Final Analysis of LATITUDE, a Phase 3 Study of Abiraterone Acetate Plus Prednisone in Patients with Newly Diagnosed High-Risk Metastatic Castration-Sensitive Prostate Cancer

Abstract

Background: Abiraterone acetate plus prednisone (AA+P) added to androgen deprivation therapy (ADT) has demonstrated significant improvement in overall survival (OS) and radiographic progression-free survival in men with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (mCSPC). In this final analysis, the long-term survival benefits and safety of AA+P and ADT are presented. Methods: LATITUDE was a multicenter, phase 3, randomized study in men who had newly diagnosed, high-risk mCSPC. Patients were randomly (1:1) assigned to AA (1-g) once-daily + P (5-mg) once-daily and ADT or matching placebos+ADT. Primary endpoint of OS was assessed from the final analysis, which was planned at the end of open-label extension phase of the study. This study is registered at ClinicalTrials.gov, NCT01715285. Findings: 1199 patients were randomized to AA+P group (n=597) or placebo group (n=602). The final analysis was conducted after a median follow-up of 51·8 (IQR: 47·15-57·03) months and 618 deaths were observed (275 [46%] in AA+P group and 343 [57%] in placebo). Treatment was ongoing for 157 (26·3%) patients in AA+P group; 72 (12·0%) crossed-over from placebo to AA+P, of which 59 (81·9%) remained on treatment. Median OS was significantly longer in AA+P group versus placebo (53·3 vs 36·5 months; HR: 0·66; 95%CI: 0·56-0·78; p<0·0001). Secondary efficacy endpoints were also significantly improved (p<0·02). Median treatment duration in AA+P group versus placebo was 25·79 vs 14·36 months, respectively. Grade 3-4 adverse events of special interest (AA+P vs placebo) were hypertension (21·9% vs 10·5%), hypokalemia (11·7% vs 1·7%), hepatotoxicity (8·9% vs 3·5%), cardiac disorders (3·9% vs 1%), and fluid retention (0·8% vs 1%). Interpretation: Combining AA+P with ADT was associated with significantly longer survival, and had a manageable safety profile in men with newly diagnosed high-risk mCSPC. These findings support the use of AA+P as a standard-of-care in high-risk mCSPC patients. Funding: Janssen Research & Development. Declaration of Interest: GS, SL, YL, SM and NT are employees of Janssen Research & Development and hold company stock. KF has received personal fees from Amgen, Astellas, AstraZeneca, Bayer, Clovis, Curevac, Essa, Genentech, Janssen, Merck Sharp & Dohme, Orion and Sanofi. KNC’s institution received funding from Janssen for the conduct of the study. AP has received personal fees for consulting/advisory roles, travel, accommodations, and expenses from Ipsen, Bayer, Roche, Bristol-Myers Squibb, and Merck; and has received research funding from Merck. ARA received funds for consulting services and expert testimony from Astellas, Bayer, and Janssen. LF received grant support and personal fees from Novartis, Pfizer, Roche, Merck, and Merck Sharp & Dohme and grant support from Janssen and AbbVie. MO received personal fees from Janssen and Sanofi. BYA reports personal fees from Janssen, Pfizer, Merck, Roche, and Sanofi. SF has served on Advisory boards for Janssen, Boehringer Ingelheim Pharma and Aventis, has received honorarium from Janssen, travel and accommodation expenses from Aventis. DY and NM have no conflict of interest to declare. Ethical Approval: The study protocol was approved by the local Institutional Review Board and was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. The study was consistent with International Conference on Harmonization and Good Clinical Practice guidelines, applicable regulatory requirements, and was compliant with the protocol. Written informed consent was obtained from all patients to participate in the study.