image: Two-year maintenance therapy with olaparib, a PARP (poly ADP ribose polymerase) inhibitor, olaparib, led to a substantial, unprecedented improvement in progression-free survival (PFS) in newly diagnosed patients with advanced ovarian cancer and a BRCA1 or 2 mutation, results from the phase 3 SOLO-1 trial show. view more
Credit: © European Society for Medical Oncology
Munich, Germany, 21 October 2018 - Two-year maintenance therapy with olaparib, a PARP (poly ADP ribose polymerase) inhibitor, olaparib, led to a substantial, unprecedented improvement in progression-free survival (PFS) in newly diagnosed patients with advanced ovarian cancer and a BRCA1 or 2 mutation, results from the phase 3 SOLO-1 trial show. (1)
"The median PFS for patients who received placebo was only 13.8 months while the median PFS for those who received olaparib was not reached but looks to be approximately three years longer than the placebo group [HR was 0.30; 95% CI: 0.23, 0.41; p<0.0001]," reported Dr Kathleen Moore, Associate Professor at the Stephenson Cancer Center, University of Oklahoma, US, presenting the results at ESMO 2018 Congress.
"While it is too early to say whether we have impacted the fraction of women who could be cured with their front-line therapy, the fact that it is estimated that over 50% of women on the olaparib arm were still progression free at four years as compared to only 11% for placebo speaks to this hope," she remarked. "The results of SOLO-1 herald a new era in treatment for women diagnosed with advanced ovarian cancer who carry a BRCA mutation [a mutation in either of the BRCA1 and BRCA2 genes]. This study demonstrates an outstanding improvement in PFS over placebo which is maintained even after the olaparib is stopped at two years," added Moore.
SOLO-1 is the first, double-blind, randomised, prospective phase 3 evaluating front line olaparib maintenance therapy after platinum-based chemotherapy in newly diagnosed advanced ovarian cancer (FIGO stage III-IV) with a BRCA mutation. "It provides the first large dataset of prospectively collected outcomes for this population of women," said Moore.
A total of 391 patients with high grade serous or endometrioid ovarian cancer who were in clinical complete or partial response after chemotherapy upon entering the study, were randomised, 2:1, to olaparib tablets 300 mg bd (n=260) or placebo (n=131) for two years. The primary endpoint was investigator-assessed PFS from randomisation. Secondary outcomes included PFS2, which was time from randomisation to the second progression event a patient might experience; overall survival; and quality of life. Median follow-up was 41 months.
PFS2 remained significantly improved among patients who had received olaparib maintenance with a median PFS2 of 41.9 months for placebo versus median not reached for the olaparib group (HR: 0.50; 95%CI: 0.35, 0.72; p=0.0002).
The most common grade ?3 toxicities with olaparib were anaemia (22%) and neutropenia (8%). There was no clinically relevant change in quality of life between groups and dosing was well tolerated with only 12% of patients discontinuing olaparib due to toxicity and not disease progression. Furthermore, there was no detriment to quality of life.
"These are outstanding results in a worsening disease setting. Not only was olaparib efficacious but it was also shown to be well tolerated," said Prof Isabelle Ray-Coquard, from Universite Claude Bernard Lyon Est, Lyon, France, commenting on the results for ESMO. "The findings promise to change practice in this subgroup of patients with a BRCA mutation."
"Now, two questions remain. Can we expand this benefit to all high-grade serous carcinomas? Looking at existing results in relapse with PARP inhibitor maintenance in all comers, we can anticipate excellent results for all patients with high grade serous or endometrioid ovarian carcinoma," added Ray-Coquard. "Also, what is the best maintenance therapy? Standard first line therapy in many countries is chemotherapy plus bevacizumab maintenance for the majority of advanced disease, but the question remains whether maintenance with olaparib alone, or in combination with bevacizumab is preferable. The PAOLA 1 trial will provide some information, and will probably be available next year."
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References
1 Abstract LBA7_PR 'Olaparib maintenance therapy following first-line platinum-based chemotherapy in patients with FIGO stage III-IV ovarian cancer (OC) with a BRCA1/2 mutation (BRCAm): Phase III SOLO1 trial' will be presented by Kathleen Moore during the Presidential Symposium 2 on Sunday, 21 October, 16:30-18:10 in Room 18 - Hall A2. Annals of Oncology, Volume 29 Supplement 8 October 2018
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LBA7_PR - Maintenance olaparib following platinum-based chemotherapy in newly diagnosed patients (pts) with advanced ovarian cancer (OC) and a BRCA1/2 mutation (BRCAm): Phase III SOLO1 trial
K.N. Moore1, N. Colombo2, G. Scambia3, B.-G. Kim4, A. Oaknin5, M. Friedlander6, A. Lisyanskaya7, A. Floquet8, A. Leary9, G.S. Sonke10, C. Gourley11, S. Banerjee12, A.M. Oza13, A. Gonzalez-Martin14, C. Aghajanian15, W. Bradley16, E.S. Lowe17, R. Bloomfield18, P. DiSilvestro19
1Stephenson Oklahoma Cancer Center, Oklahoma City, OK, USA, 2University of Milan-Bicocca and Istituto Europeo di Oncologia, Milan, Italy, 3Fondazione Policlinico Universitario A. Gemelli IRCCS Universita Cattolica, Roma, Italy, 4Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, 5Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain, 6University of New South Wales Clinical School, Prince of Wales Hospital, Randwick, NSW, Australia, 7St Petersburg City Oncology Dispensary, St Petersburg, Russian Federation, 8Institute Bergonie, Comprehensive Cancer Centre, Bordeaux, France, 9Gustave-Roussy Cancer Campus, Villejuif, France, 10The Netherlands Cancer Institute, Amsterdam, Netherlands, 11Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK, 12The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, UK, 13Princess Margaret Cancer Center, Toronto, Canada, 14 Clinica Universidad de Navarra, Madrid, Spain, 15Memorial Sloan Kettering Cancer Center, New York, NY, USA, 16Froedtert and the Medical College of Wisconsin, Milwaukee, WI, USA, 17AstraZeneca, Gaithersburg, MD, USA, 18AstraZeneca, Cambridge, UK, 19 Women and Infants Hospital, Providence, RI, USA
Background: Pts with newly diagnosed advanced OC are treated with cytoreductive surgery and platinum-based chemotherapy. Most relapse within the first 3 years and have further chemotherapy, but once relapsed are largely not curable. SOLO1 (NCT01844986) is the first Phase III trial to evaluate PARP inhibitor (olaparib [Lynparza®]) maintenance therapy after platinum-based chemotherapy in newly diagnosed advanced OC with a BRCAm.
Methods: SOLO1 is a randomized, controlled, double-blind trial. Eligible pts had newly diagnosed, FIGO stage III-IV, high-grade serous or endometrioid ovarian, primary peritoneal and/or fallopian tube cancer with a BRCAm, had received platinum-based chemotherapy and were in clinical complete or partial response. Pts were randomized 2:1 to olaparib tablets 300 mg bd or placebo. The primary endpoint was investigator-assessed progression-free survival (PFS; modified RECIST v1.1).
Results: Of 391 randomized pts, 260 received olaparib and 130 placebo (one pt did not receive placebo). Median follow-up was 41 months. Baseline characteristics were well balanced. Primary PFS analysis showed a significant 70% reduction in the risk of progression or death with olaparib versus placebo (Table). PFS sensitivity analyses, second PFS and time to first subsequent therapy or death support the primary analysis. Overall survival data are immature.
Adverse events were mostly low grade. The most common grade ?3 toxicities with olaparib were anaemia (22%) and neutropenia (8%). Olaparib dose reductions, interruptions and discontinuations occurred in 28%, 52% and 12%, respectively. There was no change from baseline in health-related quality of life scores with olaparib.
Conclusions: Maintenance olaparib led to a substantial, unprecedented improvement in PFS, with an estimated difference in median PFS for olaparib versus placebo of approximately 3 years.
Clinical trial identification: ClinicalTrials.gov NCT01844986, July 2018
Editorial Acknowledgement: Editorial assistance was provided by Gillian Keating, Mudskipper Business Limited, funded by AstraZeneca and Merck & Co., Inc..
Legal entity responsible for the study: AstraZeneca and Merck & Co., Inc.
Funding: AstraZeneca; part of an alliance between AstraZeneca and Merck & Co., Inc.
Disclosure: K.N. Moore: KNM has received fees for advisory boards from AstraZeneca, Advaxis, Clovis, Tesaro, Genentech/Roche, Immunogen, VBL Therapeutics, and Janssen.
N. Colombo: NC has received honoraria from Genetech, AstraZeneca, and PharmaMar, fees for consulting/advisory boards from Genentech, PharmaMar, AstraZeneca, Clovis Oncology, Pfizer, MSD, and Tesaro, and research funding from AstraZeneca.
G. Scambia: GS has received fees for advisory boards from Roche, AstraZeneca, PharmaMar, Clovis Oncology, and Tesaro.
A. Oaknin: AO has received fees for advisory boards from Roche, AstraZeneca, PharmaMar, Clovis Oncology, and Tesaro and support for travel/accommodation from Roche, AstraZEneca, and PharmaMar.
M. Friedlander: MF has received fees for advisory boards from AstraZeneca and MSD.
A. Floquet: AF has received fees for advisory boards from AstraZeneca, Roche, and Tesaro and support for travel from Roche.
A. Leary: AL has received fees for advisory boards from Clovis, AstraZeneca, GamaMabs, Pfizer, and Gridstone, support for travel from AstraZeneca, and preclinical research support from Merus, GamaMabs, and Sanofi.
G.S. Sonke: GSS has received research funding from AstraZeneca, Merck, Novartis, and Roche.
C. Gourley: CG has received fees for an advisory role from Roche, AstraZeneca, Tesaro, Nucana, Clovis, and Foundation One, lecture fees from AstraZeneca, and research funding from Novartis, Aprea, AstraZeneca, Tesaro, and Clovis.
S. Banerjee: SB has received research funding from AstraZeneca and fees for advisory boards from AstraZeneca, Tesaro, and Clovis.
A.M. Oza: AMO has recieved honoraria from Intas Pharma.
A. González-Martín: AG-M has received fees for a speaker role/advisory boards from AstraZeneca, Tesaro, Roche, Clovis, and PharmaMar.
C. Aghajanian: CA has received honoraria and fees for advisory boards from Tesaro, Cerulean, Bayer, VentiRx, Mateon Therapeutics, and Clovis and honoraria and fees for steering committee meetings from Mateon Therapeutics and Clovis.
E.S. Lowe: ESL is an employee of AstraZeneca and owns stock.
R. Bloomfield: RB is an employee of AstraZeneca and owns stock.
P. DiSilvestro: Consulting fees from Astra Zeneca ($1800), and Tesaro ($600) over the last 2 years.
All other authors have declared no conflicts of interest.
Journal
Annals of Oncology