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ESMO clinical practice guidelines update the recommendations for the treatment of epithelial ovarian cancer
ESMO updated treatment recommendations for epithelial ovarian cancer. In 2013, the European Society of Oncology (ESMO) issued the “Clinical Practice Guidelines for the Diagnosis, Treatment and Follow-up of Newly Diagnosed and Recurrent Epithelial Ovarian Cancer”. With the increase and update of relevant evidence, it updated it in July 2021.
This update focuses on the first-line maintenance treatment of newly diagnosed epithelial ovarian cancer.
1. Existing evidence
At present, there are mainly 4 important clinical studies exploring the first-line maintenance treatment of epithelial ovarian cancer. All trials have shown that patients’ progression-free survival (PFS) has been significantly improved.
Among them, 3 phase III trials (SOLO-1, PAOLA-1/ENGOT-ov25 and PRIMA/ENGOT-ov26) explored polyadenosine diphosphate polymerase (PARP) inhibitors (olaparib or niraparib) Maintenance treatment of newly diagnosed high-grade epithelial ovarian cancer (including fallopian tube and peritoneal cancer) after surgery and chemotherapy (ChT).
In another trial (VELIA/GOG-3005), velipari was administered in combination with ChT, followed by velipari maintenance therapy.
SOLO1 evaluated the efficacy of a 2-year single-agent first-line maintenance treatment for FIGO stage III-IV ovarian cancer patients with BRCA mutations and a complete or partial response to platinum-based chemotherapy.
The preliminary results of SOLO1 showed that compared with placebo, olaparib maintenance treatment can significantly reduce the risk of disease progression by 70% (HR=0.30, 95%CI: 0.23-0.41, P<0.001).
Long-term follow-up also proved that the benefits are long-term. The 5-year follow-up showed that the median PFS of olaparib was 56 months, and that of placebo was 14 months (HR=0.33, 95%CI: 0.25-0.43). At 5 years, 48% of patients treated with olaparib were still progression-free, compared with 21% in the placebo group.
Olapali has been approved by the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) as the first-line maintenance treatment for patients with BRCA mutations based on platinum-based chemotherapy.
PRIMA/ENGOT-ov26 evaluated niraparib as a maintenance treatment for patients with stage III-IV ovarian cancer (with or without BRCA mutation) at high risk of treatment failure for up to 3 years. The study excluded patients with stage III ovarian cancer who had no residual lesions after initial cytoreduction, and 67% of patients received neoadjuvant chemotherapy. Based on the Myriad myChoice® assay, patients were stratified according to the tumor’s homologous recombination repair defect (HRD) status (HRD score ≥ 42 points). The study mainly analyzed the HRD population, followed by the overall population.
The study showed that the PFS of the HRD population (HR=0.43, 95%CI: 0.31-0.59, P<0.001) and the entire population (HR=0.62, 95%CI: 0.50-0.76, P<0.001) have been significantly improved . Exploratory subgroup analysis showed that women with BRCA mutations benefited the most, and BRCA wild-type HRD women also benefited significantly, but less than the former. The median PFS of the HRD-negative (or HRP) population also increased by 2.7 months (HR=0.68, 95%CI: 0.49-0.94, P=0.020).
Nirapali has been approved by the EMA and the US FDA as the first-line maintenance treatment after platinum chemotherapy for all patients with ovarian cancer.
In the PAOLA-1/ENGOT-ov25 trial, patients with stage III-IV ovarian cancer with or without residual disease after surgery were treated with ChT combined with bevacizumab, and after ChT, they were randomized to receive olaparib or placebo maintenance treatment 2 Years, and both groups completed 15 months of bevacizumab treatment. The study included all patients who had no residual disease after surgery and achieved NED (no evidence of disease) or achieved complete or partial response after ChT combined with bevacizumab. Randomization of olaparib or placebo was stratified based on the BRCA mutation status of the tumor and the response to first-line treatment.
A preliminary analysis of all enrolled intent-to-treat (ITT) populations showed that patients receiving olaparib and bevacizumab had significant PFS benefits, with a median PFS of 22.1 months, while those treated with placebo and bevacizumab The median PFS was 16.6 months (HR=0.59, 95%CI: 0.49-0.72, P<0.001). Exploratory subgroup analysis showed that women with BRCA mutations (HR=0.31, 95%CI: 0.20-0.47) benefited the most, followed by HRD-positive women (HRD ≥ 42 points measured with Myriad myChoice®) (including BRCA Mutants) (HR=0.33, 95%CI: 0.25-0.45) and BRCA wild-type HRD-positive women (HR=0.43, 95%CI: 0.28-0.66). No benefit was observed in the HRD-negative/unknown population.
Olaparib has been approved by the EMA and the US FDA in combination with bevacizumab for the first-line maintenance treatment of patients with BRCA mutation and HRD ovarian cancer after platinum-based chemotherapy.
In the VELIA/GOG-3005 trial, the standard ChT for stage III-IV ovarian cancer was compared with veliparib given during ChT and then with verapali for maintenance treatment for 2 years or with only velipari given during ChT. The therapist made a comparison.
Stratified analysis showed that patients with BRCA mutations had the greatest reduction in the risk of progression or death by 56% (HR=0.44, 95%CI: 0.28-0.68, P<0.001), followed by patients with HRD (HRD ≥ 33 points measured by Myriad myChoice®) It was 43% (HR=0.57, 95%CI: 0.43-0.76, P<0.001) and 32% of the ITT population (HR=0.68, 95%CI: 0.56-0.83, P<0.001). The median PFS of Veripari and the control group in the ITT population were 23.5 and 17.3 months, respectively.
Veripari’s first-line treatment has not yet been approved.
In summary, all four trials have shown that the median PFS of the first-line maintenance treatment with PARP inhibitors has benefit, and the benefit is greatest in women with BRCA mutations.
2. Updated suggestion
All patients with high-grade ovarian cancer should be tested for BRCA1 and BRCA2 mutations (germline/system) at the time of diagnosis (I, A).
Patients with BRCA mutations and a partial or complete response to first-line platinum ChT should receive maintenance therapy with PARP inhibitors (Olapali 2 years, Nirapali 3 years). If bevacizumab is added to the first-line ChT, olaparib and bevacizumab should be used in combination, although it is not clear whether the combination will be better than olaparib alone (I, A).
It is recommended to perform genomic instability (HRD) testing. In this way, it is possible to identify a subgroup of women who are BRCA wild-type, but who would benefit more from PARP inhibitors (I, A). Those who have a positive HRD test and a partial or complete response to first-line platinum-containing ChT, regardless of whether bevacizumab is used, should receive maintenance therapy with PARP inhibitors, such as olaparib/bevacizumab (if ChT is used Bevacizumab) or niraparib alone (I, A).
Patients who were treated with bevacizumab for first-line ChT and HRD-negative, adding olaparib to bevacizumab maintenance therapy will not benefit from PFS (I, B). This is not a permitted indication, so it is not recommended.
Nirapali monotherapy has been approved for all patients with stage III-IV ovarian cancer who respond to ChT. Since there is no long-term outcome data, the decision to use the drug as a first-line or second-line maintenance treatment in HRD-negative people or when the HRD status is unknown depends on the specific conditions of the patient (I, C).
The guidelines recommend that PARP inhibitors in the first-line maintenance treatment of ovarian cancer are based on existing experimental evidence, but the indications for various PARP inhibitors may be different in each country.
Olapali single-agent maintenance therapy after first-line treatment for ovarian cancer has been approved for women with BRCA mutations. In many countries, it has also been approved for use with bevacizumab in HRD (BRCA mutant or BRCA wild-type) tumor populations.
In many countries, regardless of the biomarker status, niraparib has been approved as a single-agent maintenance treatment for patients with stage III-IV ovarian cancer who have responded to first-line treatment.
It should be noted that the effect of subsequent use of PARP inhibitors in the placebo group of these trials on overall survival (OS) is not yet clear, so subsequent studies should focus on the evaluation of OS.
In addition, the adverse reactions of oral PARP inhibitors are controllable in most patients, but some rare serious adverse events (such as acute myeloid leukemia/myelodysplasia) are slightly increased.
(source:internet, reference only)