LUGANO-MADRID – Rucaparib maintenance therapy increases progression-free survival in BRCA mutant recurrent ovarian cancer by 77%, according to late-breaking results from the ARIEL3 trial reported today at the ESMO 2017 Congress in Madrid. (1)
Most ovarian cancer presents as advanced disease and 80% of those patients will recur after first line treatment. Patients often respond again to chemotherapy, particularly platinum-based, but they almost inevitably relapse again and eventually die of their disease. Maintenance treatments are needed to reduce recurrence in patients who have already relapsed.
The PARP enzyme helps to initiate the repair of DNA damage so that cells can continue to divide. DNA repair processes are inherently impaired in tumour cells with BRCA mutations. PARP inhibitors, such as rucaparib, block DNA repair and cells with BRCA mutations die.
Just over 20% of patients with ovarian cancer have BRCA mutations and are susceptible to PARP inhibitors. Some others with the disease are also susceptible, such as patients who respond to platinum-based chemotherapy and those with a high degree of genomic loss of heterozygosity (LOH) – meaning the tumour DNA is scarred and DNA repair mechanisms are faulty.
ARIEL3 included 564 patients with high grade ovarian cancer who had responded to platinum-based chemotherapy in the second or third line of treatment. Patients were randomised 2:1 to rucaparib maintenance therapy or placebo. The primary endpoint was progression-free survival, which was measured sequentially in three groups if benefit was found in the previous group: 1) BRCA mutant; 2) BRCA mutant or BRCA wild type with high LOH (together called homologous recombination deficient or HRD); 3) intention to treat (entire study population).
Rucaparib led to a statistically significant improvement in progression-free survival in all three groups. Progression-free survival increased from 5.4 months to 16.6, 13.6, and 10.8 months in groups 1, 2, and 3, respectively, with hazard ratios of 0.23, 0.32, and 0.36, respectively.
“The improvement in progression-free survival was greatest in the BRCA mutated group, who had a 77% increase, but it was seen across three subgroups that were evaluated,” said first author Prof Jonathan Ledermann, Professor of Medical Oncology, UCL Cancer Institute, London, UK.
In exploratory analyses, patients without BRCA mutations (wild type) were divided into those with high and low LOH. As expected, patients with high LOH had more improvement in progression-free survival than those with low LOH. But in both high and low LOH subgroups, rucaparib was statistically significantly better than placebo.
Ledermann said: “We had hoped that the LOH test would distinguish responders from non-responders but both high and low LOH groups benefitted. However, the magnitude of progression-free survival benefit was greater in the BRCA wild type/LOH high patients.”
Rucaparib was well tolerated and just 13% of patients had to discontinue the medication due to side effects. The safety profile of rucaparib in ARIEL3 was consistent with previous phase II studies.
Ledermann concluded: “PARP inhibitors are the biggest development in ovarian cancer therapy since the introduction of platinum drugs in the late 1970s and early 1980s. Rucaparib is clearly an exemplary member of this exciting class of drugs that can be used to treat women with recurrent ovarian cancer in the maintenance setting.”
Commenting on the results, Dr Andrés Poveda, Head of the Gynaecological Cancer Clinic, Oncology Foundation Institute Valencia, Spain, Chair of the Gynaecologic Cancer Intergroup (GCIG), Member of the ESMO Faculty on Gynecological cancer, said: “ARIEL3 achieved a huge decrease in the risk of relapse with rucaparib. All of the patient subgroups benefitted, especially those with BRCA mutations but also homologous recombination deficient (HRD) patients.”
“In Europe the PARP inhibitor olaparib is licensed as maintenance therapy but only for patients with germline BRCA mutations,” he added. “We are awaiting a decision on niraparib, another PARP inhibitor. The addition of rucaparib would expand the population of patients receiving benefit from this type of drugs.”
Poveda concluded: “Personalised medicine has arrived in high grade serious ovarian cancer. Further studies are needed to identify predictive biomarkers of response to PARP inhibitors. Specifically, we need to know whether there are non-HRD factors that predict response.”
Notes to Editors
Please make sure to use the official name of the meeting in your reports: ESMO 2017 Congress
- Abstract LBA40_PR ‘ARIEL3: A Phase 3, Randomised, Double-Blind Study of Rucaparib vs Placebo Following Response to Platinum-Based Chemotherapy for Recurrent Ovarian Carcinoma (OC)‘ will be presented by Prof Jonathan Ledermann during Proffered Paper session ‘Gynaecological cancers’ on Friday, 8 September 2017, 16:00 to 17:30 (CEST) in the Cordoba Auditorium.
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ARIEL3: A Phase 3, Randomised, Double-Blind Study of Rucaparib vs Placebo Following Response to Platinum-Based Chemotherapy for Recurrent Ovarian Carcinoma (OC)
J. Ledermann1, A.M. Oza2, D. Lorusso3, C. Aghajanian4, A. Oaknin5, A. Dean6, N. Colombo7, J. Weberpals8, A. Clamp9, G. Scambia10, A. Leary11, R. Holloway12, D.M. O'Malley13, T. Cameron14, L. Maloney14, S. Goble15, K.K. Lin16, J. Sun17, H. Giordano14, R. Coleman18
1Gynaecological Oncology, University College London Cancer Institute and UCL Hospitals, London, UK, 2Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada, 3Unità di Ginecologia Oncologica, Fondazione IRCCS Istituto Nazionale dei Tumori and MITO, Milan, Italy, 4Gynecologic Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA, 5Medical Oncology Department, Vall d'Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, 6Department of Oncology, St John of God Subiaco Hospital, Subiaco, Australia, 77Gynecologic Cancer Program, European Institute of Oncology and University of Milan-Bicocca, Milan, Italy, 8Division of Gynecologic Oncology, Ottawa Hospital Research Institute, Ottawa, Canada, 9Department of Medical Oncology, The Christie NHS Foundation Trust and University of Manchester, Manchester, UK, 10Gynecologic Oncology, Università Cattolica Roma, Rome, Italy, 11Gynecological Unit, Gustave Roussy Cancer Center, INSERM U981, and Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO), Villejuif, France, 12Department of Gynecologic Oncology, Florida Hospital Cancer Institute, Orlando, FL, USA, 13Clinical Research Gynecologic Oncology, The Ohio State University, James Cancer Center, Columbus, OH, USA, 14Clinical Science, Clovis Oncology, Inc., Boulder, CO, USA, 15Biostatistics, Clovis Oncology, Inc., Boulder, CO, USA, 16Cancer Genomics, Clovis Oncology, Inc., Boulder, CO, USA, 17Biomarker Development and Analysis, Foundation Medicine, Cambridge, MA, USA, 18Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Background: Rucaparib has antitumour activity in BRCA-mutant or BRCA wild-type/genomic loss of heterozygosity (LOH) high associated OC. ARIEL3 evaluated rucaparib vs placebo as maintenance treatment in pts with recurrent platinum-sensitive OC.
Methods: Eligible pts received ≥2 prior platinum-based therapies, had platinum-sensitive OC (disease progression ≥6 mo after penultimate platinum), and achieved a complete response (RECIST v1.1) or partial response (RECIST v1.1 or Gynecologic Cancer InterGroup CA-125 criteria) to their most recent platinum. All responses required CA-125 to be less than the upper limit of normal. Pts were randomised 2:1 to receive oral rucaparib 600 mg BID or placebo. Investigator-assessed progression-free survival (PFS) (primary endpoint) was assessed in a step-down procedure for 3 nested groups: (1) BRCA mutant (deleterious germline or somatic BRCA mutation); (2) homologous recombination deficient (BRCA mutant or BRCA wild-type/LOH high); and (3) intent-to-treat population. PFS was also assessed by blinded independent central review (key secondary endpoint) and LOH status in pts with BRCA wild-type OC (exploratory endpoint).
Results: Data are presented for the rucaparib and placebo groups, respectively. ARIEL3 enrolled 564 pts (375 and 189 in each group). PFS data are summarised in the Table. The most common grade 3 or higher treatment-emergent AEs were anaemia (18.8% and 0.5%) and alanine/aspartate aminotransferase increase (10.5% and 0%). At the visit cutoff date (15 Apr 2017), 13.4% and 1.6% of pts discontinued due to treatment-emergent AEs (excluding disease progression); 1.6% and 1.1% of pts died due to AEs (including disease progression).
Conclusions: Rucaparib significantly improved PFS vs placebo in all primary analysis groups of pts with platinum-sensitive, recurrent OC. Improvement in PFS was observed in non-nested subgroups of pts with BRCA wild-type OC (both LOH high and LOH low).
Clinical trial identification: NCT01968213
Legal entity responsible for the study: Clovis Oncology, Inc.
Funding: Clovis Oncology, Inc.
Disclosure: J. Ledermann: Advisory Role: Clovis Oncology
A.M. Oza: Consulting or Advisory Role: Amgen, Verastem, Clovis Oncology, Immunovaccine Travel, Accommodations, Expenses: AstraZeneca Honoraria: WebRx
D. Lorusso: Consulting or Advisory Role: AstraZeneca, Clovis Oncology, Roche, PharmaMar Travel, Accommodations, Expenses: Roche, PharmaMar
A. Oaknin: Consulting or Advisory Role: PharmaMar, Clovis Oncology, Roche, AstraZeneca
N. Colombo: Advisory board: Roche, AstraZeneca, Tasaro, Pharmamar, Clovis, Advaxis
J. Weberpals: Research support: Abbvie, AstraZeneca
A. Leary: Advisory board: Clovis Oncology, Pfizer, Pharmamar, Gamamabs, Merus
R. Holloway: Speaker’s Bureau honoraria: Astra Zeneca, Clovis, Tesaro
D.M. O'Malley: Research support: Clovis Oncology Advisory Board: Janssen, Eisai
T. Cameron, L. Maloney, S. Goble, K.K. Lin, H. Giordano: Employment: Clovis Oncology Stock and Other Ownership Interests: Clovis Oncology
J. Sun: Stock and Other Ownership Interests: Foundation Medicine
R. Coleman: Research support: AstraZeneca, Roche/Genentech, Janssen, Oncomed, Millennium, Esperance, Abbvie
All other authors have declared no conflicts of interest.
Keywords: PARP inhibitor, ovarian carcinoma, HRD, rucaparib