Olaparib treatment significantly improved objective response rate (primary end point) and progression-free survival versus nonplatinum chemotherapy in patients with BRCA-mutated platinum-sensitive relapsed ovarian cancer in the open-label phase III SOLO3 trial (ClinicalTrials.gov identifier: NCT02282020). We report final overall survival (OS; prespecified secondary end point), post hoc OS analysis by number of previous chemotherapy lines, and exploratory BRCA reversion mutation analysis. Two hundred sixty-six patients were randomly assigned 2:1 to olaparib tablets (300 mg twice daily; n = 178) or physician's choice of single-agent nonplatinum chemotherapy (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan; n = 88). OS was similar with olaparib versus chemotherapy (hazard ratio [HR], 1.07 [95% CI, 0.76 to 1.49]; P = .71, median 34.9 and 32.9 months, respectively, full analysis set). OS with olaparib was favorable in patients with two previous chemotherapy lines (HR, 0.83 [olaparib v chemotherapy] [95% CI, 0.51 to 1.38]; median 37.9 v 28.8 months); however, a potential detrimental effect was seen in patients with at least three previous chemotherapy lines (HR, 1.33 [95% CI, 0.84 to 2.18]; median 29.9 v 39.4 months). BRCA reversion mutations might have contributed to this finding. No patient randomly assigned to olaparib with a BRCA reversion mutation detected at baseline (6 of 170 [3.5%]) achieved an objective tumor response.

Asan Medical Center Seoul South Korea

Biostatistics Oncology Biometrics Oncology R and D AstraZeneca Cambridge United Kingdom

Centro Medico Dalinde Mexico City Mexico

Department of Medicine and Surgery University of Milan Bicocca Milan Italy

Department of Obstetrics and Gynecology 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Gynecologic Oncology Program European Institute of Oncology IRCCS Milan Italy

Harvard Medical School Massachusetts General Hospital Boston MA

Instituto COI de Educação e Pesquisa Rio de Janeiro Brazil

Korea Institute of Radiological and Medical Sciences Seoul South Korea

Maria Sklodowska Curie National Research Institute of Oncology Warsaw Poland

O'Neal Comprehensive Cancer Center University of Alabama Birmingham AL

Oaxaca Site Management Organization Oaxaca de Juarez Mexico

Oncology R and D Late stage Development AstraZeneca Cambridge United Kingdom

Oncology R and D Late stage Development AstraZeneca Gaithersburg MD

Poznan University of Medical Sciences Poznań Poland

Seoul National University Hospital Seoul South Korea

Translational Medicine Oncology R and D AstraZeneca Cambridge United Kingdom

Università Cattolica del Sacro Cuore Fondazione Policlinico A Gemelli IRCCS Rome Italy

See more in PubMed

Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. : Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 33:244-250, 2015 PubMed PMC

AstraZeneca : LYNPARZA® (Olaparib) Tablets, for Oral Use: Prescribing Information. 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208558s009lbl.pdf

Domchek SM, Aghajanian C, Shapira-Frommer R, et al. : Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy. Gynecol Oncol 140:199-203, 2016 PubMed PMC

Penson RT, Valencia RV, Cibula D, et al. : Olaparib versus nonplatinum chemotherapy in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA1/2 mutation (SOLO3): A randomized phase III trial. J Clin Oncol 38:1164-1174, 2020 PubMed PMC

Tobalina L, Armenia J, Irving E, et al. : A meta-analysis of reversion mutations in BRCA genes identifies signatures of DNA end-joining repair mechanisms driving therapy resistance. Ann Oncol 32:103-112, 2021 PubMed

Pettitt SJ, Frankum JR, Punta M, et al. : Clinical BRCA1/2 reversion analysis identifies hotspot mutations and predicted neoantigens associated with therapy resistance. Cancer Discov 10:1475-1488, 2020 PubMed PMC

Lee EK, Matulonis UA: PARP inhibitor resistance mechanisms and implications for post-progression combination therapies. Cancers (Basel) 12:2054, 2020 PubMed PMC

Lin KK, Harrell MI, Oza AM, et al. : BRCA reversion mutations in circulating tumor DNA predict primary and acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma. Cancer Discov 9:210-219, 2019 PubMed

Kristeleit R, Lisyanskaya A, Fedenko A, et al. : Rucaparib versus standard-of-care chemotherapy in patients with relapsed ovarian cancer and a deleterious BRCA1 or BRCA2 mutation (ARIEL4): An international, open-label, randomised, phase III trial. Lancet Oncol 23:465-478, 2022 PubMed

Lukashchuk N, Armenia J, Tobalina L, et al. : BRCA reversion mutations mediated by microhomology-mediated end joining (MMEJ) as a mechanism of resistance to PARP inhibitors in ovarian and breast cancer. J Clin Oncol 40, 2022. (suppl 16; abstr 5559)

Oza AM, Lisyanskaya AS, Fedenko AA, et al. : Overall survival results from ARIEL4: A phase III study assessing rucaparib vs chemotherapy in patients with advanced, relapsed ovarian carcinoma and a deleterious BRCA1/2 mutation. Ann Oncol 33:S780, 2022. (abstract 518O)

Clovis Oncology : Dear Health Care Provider Letter (Rucaparib). 2022. https://clovisoncology.com/pdfs/US_DHCPL_final_signed.pdf

AstraZeneca : Dear Health Care Provider Letter (Olaparib). 2022. https://www.lynparzahcp.com/content/dam/physician-services/us/590-lynparza-hcp-branded/hcp-global/pdf/solo3-dhcp-final-signed.pdf

GlaxoSmithKline : Dear Health Care Provider Letter (Niraparib). 2022. https://www.zejulahcp.com/content/dam/cf-pharma/hcp-zejulahcp-v2/en_US/pdf/ZEJULA%20(niraparib)%20Dear%20HCP%20Letter%20September%202022.pdf

Moore KN, Secord AA, Geller MA, et al. : Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): A multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol 20:636-648, 2019 PubMed

See more in PubMed

ClinicalTrials.gov
NCT02282020