very few studies of QoL in nonepithelial ovarian cancer. As seen in VIVROVAIRE, there were notable differences in cognitive complaints and sexual health with BEP CT, which is important, as many of the patients with these cancers are younger. I am curious whether the differences seen with BEP in this study will persist in longer follow-up?
Isabelle Ray-Coquard, MD, PhD:
I am curious as well and expect that these differences will actually increase over time. Such extended follow-up has been conducted for testicular germ-cell tumors but not in women with rare ovarian cancers.
Ignace Vergote, MD, PhD:
Intense CT such as BEP should negatively affect patient-reported outcomes such as anxiety and fatigue. However, in this study, those were not significantly increased. This might be due to the low patient numbers (which represent a relatively large trial in this rare cancer), but I still would have expected to see effects on anxiety and fatigue.
Isabelle Ray-Coquard, MD, PhD:
We discussed this question with Dr Florence Joly, who led the VIVROVAIRE study. Her group feels the answer (based in part on breast cancer studies) is not that the patient numbers are too low, but that the healthy controls may not be as healthy as expected.
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