Estimation of Overall Survival with Subsequent Treatment Effect by Applying Inverse Probability of Censoring Weighting in the LATITUDE Study

Yosuke Koroki, Masataka Taguri, Nobuaki Matsubara, Karim Fizazi, Yosuke Koroki, Masataka Taguri, Nobuaki Matsubara, Karim Fizazi

Abstract

Background: In the LATITUDE study (ClinicalTrials.gov, NCT01715285), compared with placebos, abiraterone acetate plus prednisone (AAP) with androgen deprivation therapy (ADT) provided significant overall survival (OS) benefit in high-risk metastatic castration-sensitive prostate cancer (mCSPC) patients. It is controversial whether survival benefits would remain if all patients in the placebo group subsequently received life-extending therapies.

Objective: To estimate treatment effect in the case of all patients in the placebo group receiving life-extending subsequent therapies.

Design setting and participants: A post hoc analysis of LATITUDE final-analysis data was carried out (setting and participants have been reported previously).

Intervention: AAP or placebos plus ADT.

Outcome measurements and statistical analysis: We applied the inverse probability of censoring weighting (IPCW) method to represent the situation in which all patients in the placebo group would have received life-extending subsequent therapies. The OS hazard ratio (HR) of AAP versus placebos and associated 95% confidence interval (CI) were estimated using a Cox proportional hazards model.

Results and limitations: Of the 581 eligible patients in the placebo group, 237 (40.8%) did not receive life-extending subsequent therapies. From the unadjusted intention-to-treat analysis, the HR for OS for AAP versus placebos was 0.661 (95% CI 0.564-0.775). Using IPCW to adjust for patients in the placebo group without life-extending subsequent therapies, the HR was 0.732 (95% CI 0.604-0.887). A limitation is a lack of proof that the Cox proportional hazards model for the absence of life-extending subsequent therapy is correctly specified for the IPCW method.

Conclusions: Treatment with AAP exerts OS benefit over placebos in high-risk mCSPC patients, regardless of whether life-extending subsequent therapy is given.

Patient summary: In a previous study, high-risk metastatic castration-sensitive prostate cancer patients who received abiraterone acetate plus prednisone (AAP) with androgen deprivation therapy generally survived longer than those given placebos. The benefit of adding AAP continues regardless of whether life-extending subsequent therapy is given.

Keywords: Abiraterone; Inverse probability of censoring weighting; Metastatic castration-sensitive prostate cancer; Overall survival; Subsequent therapy.

© 2021 The Author(s).

Figures

Fig. 1
Fig. 1
Study design. In the LATITUDE study, patients were randomly assigned to either abiraterone acetate plus prednisone (AAP) plus androgen deprivation therapy (ADT) (the AAP group) or dual placebos plus ADT (the placebo group).
Fig. 2
Fig. 2
Overall survival (OS) Kaplan-Meier estimates both unadjusted (intention-to-treat analysis) and adjusted for patients in the placebo group who did not receive life-extending subsequent therapy, applying the naïve censoring method and the inverse probability of censoring weighting (IPCW) method. Patients at risk are presented for the naïvely censored curve. Patients at risk are not included for the IPCW curve due to the lack of a clear clinical interpretation of the number of patients at risk associated with the weighted methodology. Patients in the abiraterone acetate plus prednisone (AAP) group received AAP plus androgen deprivation therapy (ADT), and patients in the placebo group received dual placebos plus ADT. CI = confidence interval; NR = not reached.
Fig. 3
Fig. 3
Forest plots both unadjusted and adjusted for patients in the placebo group not receiving life-extending subsequent therapy, applying either naïve censoring or inverse probability of censoring weighting (IPCW). All p values are from the hazard ratio (HR) of the Cox proportional hazards model. Patients in the abiraterone acetate plus prednisone (AAP) group received AAP plus androgen deprivation therapy (ADT), and patients in the placebo group received dual placebos plus ADT. CI = confidence interval.

References

    1. Sung H., Ferlay J., Siegel R.L., et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–249.
    1. Dong L., Zieren R.C., Xue W., de Reijke T.M., Pienta K.J. Metastatic prostate cancer remains incurable, why? Asian J Urol. 2019;6:26–41.
    1. Kyriakopoulos C.E., Chen Y.H., Carducci M.A., et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018;36:1080–1087.
    1. James N.D., Sydes M.R., Clarke N.W., et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387:1163–1177.
    1. Fizazi K., Tran N., Fein L., et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2019;20:686–700.
    1. James N.D., de Bono J.S., Spears M.R., et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017;377:338–351.
    1. Chi K.N., Chowdhury S., Bjartell A., et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol. 2021;39:2294–2303.
    1. Armstrong A.J., Szmulewitz R.Z., Petrylak D.P., et al. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2019;37:2974–2986.
    1. Davis I.D., Martin A.J., Stockler M.R., et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381:121–131.
    1. Berthold D.R., Pond G.R., Soban F., de Wit R., Eisenberger M., Tannock I.F. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008;26:242–245.
    1. Ryan C.J., Smith M.R., Fizazi K., et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16:152–160.
    1. Beer T.M., Armstrong A.J., Rathkopf D., et al. Enzalutamide in men with chemotherapy-naive metastatic castration-resistant prostate cancer: extended analysis of the phase 3 PREVAIL study. Eur Urol. 2017;71:151–154.
    1. de Bono J., Eisenberger M., Sartor O. Abiraterone in metastatic prostate cancer. N Engl J Med. 2017;377:1694–1695.
    1. Robins J.M., Finkelstein D.M. Correcting for noncompliance and dependent censoring in an AIDS clinical trial with inverse probability of censoring weighted (IPCW) log-rank tests. Biometrics. 2000;56:779–788.
    1. Rimawi M., Hilsenbeck S.G. Making sense of clinical trial data: is inverse probability of censoring weighted analysis the answer to crossover bias? J Clin Oncol. 2012;30:453–458.
    1. Feyerabend S., Saad F., Perualila N.J., et al. Adjusting overall survival estimates for treatment switching in metastatic, castration-sensitive prostate cancer: results from the LATITUDE study. Target Oncol. 2019;14:681–688.
    1. Hernan M.A., Brumback B., Robins J.M. Marginal structural models to estimate the joint causal effect of nonrandomized treatments. J Am Stat Assoc. 2001;96:440–448.
    1. Cornford P., van den Bergh R.C.N., Briers E., et al. EAU-EANM-ESTRO-ESUR-SIOG guidelines on prostate cancer. Part II-2020 update: treatment of relapsing and metastatic prostate cancer. Eur Urol. 2021;79:263–282.
    1. Parker C., Castro E., Fizazi K., et al. Prostate cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31:1119–1134.
    1. George D.J., Sartor O., Miller K., et al. Treatment patterns and outcomes in patients with metastatic castration-resistant prostate cancer in a real-world clinical practice setting in the United States. Clin Genitourin Cancer. 2020;18:284–294.
    1. Fizazi K., Scher H.I., Molina A., et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012;13:983–992.
    1. Scher H.I., Fizazi K., Saad F., et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187–1197.
    1. de Bono J.S., Oudard S., Ozguroglu M., et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147–1154.
    1. Parker C., Nilsson S., Heinrich D., et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213–223.
    1. Robins J.M., Tsiatis A.A. Correcting for non-compliance in randomized trials using rank preserving structural failure time models. Commun Stat Theory Methods. 1991;20:2609–2631.
    1. Branson M., Whitehead J. Estimating a treatment effect in survival studies in which patients switch treatment. Stat Med. 2002;21:2449–2463.
    1. Jonsson L., Sandin R., Ekman M., et al. Analyzing overall survival in randomized controlled trials with crossover and implications for economic evaluation. Value Health. 2014;17:707–713.
    1. Robins J.M. In: Latent variable modeling and applications to causality. Lecture notes in statistics. Berkane M., editor. Springer; New York, NY: 1997. Causal inference from complex longitudinal data; pp. 69–117.

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