Andrés Poveda1, Anne Floquet2, Jonathan A Ledermann3, Rebecca Asher4, Richard T Penson5, Amit M Oza6, Jacob Korach7, Tomasz Huzarski8, Sandro Pignata9, Michael Friedlander10, Alessandra Baldoni11, Tjoung-Won Park-Simon12, Kenji Tamura13, Gabe S Sonke14, Alla Lisyanskaya15, Jae-Hoon Kim16, Elias Abdo Filho17, Tsveta Milenkova18, Elizabeth S Lowe19, Phil Rowe18, Ignace Vergote20, Eric Pujade-Lauraine21. 1. Initia Oncology, Hospital Quirónsalud, Valencia, Spain; Grupo Español de Investigación en Cáncer de Ovario, Madrid, Spain. Electronic address: apoveda@initiaoncologia.com. 2. Institut Bergonié, Comprehensive Cancer Centre, Bordeaux, France; Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens, Paris, France. 3. UCL Cancer Institute, University College London, London, UK; National Cancer Research Institute, London, UK. 4. National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia. 5. Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA. 6. Princess Margaret Cancer Centre, Toronto, ON, Canada. 7. Sheba Medical Center, Tel Aviv University, Tel Hashomer, Israel; Israeli Society of Gynecologic Oncology, Ramat Gan, Israel. 8. International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland; Read-Gene SA, Grzepnica, Szczecin, Poland. 9. Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Naples, Italy; Multicenter Italian Trials in Ovarian Cancer and Gynecologic Malignancies, Naples, Italy. 10. University of New South Wales Clinical School, Prince of Wales Hospital, Randwick, NSW, Australia. 11. Istituto Oncologico Veneto, Padova, Italy; Mario Negri Gynecologic Oncology Group, Milan, Italy. 12. Hannover Medical School, Hannover, Germany; German Society of Gynecological Oncology, Essen, Germany. 13. National Cancer Center Hospital, Tokyo, Japan. 14. The Netherlands Cancer Institute, Amsterdam, Netherlands; Dutch Gynecological Oncology Group, Amsterdam, Netherlands. 15. St Petersburg City Clinical Oncology Dispensary, St Petersburg, Russia. 16. Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, South Korea; Korean Gynecologic Oncology Group, Seoul, South Korea. 17. Instituto do Câncer do Estado São Paulo-Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. 18. AstraZeneca, Cambridge, UK. 19. AstraZeneca, Gaithersburg, MD, USA. 20. University Hospital Leuven, Leuven Cancer Institute, Belgium; Belgium and Luxembourg Gynaecological Oncology Group, Leuven, Belgium. 21. Association de Recherche Contre les Cancers dont Gynécologiques-ARCAGY, Paris, France.
Abstract
BACKGROUND:Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has previously been shown to extend progression-free survival versus placebo when given to patients with relapsed high-grade serous or endometrioid ovarian cancer who were platinum sensitive and who had a BRCA1 or BRCA2 (BRCA1/2) mutation, as part of the SOLO2/ENGOT-Ov21 trial. The aim of this final analysis is to investigate the effect of olaparib on overall survival. METHODS: This double-blind, randomised, placebo-controlled, phase 3 trial was done across 123 medical centres in 16 countries. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status at baseline of 0-1, had histologically confirmed, relapsed, high-grade serous or high-grade endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer, and had received two or more previous platinum regimens. Patients were randomly assigned (2:1) to receive olaparib tablets (300 mg in two 150 mg tablets twice daily) or matching placebo tablets using an interactive web or voice-response system. Stratification was by response to previous chemotherapy and length of platinum-free interval. Treatment assignment was masked to patients, treatment providers, and data assessors. The primary endpoint of progression-free survival has been reported previously. Overall survival was a key secondary endpoint and was analysed in all patients as randomly allocated. Safety was assessed in all patients who received at least one treatment dose. This trial is registered with ClinicalTrials.gov, NCT01874353, and is no longer recruiting patients. FINDINGS:Between Sept 3, 2013 and Nov 21, 2014, 295 patients were enrolled. Patients were randomly assigned to receive either olaparib (n=196 [66%]) or placebo (n=99 [34%]). One patient, randomised in error, did not receive olaparib. Median follow-up was 65·7 months (IQR 63·6-69·3) with olaparib and 64·5 months (63·4-68·7) with placebo. Median overall survival was 51·7 months (95% CI 41·5-59·1) with olaparib and 38·8 months (31·4-48·6) with placebo (hazard ratio 0·74 [95% CI 0·54-1·00]; p=0·054), unadjusted for the 38% of patients in the placebo group who received subsequent PARP inhibitor therapy. The most common grade 3 or worse treatment-emergent adverse event was anaemia (which occurred in 41 [21%] of 195 patients in the olaparib group and two [2%] of 99 patients in the placebo group). Serious treatment-emergent adverse events were reported in 50 (26%) of 195 patients receiving olaparib and eight (8%) of 99 patients receiving placebo. Treatment-emergent adverse events with a fatal outcome occurred in eight (4%) of the 195 patients receiving olaparib, six of which were judged to be treatment-related (attributed to myelodysplastic syndrome [n=3] and acute myeloid leukaemia [n=3]). INTERPRETATION:Olaparib provided a median overall survival benefit of 12·9 months compared with placebo in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Although statistical significance was not reached, these findings are arguably clinically meaningful and support the use of maintenance olaparib in these patients. FUNDING: AstraZeneca and Merck.
RCT Entities:
BACKGROUND:Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has previously been shown to extend progression-free survival versus placebo when given to patients with relapsed high-grade serous or endometrioid ovarian cancer who were platinum sensitive and who had a BRCA1 or BRCA2 (BRCA1/2) mutation, as part of the SOLO2/ENGOT-Ov21 trial. The aim of this final analysis is to investigate the effect of olaparib on overall survival. METHODS: This double-blind, randomised, placebo-controlled, phase 3 trial was done across 123 medical centres in 16 countries. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status at baseline of 0-1, had histologically confirmed, relapsed, high-grade serous or high-grade endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer, and had received two or more previous platinum regimens. Patients were randomly assigned (2:1) to receive olaparib tablets (300 mg in two 150 mg tablets twice daily) or matching placebo tablets using an interactive web or voice-response system. Stratification was by response to previous chemotherapy and length of platinum-free interval. Treatment assignment was masked to patients, treatment providers, and data assessors. The primary endpoint of progression-free survival has been reported previously. Overall survival was a key secondary endpoint and was analysed in all patients as randomly allocated. Safety was assessed in all patients who received at least one treatment dose. This trial is registered with ClinicalTrials.gov, NCT01874353, and is no longer recruiting patients. FINDINGS: Between Sept 3, 2013 and Nov 21, 2014, 295 patients were enrolled. Patients were randomly assigned to receive either olaparib (n=196 [66%]) or placebo (n=99 [34%]). One patient, randomised in error, did not receive olaparib. Median follow-up was 65·7 months (IQR 63·6-69·3) with olaparib and 64·5 months (63·4-68·7) with placebo. Median overall survival was 51·7 months (95% CI 41·5-59·1) with olaparib and 38·8 months (31·4-48·6) with placebo (hazard ratio 0·74 [95% CI 0·54-1·00]; p=0·054), unadjusted for the 38% of patients in the placebo group who received subsequent PARP inhibitor therapy. The most common grade 3 or worse treatment-emergent adverse event was anaemia (which occurred in 41 [21%] of 195 patients in the olaparib group and two [2%] of 99 patients in the placebo group). Serious treatment-emergent adverse events were reported in 50 (26%) of 195 patients receiving olaparib and eight (8%) of 99 patients receiving placebo. Treatment-emergent adverse events with a fatal outcome occurred in eight (4%) of the 195 patients receiving olaparib, six of which were judged to be treatment-related (attributed to myelodysplastic syndrome [n=3] and acute myeloid leukaemia [n=3]). INTERPRETATION:Olaparib provided a median overall survival benefit of 12·9 months compared with placebo in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Although statistical significance was not reached, these findings are arguably clinically meaningful and support the use of maintenance olaparib in these patients. FUNDING: AstraZeneca and Merck.
Authors: Konstantin Weber-Lassalle; Corinna Ernst; Alexander Reuss; Kathrin Möllenhoff; Klaus Baumann; Christian Jackisch; Jan Hauke; Dimo Dietrich; Julika Borde; Tjoung-Won Park-Simon; Lars Hanker; Katharina Prieske; Sandra Schmidt; Nana Weber-Lassalle; Esther Pohl-Rescigno; Stefan Kommoss; Frederik Marmé; Florian Heitz; Julia C Stingl; Rita K Schmutzler; Philipp Harter; Eric Hahnen Journal: J Natl Cancer Inst Date: 2022-04-11 Impact factor: 13.506
Authors: A Russo; L Incorvaia; E Capoluongo; P Tagliaferri; S Gori; L Cortesi; M Genuardi; D Turchetti; U De Giorgi; M Di Maio; M Barberis; M Dessena; M Del Re; A Lapini; C Luchini; B A Jereczek-Fossa; A Sapino; S Cinieri Journal: ESMO Open Date: 2022-05-19