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Clinical Trial
. 2025 Aug 1;8(8):e2527988.
doi: 10.1001/jamanetworkopen.2025.27988.

Statin Use in Patients With Advanced Prostate Cancer in the TITAN and SPARTAN Trials

Soumyajit Roy  1 , Zeynep Irem Ozay  2 , Avirup Guha  3   4 , Yilun Sun  1 , Kim N Chi  5 , Scott C Morgan  6 , Shawn Malone  6 , Christopher J D Wallis  7 , Jason R Brown  8 , Pedro C Barata  8 , Amar U Kishan  9 , Angela Y Jia  1 , Nicholas G Zaorsky  1 , Umang Swami  2 , Simon Chowdhury  10 , Eric J Small  11 , Daniel E Spratt  1 , Fred Saad  12 , Neeraj Agarwal  2
Affiliations
Clinical Trial

Statin Use in Patients With Advanced Prostate Cancer in the TITAN and SPARTAN Trials

Soumyajit Roy et al. JAMA Netw Open. .

Abstract

Importance: The impact of statins on overall survival (OS) in patients with prostate cancer treated using intensified therapy with apalutamide is not fully understood.

Objective: To determine whether statin exposure was associated with OS and grade 3 or greater cardiac adverse events (AEs) in patients treated with apalutamide.

Design, setting, and participants: This cohort study used individual patient data from 2 multicenter phase 3 randomized clinical trials, SPARTAN (October 14, 2013, to December 15, 2016) and TITAN (December 15, 2015, to July 25, 2017). The final analysis was done on May 21, 2025. TITAN and SPARTAN randomized patients to receive androgen deprivation therapy with or without apalutamide in metastatic hormone-sensitive prostate cancer (TITAN) and nonmetastatic castration-resistant prostate cancer (SPARTAN).

Exposure: Statin exposure during the assigned treatment; statin exposure could have started before and ended either during or after the assigned treatment.

Main outcomes and measures: Inverse probability of treatment-weighted (IPTW) multivariable Cox proportional hazard regression model and covariate-adjusted OS were estimated for patients with and without statin exposure in each trial. Fine and Gray regression models were applied to determine the association of statin exposure with risk of grade 3 or greater cardiac AEs, considering deaths as competing events.

Results: Among 2187 patients included in this analysis, 1288 received apalutamide (517 in TITAN; 770 in SPARTAN) and 900 received placebo. The median (IQR) age was 65 (60-70) years in TITAN and 70 (65-80) years in SPARTAN. Patients with statin exposure were older with higher body mass index, while the proportion of patients with ECOG performance status score 1 was relatively lower. Statin exposure was associated with superior OS in patients treated with apalutamide (TITAN: hazard ratio [HR], 0.53; 95% CI, 0.32-0.87; SPARTAN: HR, 0.54; 95% CI, 0.39-0.74), but not in patients who received the placebo (TITAN: HR, 0.65; 95% CI, 0.38-1.13; SPARTAN: HR, 1.16; 95% CI, 0.76-1.77). Covariate-adjusted 3-year OS among patients with vs without statins were 81% vs 67% (difference, 14% [95% CI, 5%-22%]) and 86% vs 78% (difference, 8% [95% CI, 3%-13%]) in the apalutamide-treated patients from TITAN and SPARTAN trials, respectively. Patients receiving statins had a higher risk of grade 3 or higher cardiac AEs in both apalutamide (subdistribution HR, 2.62 [95% CI, 1.35-5.08]) and placebo (subdistribution HR, 2.36 [95% CI, 0.96-5.84]) groups.

Conclusions and relevance: In this cohort study, statin exposure was associated with longer OS in patients treated with apalutamide. Statin-exposed patients had a higher risk of grade 3 or greater cardiac AEs, which may reflect their preexisting cardiovascular comorbidity.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Roy reported receiving grants from Swim Across America and owning stock in Pfizer and Merck Pharmaceuticals outside the submitted work. Dr Chi reported grants from Janssen (paid to institution) during the conduct of the study and grants from Janssen (paid to institution) and AstraZeneca and personal fees from Janssen, Amgen, Astellas, Bayer, Bristol Myers Squibb, Merck, Novartis, Pfizer, Roche, and AstraZeneca outside the submitted work. Dr Morgan reported receiving grants from Knight Therapeutics (paid to institution) outside the submitted work. Dr Wallis reported receiving personal fees from Johnson & Johnson, Nanostics, Precision Point Specialty, Sesen Bio, AbbVie, Astellas, AstraZeneca, Bayer, EMD Serono, Knight Therapeutics, Merck, Science and Medicine Canada, TerSera, Tolmar, Sumitomo Pharmaceuticals, Pfizer, Intuitive Surgical, and MashUP Media outside the submitted work. Dr Brown reported receiving personal fees from Johnson & Johnson, Merck, and Pfizer the conduct of the study and nonfinancial support from EMD Serono outside the submitted work. Dr Barata reported receiving personal fees from Pfizer, AstraZeneca, Bayer, Exelixis, Astellas, Telix, Merck, and Johnson & Johnson outside the submitted work. Dr Kishan reported receiving personal fees from Janssen, Novartis, Lantheus, and Boston Scientific and grants from Varian Medical Systems outside the submitted work. Dr Jia reported receiving grants from Novartis and personal fees from BlueEarth Diagnostic outside the submitted work. Dr Zaorsky reported receiving grants from American Cancer Society, Department of Defense and National Institutes of Health (NIH) and personal fees from Springer Nature and American College of Radiation Oncology outside the submitted work. Dr Swami reported receiving personal fees from Astellas, Exelixis, Seattle Genetics, Imvax, Sanofi, AstraZeneca, Gilead, Pfizer, Adaptimmune, Janssen, and Flatiron Health and grants from Janssen, Exelixis, and Astellas/Seattle Genetics (paid to institution) outside the submitted work. Dr Chowdhury reported receiving personal fees from Janssen, Bayer, and Astellas outside the submitted work. Dr Spratt reported receiving personal fees from AstraZeneca, Bayer, Boston Scientific, Janssen, Pfizer, and Novartis outside the submitted work. Dr Saad reported receiving grants and personal fees from Janssen during the conduct of the study and grants and personal fees from Bayer, Astellas, Pfizer, and AstraZeneca outside the submitted work. Dr Agarwal reported receiving grants from Arnivas, Astellas, AstraZeneca, Bavarian Nordic, Bayer, Bristol Meyers Squibb, Calithera, Celldex, Clovis, CRISPR Therapeutics, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon (paid to institution) outside the submitted work. No other disclosures were reported.

Figures

Figure.
Figure.. Confounder-Adjusted Overall Survival Curves for Patients With and Without Statin Exposure in Apalutamide and Placebo Groups From the TITAN and SPARTAN Trials
See this image and copyright information in PMC

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