eUpdate – Newly Diagnosed Epithelial Ovarian Carcinoma Treatment Recommendations

eUpdate – Newly Diagnosed Epithelial Ovarian Carcinoma Treatment Recommendations 

Published: 19 July 2021

N. Colombo & J.A. Ledermann, on behalf of the ESMO Guidelines Committee

Clinical Practice Guideline

This update refers to Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. J. A. Ledermann, F. A. Raja, C. Fotopoulou, et. al, on behalf of the ESMO Guidelines Working Group

Chemotherapy in newly diagnosed ovarian cancer

Targeted therapy

Three phase III trials (SOLO-1, PAOLA-1/ENGOT-ov25 and PRIMA/ENGOT-OV26) in newly diagnosed high-grade epithelial ovarian cancers (including fallopian tube and peritoneal) have investigated maintenance therapy with the poly-adenosine diphosphate (ADP)-ribose polymerase (PARP) inhibitors olaparib or niraparib after surgery and chemotherapy (ChT).^2-4 In another trial (VELIA/GOG-3005), veliparib was given with ChT followed by maintenance.⁵ All four trials have demonstrated significant improvements in progression-free survival (PFS).

SOLO1 assessed first-line maintenance monotherapy with olaparib given for 2 years in women with FIGO (Fédération Internationale de Gynécologie et d’Obstétrique) stage III-IV ovarian cancer and a BRCA mutation with a partial or complete response to platinum-based ChT.² Primary results from SOLO1 showed that maintenance with olaparib significantly reduced the risk of disease progression by 70% [hazard ratio (HR) 0.30, 95% confidence interval (CI) 0.23-0.41, P<0.001] compared with placebo.² Extended follow-up has demonstrated sustained long-term benefit, with 5-year follow-up showing a median PFS of 56 months with olaparib versus 14 months with placebo (HR 0.33, 95% CI 0.25-0.43). At 5 years, 48% of patients treated with olaparib remained progression-free compared with 21% in the placebo group.⁶ Olaparib has been approved by both    the European Medicines Agency (EMA) and Food and Drug Administration (FDA) as maintenance therapy in BRCA-mutated patients in first remission after platinum-based therapy.

PRIMA/ENGOT-OV26 evaluated niraparib as maintenance therapy for up to 3 years in patients with stage III-IV disease at high risk of treatment failure, with or without BRCA mutation.³  Patients with stage III ovarian cancer and no residual disease after primary debulking surgery were excluded and 67% of patients had received neoadjuvant ChT. Patients were stratified according to homologous recombination repair deficiency (HRD) status of the tumour using the Myriad myChoice assay (defined as an HRD score of 42 or higher). The primary analysis was performed on the HRD population, followed hierarchically by the all-comer population. The study showed a significant improvement in PFS in the HRD population (HR 0.43, 95% CI 0.31-0.59, P<0.001) and in the overall population (HR 0.62, 95% CI 0.50-0.76, P<0.001). An exploratory subgroup analysis showed that the greatest benefit occurred in women with a BRCA mutation and a significant but lesser benefit in women who were BRCA wild type with HRD.  There was also an increase of 2.7 months in the median PFS in the HRD-negative, sometimes termed homologous recombination proficient (HRP) population (HR 0.68, 95% CI 0.49-0.94, P=0.020). Niraparib has been approved by both EMA and FDA as maintenance therapy for unselected patients in first remission after platinum-based therapy.

In the PAOLA-1/ENGOT-ov25 trial, patients with stage III-IV ovarian cancer, with or without residual tumour after surgery, were treated with ChT and bevacizumab, and after ChT randomised to maintenance therapy with olaparib tablets or placebo for two years, as well as completing 15 months bevacizumab in both arms of the trial.⁴ The study included all patients who had no residual disease after surgery and remained NED (no evidence of disease) or achieved a complete or partial response after ChT and bevacizumab. Randomisation to olaparib or placebo was stratified based on tumour BRCA mutation status and response to first-line treatment. The primary analysis in the all-comer intention-to-treat (ITT) population showed a significant benefit in PFS in patients receiving olaparib and bevacizumab with a median PFS of 22.1 months compared with 16.6 months with placebo and bevacizumab (HR 0.59, 95% CI 0.49-0.72, P<0.001). Exploratory subgroup analyses showed the greatest benefit among women with a BRCA mutation (HR 0.31, 95% CI 0.20-0.47) followed by HRD-positive women (defined using the Myriad myChoice assay as an HRD score of 42 or higher) -including women with  BRCA mutation (HR 0.33, 95% CI 0.25-0.45) and HRD-positive women with BRCA wild-type (HR 0.43, 95% CI 0.28-0.66). No benefit was observed in the HRD-negative/unknown population.⁴ Olaparib has been approved by both the EMA and FDA as maintenance therapy in combination with bevacizumab in BRCA mutated and HRD patients in first remission after platinum-based therapy.

In the VELIA/GOG-3005 trial, standard ChT in stage III-IV ovarian cancer was compared with veliparib given during ChT and then as maintenance for up to 2 years, or with veliparib given only with ChT.⁵ A hierarchical testing analysis showed the greatest reduction in the risk of progression or death of 56% among patients with a BRCA mutation (HR 0.44, 95% CI 0.28-0.68, P<0.001), followed by 43% in patients with HRD, using the Myriad Mychoice cut off value of 33 (HR 0.57, 95% CI 0.43-0.76, P<0.001) and 32% in the ITT population (HR 0.68, 95% CI 0.56-0.83, P<0.001). The median PFS in the ITT group was 23.5 and 17.3 months in the veliparib and control groups, respectively. Veliparib in first-line therapy has not been submitted for regulatory approval.

All trials have shown a benefit in median PFS for PARP inhibitor maintenance therapy in the first-line setting, with the greatest effect seen in women with a BRCA mutation.^2-6  It is unclear to what extent later use of PARP inhibitors in the placebo arm will have on the overall survival (OS), thus underscoring the importance of uncensored evaluation of OS as the studies mature.

Olaparib monotherapy maintenance after first-line treatment is licensed in women with a BRCA mutation. In many countries, it is also licensed together with bevacizumab in a broader population in tumours with HRD (BRCA mutation or BRCA wild type). Many countries have also approved niraparib as a single agent in women with stage III-IV ovarian cancer who have responded to first-line therapy, irrespective of biomarker status. The side-effects of oral PARP inhibitors are manageable in most patients but a slight increase in rare serious adverse events such Acute Myeloid Leukaemia/Myelodysplasia is recognised.  Long-term outcome data (survival) are not yet available; this will aid decision-making about which subgroups of patients benefit more from first-line use of PARP inhibitors or their use at recurrence.

Recommendations

• All patients with high-grade ovarian cancer should be tested for BRCA1 and BRCA2 mutation (germline/somatic)at diagnosis. [I, A].
• Patients with a BRCA mutation and a partial or complete response to front-line platinum-based ChT should receive maintenance treatment with a PARP inhibitor (two years for olaparib [ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS)  v1.1 score: 4], three years for niraparib [ESMO-MCBS v1.1 score: 3]. The combination of olaparib and bevacizumab should be used when bevacizumab is added to front-line ChT [I, A; ESMO-MCBS v1.1 score: 3] though it is not clear that this provides superior results to the use of olaparib alone.
• Testing for genomic instability (HRD) is recommended. It identifies a subgroup of women who are BRCA wild type but derive greater benefit from a PARP inhibitor [I, A]. Patients with a positive HRD test and a partial or complete response to front-line platinum-based ChT, with or without bevacizumab, should receive maintenance treatment with a PARP inhibitor, either olaparib/bevacizumab (if started with ChT) or niraparib monotherapy [I, A; ESMO-MCBS v1.1 score: 3].
• Patients receiving bevacizumab with front-line ChT and who are HRD-negative do not have a PFS benefit from the addition of olaparib to maintenance bevacizumab [I, B]. This is not a licenced indication and consequently is not recommended.
• Niraparib monotherapy is licensed for all patients with stage III-IV ovarian cancer who have responded to ChT. Long-term outcome data are not available, a decision about using the drug as first-line or at recurrence in the HRD-negative population or in the absence of knowledge about HRD status, needs to be made on a case-by-case basis [I, C; ESMO-MCBS v1.1 score: 3]

Table 1. ESMO-MCBS table for new therapies/indications in newly diagnosed epithelial ovarian carcinoma^a

Acknowledgements

The ESMO Guidelines Committee acknowledges and thanks the following people who have acted as reviewers for this update: Philipp Harter and Domenica Lorusso, ESMO Faculty (gynaecological cancers). Nathan Cherny, Chair of the ESMO-MCBS Working Group, Urani Dafni ESMO-MCBS Working Group Member/Frontier Science Foundation Hellas and Giota Zygoura of Frontier Science Foundation Hellas provided review and validation of the ESMO-MCBS scores. Nicola Latino (ESMO Scientific Affairs staff) provided coordination and support of the ESMO-MCBS scores and preparation of the ESMO-MCBS table. 

Funding

No external funding has been received for the preparation of these guidelines. Production costs have been covered by ESMO from central funds.

Disclosures

NC has received honoraria for lecture from AstraZeneca, Tesaro and Novartis; honoraria for advisory board from Roche, PharmaMar, AstraZeneca, Merck Sharp & Dohme, Merck, Clovis Oncology, Tesaro, GlaxoSmithKline, Pfizer, Takeda, BIOCAD, Immunogen, Mersana and Eisai; she has received research grant from AstraZeneca, PharmaMar and Roche. JAL has received honoraria for lectures and advisory boards from AstraZeneca, Tesaro Bio/GlaxoSmithKline and Eisai; honoraria for lectures from Clovis Oncology, for advisory boards from Artios Pharma, Merck Sharp & Dohme, Merck and Amgen; he has received compensation from Regeneron and institutional research grants from AstraZeneca Merck Sharp & Dohme and Merck; he has performed non-remunerated work in clinical trials for Merck Sharp and Dohme, Clovis Oncology, Pfizer, GSK/Tesaro Bio and AstraZeneca.  

References

1. Ledermann JA, Raja FA, Fotopoulou C et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.  Ann Oncol. 2013; 24 (Suppl 6): vi24-vi32.
2. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495-2505.
3. González-Martín A, Pothuri B, Vergote I, et al. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391-2402.
4. Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381(25):2416-2428.
5. Coleman RL, Fleming GF, Brady MF, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med. 2019;381(25):2403-2415.
6. Banerjee S, Moore K, Colombo N, et al. Maintenance olaparib for patients (pts) with newly diagnosed, advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): 5-year (y) follow-up (f/u) from SOLO1. Ann Oncol. 2020;31 (Suppl 4):abstr 811MO.
7. Cherny NI, Dafni U, Bogaerts J et al. ESMO-Magnitude of Clinical Benefit Scale Version 1.1. Ann Oncol. 2017; 28: 2340-2366.