Integrated safety analysis of the poly (ADP-ribose) polymerase (PARP) inhibitor rucaparib in patients (pts) with ovarian cancer in the treatment and maintenance settings

abstracts

Annals of Oncology

Volume 30 | Supplement 5 | October 2019

1002P

Integrated safety analysis of the poly (ADP-ribose) polymerase (PARP) inhibitor rucaparib in patients (pts) with ovarian cancer in the treatment and maintenance settings

R.S. Kristeleit1, A.M. Oza2, A. Oaknin3, C. Aghajanian4, A.V. Tinker5, O. Tredan6, D.M. O’Malley7, A. Leary8, G.E. Konecny9, D. Lorusso10, J.I. Weberpals11, S. Goble12, L. Maloney13, T. Cameron14, E. Swisher15, I.A. McNeish16, R. Shapira-Frommer17, J.A. Ledermann18, R.L. Coleman19 1 Department of Oncology, UCL Cancer Institute, University College London and UCL Hospitals, London, CT, UK, 2Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada, 3Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, 4Gynecologic Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA, 5Medical Oncology, BC Cancer Agency, Vancouver, BC, Canada, 6Department of Medical Oncology, Centre Le´on Be´rard and University Claude Bernard and Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO), Lyon, France, 7Clinical Research Gynecologic Oncology, The Ohio State University, James Cancer Center, Columbus, OH, USA, 8Gynecologic Unit, Gustave Roussy Cancer Centre, INSERM U981, and Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO), Villejuif, France, 9Department of Medicine, University of California Los Angeles, Santa Monica, CA, USA, 10Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy, 11 Division of Gynecologic Oncology, Ottawa Hospital Research Institute, Ottawa, ON, Canada, 12Biostatistics, Clovis Oncology, Inc., Boulder, CO, USA, 13Clinical Development, Clovis Oncology, Inc., Boulder, CO, USA, 14Clinical Science, Clovis Oncology UK Ltd., Cambridge, UK, 15Division of Gynecologic Oncology, University of Washington, Seattle, WA, USA, 16Department of Surgery and Cancer, Imperial College London, London, UK, 17 Department of Oncology, Chaim Sheba Medical Center, Tel HaShomer, Israel, 18 Department of Oncology, UCL Cancer Institute, University College London and UCL Hospitals, London, London, UK, 19Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Background: Rucaparib is approved in the European Union and the United States for use as treatment or maintenance for women with ovarian cancer. Here we present an integrated analysis of rucaparib safety in these settings. Methods: Treatment-emergent adverse events (TEAEs) of any grade, grade 3 TEAEs, median time to onset of TEAEs, and discontinuations due to a treatment-related TEAE were evaluated for all pts with epithelial ovarian, fallopian tube, or primary peritoneal cancer who received 1 dose of rucaparib 600 mg in CO-338-010 (Study 10; NCT01482715), ARIEL2 (CO-338-017; NCT01891344), or ARIEL3 (CO-338-014; NCT01968213). Results: The integrated safety analysis included 937 rucaparib-treated pts from the treatment (Study 10, n ¼ 74; ARIEL2, n ¼ 491) and maintenance (ARIEL3, n ¼ 372) settings (visit cutoff date, 31 December 2017). Any-grade TEAEs occurring in  20% of pts are shown in the table, along with median time to onset. Overall, 99/937 (10.6%) pts discontinued due to an any-grade treatment-related TEAE (treatment setting: 53/ 565 [9.4%]); maintenance setting: 46/372 [12.4%]), the most frequent of which were asthenia/fatigue (21/937 [2.2%]), anaemia/haemoglobin decreased (18/937 [1.9%]),

doi:10.1093/annonc/mdz250 | v409

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Therapeutics; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Cerulean Pharma; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: VentiRx. A. Oaknin: Advisory / Consultancy: Clovis Oncology, Inc.; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: ImmunoGen; Advisory / Consultancy: Genmab/Seattle Genetics; Advisory / Consultancy, Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro. A. Dean: Advisory / Consultancy: Precision Oncology Australia; Advisory / Consultancy: Shire Pharmaceuticals; Advisory / Consultancy: Specialised Therapeutics Australia. N. Colombo: Advisory / Consultancy: Clovis Oncology, Inc.; Advisory / Consultancy: Advaxis; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BIOCAD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: PharmaMar; Advisory / Consultancy: Roche; Advisory / Consultancy: Tesaro. J.I. Weberpals: Research grant / Funding (institution): AbbVie; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. A.R. Clamp: Travel / Accommodation / Expenses: Clovis Oncology, Inc.; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Roche. G. Scambia: Advisory / Consultancy: Clovis Oncology, Inc.; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: PharmaMar; Advisory / Consultancy: Roche; Advisory / Consultancy: Tesaro. A. Leary: Advisory / Consultancy: Clovis Oncology, Inc.; Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Pfizer; Advisory / Consultancy: PharmaMar; Research grant / Funding (institution): GamaMabs; Research grant / Funding (institution): Merus. R.W. Holloway: Advisory / Consultancy, Speaker Bureau / Expert testimony: Clovis Oncology, Inc.; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Tesaro. M. Amenedo Gancedo: Speaker Bureau / Expert testimony: Clovis Oncology, Inc.; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: PharmaMar; Speaker Bureau / Expert testimony: Roche. P.C. Fong: Advisory / Consultancy: Clovis Oncology, Inc.; Honoraria (self), Advisory / Consultancy: AstraZeneca. J.C. Goh: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: Janssen; Speaker Bureau / Expert testimony: Ipsen; Speaker Bureau / Expert testimony: Merck Sharp & Dohme; Travel / Accommodation / Expenses: Astellas Pharma, Inc. D.M. O’Malley: Advisory / Consultancy, Research grant / Funding (institution), Non-remunerated activity/ies: Clovis Oncology, Inc.; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Gynecologic Oncology Group; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy: Myriad; Advisory / Consultancy, Research grant / Funding (institution): Tesaro; Non-remunerated activity/ies: Amgen; Research grant / Funding (institution), Nonremunerated activity/ies: ImmunoGen; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Ambry; Advisory / Consultancy: Health Analytics; Research grant / Funding (institution): Agenus; Research grant / Funding (institution): Ajinomoto; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): ERGOMED Clinical Research; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): INC Research. T. Cameron: Shareholder / Stockholder / Stock options, Employee: Clovis Oncology, Inc. L. Maloney: Shareholder / Stockholder / Stock options, Employee: Clovis Oncology, Inc. S. Goble: Shareholder / Stockholder / Stock options, Employee: Clovis Oncology, Inc. R.L. Coleman: Advisory / Consultancy, Research grant / Funding (institution): Clovis Oncology, Inc.; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Advisory / Consultancy, Research grant / Funding (institution): AbbVie; Advisory / Consultancy, Research grant / Funding (institution): Esperance; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Millennium; Advisory / Consultancy, Research grant / Funding (institution): OncoMed; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): GamaMabs; Research grant / Funding (institution): Genmab; Research grant / Funding (institution): Gradalis.

abstracts

Annals of Oncology

and thrombocytopenia/platelets decreased (17/937 [1.8%]). The most frequent grade 3 treatment-related TEAE leading to discontinuation was anaemia/haemoglobin decreased (15/937 [1.6%]); only 2/937 (0.2%) pts discontinued due to grade 3 AST/ ALT increased. Any-grade treatment-emergent myelodysplastic syndrome and/or acute myeloid leukaemia were reported in 5/937 (0.5%) pts. Conclusions: This integrated analysis aligns with the known safety profile of rucaparib. Any-grade gastrointestinal TEAEs and asthenia/fatigue typically occurred within the first month, with any-grade haematological TEAEs occurring later. Onset of grade 3 TEAEs mainly occurred after month 1.

Table: 1002P

Any TEAE Nausea Asthenia/fatiguea Vomiting Anaemia/haemoglobin decreaseda Abdominal paina Constipation ALT/AST increaseda Dysgeusia Decreased appetite Diarrhoea Thrombocytopenia/ platelets decreaseda

Grade 3

Any grade n (%)

Time to onset, n (%) Median (95% CI), days

Time to onset, Median (95% CI), days

937 (100) 721 (76.9) 685 (73.1) 397 (42.4) 395 (42.2)

5 (4–5) 15 (13–15) 15 (13–23) 56 (53–57)

579 (61.8) 43 (4.6) 90 (9.6) 40 (4.3) 217 (23.2)

35 (13–71) 53 (37–68) 42 (14–85) 83 (74–85)

388 (41.4) 356 (38.0) 352 (37.6) 352 (37.6) 307 (32.8) 305 (32.6) 245 (26.1)

45 (33–56) 29 (22–43) 15 (14–15) 7 (5–9) 22 (16–29) 29 (17–35) 52 (43–57)

40 (4.3) 15 (1.6) 99 (10.6) 1 (0.1) 19 (2.0) 15 (1.6) 56 (6.0)

112 (46–189) 120 (81–232) 15 (15–16) 197 (NA) 85 (25–127) 31 (11–103) 47 (29–63)

a

Combined terms. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; NA, not applicable due to only 1 case of dysguesia.

Clinical trial identification: NCT01482715, NCT01891344, NCT01968213. Editorial acknowledgement: Nathan Yardley, PhD, and Shannon Davis of Ashfield Healthcare Communications (Middletown, CT, USA), funded by Clovis Oncology, Inc. (Boulder, CO, USA). Legal entity responsible for the study: Clovis Oncology, Inc. Funding: Clovis Oncology, Inc. Disclosure: R.S. Kristeleit: Advisory / Consultancy: Clovis Oncology, Inc.; Advisory / Consultancy: Roche; Advisory / Consultancy: Tesaro. A.M. Oza: Advisory / Consultancy: Clovis Oncology, Inc.; Advisory / Consultancy: Amgen; Advisory / Consultancy: Immunovaccine; Advisory / Consultancy: Verastem; Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self): WebRx. A. Oaknin: Advisory / Consultancy: Clovis Oncology, Inc.; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: ImmunoGen; Advisory / Consultancy: Genmab/ Seattle Genetics; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro. C. Aghajanian: Honoraria (self), Advisory / Consultancy, Nonremunerated activity/ies: Clovis Oncology, Inc.; Honoraria (self), Non-remunerated activity/ies: Mateon Therapeutics; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Cerulean Pharma; Honoraria (self), Advisory / Consultancy: VentiRx. A.V. Tinker: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. D.M. O’Malley: Advisory / Consultancy, Research grant / Funding (institution), Non-remunerated activity/ies: Clovis Oncology, Inc.; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Tesaro; Advisory / Consultancy, Research grant / Funding (institution): Gynecologic Oncology Group; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy: Myriad; Non-remunerated activity/ies: Amgen; Research grant / Funding (institution), Non-remunerated activity/ies: ImmunoGen; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Ambry; Advisory / Consultancy: Health Analytics; Research grant / Funding (institution): Agenus; Research grant / Funding (institution): Ajinomoto; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Ergomed Clinical Research; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): INC Research. A. Leary: Advisory / Consultancy: Clovis Oncology, Inc.; Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Pfizer, Inc.; Advisory / Consultancy: PharmaMar; Research grant / Funding (institution): GamaMabs; Research grant / Funding (institution): Merus. G.E. Konecny: Speaker Bureau / Expert testimony: Clovis Oncology, Inc.; Speaker Bureau / Expert testimony: AstraZeneca; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Merck; Honoraria (self): Novartis. D. Lorusso: Advisory / Consultancy: Clovis Oncology, Inc.; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Merck; Advisory / Consultancy: ImmunoGen; Advisory /

v410 | Gynaecological Cancers

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Clinical factors associated with prolonged response and survival under olaparib as maintenance therapy in BRCA mutated ovarian cancers

S.I. Labidi-Galy1, T. deLa Motte Rouge2, O. Derbel3, A. Wolfer4, E. Kalbacher5, T. Olivier6, J-D. Combes7, K. Hu-Heimgartner1, O. Tredan8, H. Guevara9, V. HeinzelmannSchwarz10, M. Fehr11, V. de Castelbajac12, P. Vaflard13, L. Crivelli14, V. Bonadona9, V. Viassolo1, F. Bazan15, M. Rodrigues16, I.L. Ray-Coquard8 1 Depatment of Oncology, Hoˆpitaux Universitaires de Gene`ve - HUG, Geneva, Switzerland, 2Department of Medical Oncology, Centre Eugene - Marquis, Rennes, France, 3Institut du Cancer, Hoˆpital Prive Jean Mermoz, Lyon, France, 4Department of Oncology, CHUV - Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, 5 Department of Oncology, CHRU Besancon - Hopital Jean Minjoz, Besanc¸on, France, 6 Department of Oncology, Hoˆpitaux Universitaires de Gene`ve - HUG, Geneva, Switzerland, 7Infections and Cancer Epidemiology Group, IARC, Lyon, France, 8 Department of Medical Oncology, Centre Le´on Be´rard, Lyon, France, 9Department of Medical Oncology, Centre Le´on Be´rard, Lyon, France, 10Department of Gynecology, Universit€ atsspital Basel, Basel, Switzerland, 11Frauenklinik, Kantonsspital Frauenfeld, Frauenfeld, Switzerland, 12Department of Oncology, Institut Curie, Paris, France, 13 Department of Medical Oncology, Institut Curie, Paris, France, 14Division of Cancer Genetics, Centre Eugene - Marquis, Rennes, France, 15Doubs, CHU Besanc¸on, Hoˆpital Jean Minjoz, Besanc¸on, France, 16Department of Medical Oncology, Institut Curie, Paris, France Background: To investigate clinical factors associated with prolonged progression-free survival (PFS) and overall survival (OS) in relapsing epithelial ovarian cancer (EOC) patients with BRCA mutations and receiving olaparib as maintenance therapy in real-world. Methods: Multicenter (8 hospitals) European retrospective study of relapsing EOC patients having germline or somatic mutations of BRCA1/BRCA2 genes and treated with olaparib as maintenance therapy after platinum-based chemotherapy. Results: One hundred and fifteen patients were included. Median age was 54 years. There were 90 BRCA1 carriers, 24 BRCA2 carriers and one patient had germline mutation of BRCA1 and BRCA2. Six patients had somatic mutations (all BRCA1) and 109 had germline mutations. Ninety percent had serous carcinomas and were platinumsensitive. Following ultimate platinum-based chemotherapy, 69% of the patients had normalization of CA-125 levels and 87% had RECIST objective responses, either partial (53%) or complete (34%). After a median follow-up of 21 months, median PFS was 12.7 months and median OS was 35.4 months. In multivariate analysis, factors associated with prolonged PFS under olaparib were: platinum-free interval (PFI)  12 months, RECIST complete response (CR) or partial response (PR) and normalization of CA-125 upon ultimate platinum-based chemotherapy. Factors associated with prolonged OS were PFI  12 months, CR and normalization of CA-125. Conclusions: Platinum-free interval  12 months, complete response and normalized CA-125 levels after ultimate platinum-based chemotherapy are associated with prolonged PFS and OS in relapsing BRCA mutated ovarian cancer patients who received olaparib as maintenance therapy. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: S.I. Labidi-Galy: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. T. de La Motte Rouge: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. O. Derbel: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. A. Wolfer: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. E. Kalbacher: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. O. Tredan: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. V. Heinzelmann-Schwarz: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. F. Bazan: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. M. Rodrigues: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca. I.L. Ray-Coquard: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca. All other authors have declared no conflicts of interest.

Volume 30 | Supplement 5 | October 2019

Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz250.010/5577167 by guest on 25 October 2019

TEAE

Consultancy, Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy: Takeda. J.I. Weberpals: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): AbbVie. S. Goble: Shareholder / Stockholder / Stock options, Employee: Clovis Oncology, Inc. L. Maloney: Shareholder / Stockholder / Stock options, Employee: Clovis Oncology, Inc. T. Cameron: Shareholder / Stockholder / Stock options, Employee: Clovis Oncology, Inc. I.A. McNeish: Advisory / Consultancy: Clovis Oncology, Inc.; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Takeda. R. Shapira-Frommer: Advisory / Consultancy: Clovis Oncology, Inc.; Advisory / Consultancy: Merck/Merck Sharp & Dohme. J.A. Ledermann: Honoraria (self), Advisory / Consultancy: Clovis Oncology, Inc.; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: Pfizer; Advisory / Consultancy: Artios Pharma; Advisory / Consultancy: Cristal Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Merck/Merck Sharp & Dohme; Advisory / Consultancy: Roche; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Tesaro. R.L. Coleman: Advisory / Consultancy, Research grant / Funding (institution): Clovis Oncology, Inc.; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): AbbVie; Advisory / Consultancy, Research grant / Funding (institution): Esperance; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Millennium; Advisory / Consultancy, Research grant / Funding (institution): OncoMed; Advisory / Consultancy: Bayer; Advisory / Consultancy: GamaMabs; Advisory / Consultancy: Genmab; Advisory / Consultancy: Gradalis. All other authors have declared no conflicts of interest.