Adjusting Overall Survival Estimates for Treatment Switching in Metastatic, Castration-Sensitive Prostate Cancer: Results from the LATITUDE Study

Abstract

Background: LATITUDE was the first phase 3 trial examining the survival benefit of adding abiraterone acetate (AA) + prednisone (P) to androgen-deprivation therapy (ADT) in newly diagnosed metastatic, castration-sensitive prostate cancer (mCSPC). Due to significant improvement in overall survival after the first interim analysis, patients in the placebos + ADT arm could switch to AA + P + ADT during an open-label extension. As in other studies where switching is allowed, statistical adjustments are needed to assess the real benefit of new drugs.

Patients and methods: This was a post hoc analysis to estimate the true survival benefit of AA + P + ADT in patients with newly diagnosed mCSPC by applying statistical adjustments commonly used to adjust for treatment switching.

Results: Of 112 patients still receiving placebos + ADT at the first interim analysis, 72 switched to AA + P + ADT during the open-label extension. Final analysis was conducted after median follow-up of 51.8 months. Compared to the placebos + ADT arm, the risk of death in the AA + P + ADT arm was 34% lower [hazard ratio (HR) = 0.663 (95% confidence interval 0.566-0.778)] by unadjusted intent-to-treat analysis, 37% lower [HR = 0.629 (95% confidence interval 0.526-0.753)] by rank preserving structure failure time modeling, and 38% lower [HR = 0.616 (95% confidence interval 0.524-0.724)] by inverse probability of censoring weights.

Conclusions: Analyses adjusting for treatment switching using two different statistical approaches confirm the improved survival benefit of adding AA + P to ADT in patients with newly diagnosed mCSPC.

Trial registration: ClinicalTrials.gov identifier NCT01715285.

Conflict of interest statement

S Feyerabend has nothing to disclose. F. Saad reports grants, personal fees, and non-financial support from Janssen and Sanofi related to the conduct of the study, and grants, personal fees, and non-financial support from Astellas and Bayer unrelated to the submitted work. N.J. Perualila, S. Van Sanden, J. Diels, T. Ito, and P. De Porre are employees of Janssen. S. Van Sanden, T. Ito, and P. De Porre are shareholders of Janssen’s parent company, Johnson & Johnson. K. Fizazi reports financial support for participation in advisory boards for Amgen, AstraZeneca, Astellas, Bayer, Janssen, Sanofi, Orion, and CureVac.

Figures

Fig. 1

Disposition. Patients were randomized in a 1:1 ratio to receive AA + P + ADT or placebos + ADT. Because of a positive result at the first interim analysis, patients had the opportunity to enroll in an open-label extension phase in which they received AA + P + ADT for up to 3 years. Patients who had previously received placebos could switch to the AA + P arm if they met the entry eligibility requirements for hepatic function and cardiovascular disease before starting AA + P. “Deaths” refers to discontinuation of treatment due to death only. AA abiraterone acetate, ADT androgen-deprivation therapy, P prednisone

Fig. 2

Treatment timeline of patients who switched from placebos + ADT to AA + P + ADT. Clinical progression was defined as deterioration of ECOG performance status to grade 3 or higher or need to initiate any of the following because of tumor progression (even in the absence of radiographic evidence of disease): anticancer therapy for prostate cancer; radiation therapy or surgical interventions for complications due to tumor progression; or cancer pain requiring immediate administration of chronic opioid analgesics. If a patient had radiographic progression (without clinical progression) and alternate therapy was not initiated, treatment could continue at the discretion of the investigator. “Death” refers to discontinuation of treatment due to death only. Radiographic progression was defined as detection of soft tissue lesions by computed tomography/magnetic resonance imaging per RECIST 1.1 or by bone lesion progression on bone scans per modified Prostate Cancer Working Group 2 criteria. AA abiraterone acetate, ADT androgen deprivation therapy, ECOG Eastern Cooperative Oncology Group, P prednisone

Fig. 3

Kaplan-Meier curves for overall survival. a Survival distribution and median overall survival were estimated by Kaplan–Meier analysis. b HRs and associated 95% CIs were estimated using an unstratified Cox proportional hazards model. AA abiraterone acetate, ADT androgen-deprivation therapy, CI confidence interval, HR hazard ratio, IPCW inverse probability of censoring weights, ITT intent to treat, OS overall survival, P prednisone, RPSFTM rank preserving structure failure time model