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      string(257) "NCT01715285 - A Randomized, Double-blind, Comparative Study of Abiraterone Acetate Plus Low-Dose Prednisone Plus Androgen Deprivation Therapy (ADT) Versus ADT Alone in Newly Diagnosed Subjects With High-Risk, Metastatic Hormone-naive Prostate Cancer (mHNPC)"
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  ["project_title"]=>
  string(133) "Causal Mediation by PSA and pain in metastatic hormone sensitive prostate cancer: a pooled analysis of 4 randomized controlled trials"
  ["project_narrative_summary"]=>
  string(692) "We propose a pooled analysis of 4 randomized controlled trials (ARASENS, LATITUDE, TITAN, and ENZALUTAMIDE) to determine if early PSA drop and early pain progression (as defined in the trial) had any causal mediation role on the treatment effect from novel hormonal agents in conjunction with testosterone suppression with or without docetaxel on overall survival (OS). In other words, we would like to determine if PSA drop and pain progression could be some of the pivotal factors through which this combination exerts its effect on OS. If found to be mediators, this information will provide motivation for us to predict patients who could predict have early PSA drop or pain progression. "
  ["project_learn_source"]=>
  string(11) "data_holder"
  ["principal_investigator"]=>
  array(7) {
    ["first_name"]=>
    string(9) "Soumyajit"
    ["last_name"]=>
    string(3) "Roy"
    ["degree"]=>
    string(10) "MBBS, MSc."
    ["primary_affiliation"]=>
    string(30) "Rush University Medical Center"
    ["email"]=>
    string(23) "soumyajitroy8@gmail.com"
    ["state_or_province"]=>
    string(2) "IL"
    ["country"]=>
    string(3) "USA"
  }
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    ["value"]=>
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    ["label"]=>
    string(68) "No external grants or funds are being used to support this research."
  }
  ["project_date_type"]=>
  string(18) "full_crs_supp_docs"
  ["property_scientific_abstract"]=>
  string(1610) "Background: Whether early PSA response or pain response is a causal mediator of treatment effect on OS in mHSPC patients, is largely unknown.  

Objective: To determine if early PSA response at or before 6 months or early pain progression by 6 months played an independent causal mediating role in treatment effect on OS. We also would evaluate if early dynamic change in PSA or pain within first 6 months after random assignment predicts for difference in OS. 

Study Design: A pooled analysis using individual patient data from ARASENS (NCT02799602), TITAN (NCT02489318), LATITUDE (NCT01715285), ENZAMET (NCT02446405).

Participants: Eligible patients will include mHSPC patients that were randomly assigned to any of the two randomized treatment regimens in the 4 trials.

Primary outcome: Overall survival (OS).

Secondary outcome(s): Time to PSA progression and time to castrate resistance.  

Statistical Analyses: We will explore if treatment effect on OS is mediated through early PSA nadir at 6 months after adjustment for exposures using causal mediation analysis. The mediation analysis will be adjusted for confounders that affect the mediator-outcome association. If early PSA response is found to be a causal mediator of treatment effect on OS, we will train and validate a model to predict early PSA response at or before 6 months of random assignment. The model will be built using TITAN, LATITUDE, and ARASENS and then validate in ENZAMET trial. Bayesian joint model will be applied to determine association of dynamic change in PSA and pain with outcomes. "
  ["project_brief_bg"]=>
  string(2303) "The combination of androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPI) with or without docetaxel is a standard-of-care systemic treatment strategy for men with metastatic hormone sensitive prostate cancer (mHSPC) based on a succession of large randomized controlled trials (Fizazi et al., 2021; Fizazi et al., 2021; Hussain et al., 2023; Smith et al., 2022; Chi et al., 2021; Fizazi et al., 2019; James et al., Armstrong et al., 2022, Attard et al., 2023). ARASENS, TITAN, and LATITUDE are some of these randomized controlled trials which have proven the efficacy of ARPI with or without docetaxel for men with mHSPC (Hussain et al., 2023; Smith et al., 2022; Chi et al., 2021; Fizazi et al., 2019). These trials have demonstrated OS advantages with addition of ARPI to ADT  (with or without docetaxel).



PSA response has been found to predict for improved outcome in patients treated with ADT plus ARPI(Chowdhury et al., 2023; Matsubara et al., 2020; Hussain et al., 2006; Saad et al., 2023). However, it remains unclear if early PSA response played a causal mediating role for the treatment effect from ADT plus ARPI (+/- docetaxel) on OS and whether this mediating effect is differential between the two treatment groups. Association of early pain response with outcomes secondary analysis of LATITUDE trial (Roy et al., 2023). However, it remains unknown if pain progression could play a causal mediation role on the treatment effect. Therefore, we propose a pooled analysis using individual patient data from ARASENS, LATITUDE, TITAN, ENZAMET to determine if PSA response of ≤0.2 ng/mL by 6 months or early pain progression by 6 months played an independent causal mediating role for intensified hormonal manipulation (ARPI with ADT +/- docetaxel) effect on OS. This pooled analysis will not only validate findings obtained from secondary analyses of individual studies, but also will validate the utility of early PSA response and early pain response as causal mediators for treatment effect from intensified hormonal manipulation on OS in mHSPC patients. Further if early PSA response or pain progression is found to be a causal mediator, our proposal will also provide a validated tool to predict early PSA response using baseline characteristics. "
  ["project_specific_aims"]=>
  string(1340) " Specific Aim 1: Does early PSA response of ≤0.2 ng/mL and pain progression by 6 months since random allocation plays a causal mediation role on the treatment effect on OS? We will decompose the total effect into direct and indirect effects to identify the mediation effect. 

Sub Aim 1.1: If time to early PSA response ≤0.2 ng/mL at or before 6 months has any association with OS? 

Sub Aim 1.2: If we find early PSA response as a causal mediator, we plan to train and validate a model to predict early PSA response based on available baseline characteristics from the trials. A similar approach will be used for pain progression. 

Objectives:

- We will determine if early PSA response of ≤0.2 ng/mL by 6 months played a mediating role on the treatment effect on OS and if there was a difference in the average causal mediation effect by PSA nadir varied between the two treatment groups (ADT with or without docetaxel versus ADT plus ARPI with or without docetaxel). A minimally sufficient set of confounders will be chosen to determine causal mediation role. If early PSA response is found to be a causal mediator, we will train and validate a model based on baseline characteristics to predict early PSA response at or before 6 months. A similar approach will be used for early pain progression. 

"
  ["project_study_design"]=>
  array(2) {
    ["value"]=>
    string(5) "other"
    ["label"]=>
    string(5) "Other"
  }
  ["project_study_design_exp"]=>
  string(94) "Causal mediation analysis from individual patient data from three randomized controlled trials"
  ["project_purposes"]=>
  array(2) {
    [0]=>
    array(2) {
      ["value"]=>
      string(56) "new_research_question_to_examine_treatment_effectiveness"
      ["label"]=>
      string(114) "New research question to examine treatment effectiveness on secondary endpoints and/or within subgroup populations"
    }
    [1]=>
    array(2) {
      ["value"]=>
      string(5) "other"
      ["label"]=>
      string(5) "Other"
    }
  }
  ["project_purposes_exp"]=>
  string(59) "Causal mediation analysis and model building and validation"
  ["project_software_used"]=>
  array(2) {
    ["value"]=>
    string(7) "rstudio"
    ["label"]=>
    string(7) "RStudio"
  }
  ["project_research_methods"]=>
  string(1178) "We propose a pooled analysis using individual patient data 4 randomized controlled trials. In ARASENS (NCT02799602), 1306 mHSPC patients were randomly assigned to darolutamide versus placebo with ADT plus docetaxel. In TITAN trial (NCT02489318), 1052 patients with mHSPC were randomly assigned to apalutamide versus placebo with ADT with or without docetaxel. In LATITUDE (NCT01715285), 1199 patients with de novo mHSPC patients were randomly assigned to abiraterone versus placebo with ADT. In ENZAMET (NCT02446405), 1125 patients were randomly assigned to ADT with or without enzalutamide with or without docteaxel.  Eligible patients will include patients with histologically confirmed prostate cancer, and metastases detected on conventional imaging. We will include all patients that were randomly assigned to any of the two randomized treatment arms and had complete information on outcomes and variables of interest including baseline and post-baseline PSA and pain response. Patients with no post-baseline PSA or pain score will be excluded. ARASENS will be delivered on VIVLI and author has ENZAMET data which will be uploaded to VIVLI where the analyses will be done. "
  ["project_main_outcome_measure"]=>
  string(543) "Main outcome:

Overall survival (OS): OS will be determined as time from randomization to incidence of death from any cause. Alive patients will be censored at the date of last contact. 



Secondary outcome(s):

Time to PSA progression will be estimated using the trial definition and cumulative incidence of PSA progression will be estimated using deaths as competing risk event. Time to castrate resistance will also be included as a secondary outcome measure and will be defined based on trial definition.  

"
  ["project_main_predictor_indep"]=>
  string(314) "Primary Exposure: 

Treatment arm: Categorical (ARPI plus ADT with/without docetaxel vs. ADT with/without docetaxel plus placebo)



Causal Mediators:

Early PSA response of ≤0.2 ng/mL at or before 6 months. 

Pain progression at or before 6 months as defined in the trials.

"
  ["project_other_variables_interest"]=>
  string(856) "- Age (in years) at the time of random assignment. 

- Gleason Score at initial diagnosis. 

- Eastern Cooperative Oncology Group Performance Status. 

- Prior Androgen Deprivation therapy (ADT): (yes/no). 

- Tumor stage at diagnosis: (T1 to T2 vs. T3 to T4). 

- PSA at the time of trial enrolment (in ng/mL). 

- Serial PSA  data (baseline and post baseline)

- Risk group per LATITUDE definition. 

- Volume of metastatic disease burden per CHAARTED definition. 

- Number of skeletal metastases. 

- Location of skeletal metastases (outside versus within pelvis or vertebral column). 

- Visceral metastasis (yes versus no). 

- Nodal stage (N0 versus N1). 

- Serial pain scores as measured by Brief Pain Inventory–Short Form questionnaire (baseline and post-baseline). "
  ["project_stat_analysis_plan"]=>
  string(3999) "We will compare the cumulative incidence of PSA progression considering deaths as competing risk events and will compare the incidence rates using Fine-Gray’s tests among early PSA responders versus non-responders across the treatment groups. We will explore if treatment effect on OS is mediated through treatment effect on early PSA nadir by 6 months using causal mediation analysis (CMA) methods suggested by VanderWeele et al, 2011 i.e., decomposing the total treatment effect into direct and indirect effects. The CMA will be adjusted for confounders that affect the mediator-outcome association. Direct counterfactual imputation with bootstrapped standard errors, bias-corrected and accelerated confidence intervals will be calculated. We will pool ADT +/- docetaxel together given insignificant benefit of docetaxel over ADT alone based on recent network meta-analyses (Riaz et al., 2023, Roy et al., 2022). We will focus on total natural indirect effect, i.e., the effect of X on Y through M, when the direct effect is held constant at the treatment-group level X = 1 (ADT +/- docetaxel); TNIE = E[Yi(1, Mi(1)) − Yi(1, Mi(0))], and the pure natural indirect effect, i.e., the effect of X on Y through M, when the direct effect is held constant at the control-group level X = 0 (ADT+/- docetaxel + ARPI); PNIE = E[Yi(0, Mi(1)) − Yi(0, Mi(0))]. We will also calculate proportion mediated which estimates the extent to which the mediating variable accounts for a total effect. A multivariable Cox proportional hazard model will be applied to explore a continuous and potentially nonlinear relationship between time to early PSA response with OS in each treatment group where time to early PSA response will be fitted with restricted cubic spline. We will calculate inverse probability weighting (IPW) for adjusted OS estimates for those with and without early PSA response in the two treatment groups. IPW-adjusted OS estimates will be also calculated for patients with PSA nadir of 0.2 ng/mL in the two treatment groups. A similar approach will be applied for causal mediation analysis for early pain progression by 6 months with OS. Further, to determine the association of dynamic change in PSA or pain score with OS, we will apply separate Bayesian joint models. A multivariable Cox proportional hazard regression model will be constructed for the time-to-event sub-model and a linear mixed-effects model will be built for the longitudinal sub-model. Time of assessment will be included as random slope while patients will be included as random intercepts in the mixed model. The two sub-models will be linked through a shared random effect. If found to be a causal mediator we will build a model to predict early PSA response. These models will be built based on TITAN, ARASENS, and LATITUDE and validated using ENZAMET trial. 



If early PSA response is found to be a mediator in the causal pathway of treatment effect on OS, we will train and validate a model to predict early PSA response by 6 months of random assignment. We will select baseline characteristics available in the trial databases. An elastic net logistic regression model will be applied for variable selection and model training in the training data (after splitting the cohort into 70:30 ratio). Performance of the final model, including area under curve with 95% confidence intervals will be checked in the testing dataset. Further, bootstrapped calibration of the model will also be checked in the testing dataset.



In presence of missing data, we will perform 2 sensitivity analyses to determine the robustness of our findings. One will be a complete case analysis with multivariable Cox proportional hazard regression model (adjusting for confounders in anticipation of selection bias) while the other will be to perform the multivariable Cox proportional hazard model in a multiply imputed dataset. We will use R studio with its packages in VIVLI platform to perform the analyses."
  ["project_timeline"]=>
  string(218) "Proposal submission: November 8, 2024. 

Proposal review and DUA execution: November 20, 2024

Data analysis start: December 21, 2024

Anticipated Data analysis completion: February 27, 2026. 

"
  ["project_dissemination_plan"]=>
  string(207) "- Abstract presentation in ASCO 2026- Submission of manuscript first-quartile oncology journals: Journal of Clinical Oncology, Journal of National Cancer Institute, European Urology, Annals of Oncology etc. "
  ["project_bibliography"]=>
  string(9638) "
Armstrong AJ, Azad AA, Iguchi T, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, Villers A, Alcaraz A, Alekseev B, Shore ND, Gomez-Veiga F, Rosbrook B, Zohren F, Yamada S, Haas GP, Stenzl A. Improved Survival With Enzalutamide in Patients With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. 202; 40(15): 1616-1622.
 
Armstrong AJ, Garrett-Mayer E, Ou Yang YC, Carducci MA, Tannock I, de Wit R, Eisenberger M. Prostate-specific antigen and pain surrogacy analysis in metastatic hormone-refractory prostate cancer. J Clin Oncol. 2007; 25(25): 3965-3970. doi: 10.1200/JCO.2007.11.4769.
 
Attard G, Murphy L, Clarke NW, Sachdeva A, Jones C, Hoyle A, Cross W, Jones RJ, Parker CC, Gillessen S, Cook A, Brawley C, Gilson C, Rush H, Abdel-Aty H, Amos CL, Murphy C, Chowdhury S, Malik Z, Russell JM, Parkar N, Pugh C, Diaz-Montana C, Pezaro C, Grant W, Saxby H, Pedley I, O’Sullivan JM, Birtle A, Gale J, Srihari N, Thomas C, Tanguay J, Wagstaff J, Das P, Gray E, Alzouebi M, Parikh O, Robinson A, Montazeri AH, Wylie J, Zarkar A, Cathomas R, Brown MD, Jain Y, Dearnaley DP, Mason MD, Gilbert D, Langley RE, Millman R, Matheson D, Sydes MR, Brown LC, Parmar MKB, James ND; STAMPEDE investigators. Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol. Lancet Oncol. 2023;24(5):443-456. doi: 10.1016/S1470-2045(23)00148-1.
 
Chi KN, Chowdhury S, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, Juárez A, Merseburger AS, Özgüroğlu M, Uemura H, Ye D, Brookman-May S, Mundle SD, McCarthy SA, Larsen JS, Sun W, Bevans KB, Zhang K, Bandyopadhyay N, Agarwal N. 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(20): 2294-2303. doi: 10.1200/JCO.20.03488.
 
Chowdhury, S., Bjartell, A., Agarwal, N., Chung, B. H., Given, R. W., Pereira de Santana Gomes, A. J., Merseburger, A. S., Özgüroğlu, M., Soto, Á. J., Uemura, H., Ye, D., Brookman-May, S. D., Londhe, A., Bhaumik, A., Mundle, S. D., Larsen, J. S., McCarthy, S. A., & Chi, K. N. Deep, rapid, and durable prostate-specific antigen decline with apalutamide plus androgen deprivation therapy is associated with longer survival and improved clinical outcomes in TITAN patients with metastatic castration-sensitive prostate cancer. Annals of Oncology 2023; 34(5): 477–485. https://doi.org/10.1016/j.annonc.2023.02.009
 
Delanoy, N., Robbrecht, D., Fizazi, K., Mercier, F., Sartor, O., Wit, R. De, & Oudard, S. Pain progression at initiation of chemotherapy in metastatic castration-resistant prostate cancer (mCRPC) is associated with a poor prognosis: A post-hoc analysis of FIRSTANA. Annals of Oncology 2019; 30: v335–v336. https://doi.org/10.1093/ANNONC/MDZ248.016
 
Fizazi, K., Galceran, J. C., Foulon, S., Roubaud, G., McDermott, R., Fléchon, A., Tombal, B., Supiot, S., Berthold, D. R., Ronchin, P., Kacso, G., Mescam, G. G., Calabro’, F., Berdah, J. F., Hasbini, A., Silva, M., Thiery-Vuillemin, A., Latorzeff, I., Rieger, I., & Bossi, A. A phase III trial with a 2×2 factorial design in men with de novo metastatic castration-sensitive prostate cancer: Overall survival with abiraterone acetate plus prednisone in PEACE-1. Annals of Oncology, 2021; 32: S1299. https://doi.org/10.1016/J.ANNONC.2021.08.2099
 
Fizazi, K., Maldonado, X., Foulon, S., Roubaud, G., McDermott, R. S., Flechon, A., TOMBAL, B. F., Supiot, S., Berthold, D. R., Ronchin, P., Kacso, G., Gravis, G., Calabro, F., Berdah, J. F., Hasbini, A., Silva, M., Thiery-Vuillemin, A., Rieger, I., Tanguy, M. L., & Bossi, A. A phase 3 trial with a 2×2 factorial design of abiraterone acetate plus prednisone and/or local radiotherapy in men with de novo metastatic castration-sensitive prostate cancer (mCSPC): First results of PEACE-1. Journal of Clinical Oncology 2021; 39(15\_suppl): 5000. https://doi.org/10.1200/JCO.2021.39.15\_suppl.5000
 
Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, Özgüroğlu M, Ye D, Feyerabend S, Protheroe A, Sulur G, Luna Y, Li S, Mundle S, Chi KN. 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(5): 686-700. doi: 10.1016/S1470-2045(19)30082-8.
 
Hussain, M., Tangen, C. M., Higano, C., Schelhammer, P. F., Faulkner, J., Crawford, E. D., Wilding, G., Akdas, A., Small, E. J., Donnelly, B., MacVicar, G., & Raghavan, D. Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data from Southwest Oncology Group Trial 9346 (INT-0162). Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 2006; 24(24): 3984–3990. https://doi.org/10.1200/JCO.2006.06.4246
 
Hussain, M., Tombal, B., Saad, F., Fizazi, K., Sternberg, C. N., Crawford, E. D., Shore, N., Kopyltsov, E., Kalebasty, A. R., Bögemann, M., Ye, D., Cruz, F., Suzuki, H., Kapur, S., Srinivasan, S., Verholen, F., Kuss, I., Joensuu, H., & Smith, M. R. Darolutamide Plus Androgen-Deprivation Therapy and Docetaxel in Metastatic Hormone-Sensitive Prostate Cancer by Disease Volume and Risk Subgroups in the Phase III ARASENS Trial. JCO 2023; 41: 3595-3607. DOI:10.1200/JCO.23.00041
 
James ND, de Bono JS, Spears MR, Clarke NW, Mason MD, Dearnaley DP, Ritchie AWS, Amos CL, Gilson C, Jones RJ, Matheson D, Millman R, Attard G, Chowdhury S, Cross WR, Gillessen S, Parker CC, Russell JM, Berthold DR, Brawley C, Adab F, Aung S, Birtle AJ, Bowen J, Brock S, Chakraborti P, Ferguson C, Gale J, Gray E, Hingorani M, Hoskin PJ, Lester JF, Malik ZI, McKinna F, McPhail N, Money-Kyrle J, O’Sullivan J, Parikh O, Protheroe A, Robinson A, Srihari NN, Thomas C, Wagstaff J, Wylie J, Zarkar A, Parmar MKB, Sydes MR; STAMPEDE Investigators. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med. 2017 Jul 27;377(4):338-351. doi: 10.1056/NEJMoa1702900.
 
Matsubara, N., Chi, K. N., Özgüroğlu, M., Rodriguez-Antolin, A., Feyerabend, S., Fein, L., Alekseev, B. Y., Sulur, G., Protheroe, A., Li, S., Mundle, S., De Porre, P., Tran, N., & Fizazi, K. Correlation of Prostate-specific Antigen Kinetics with Overall Survival and Radiological Progression-free Survival in Metastatic Castration-sensitive Prostate Cancer Treated with Abiraterone Acetate plus Prednisone or Placebos Added to Androgen Deprivation Therapy: Post Hoc Analysis of Phase 3 LATITUDE Study. European Urology 2020; 77(4): 494–500. https://doi.org/10.1016/J.EURURO.2019.11.021
 
Riaz IB, Naqvi SAA, He H, Asghar N, Siddiqi R, Liu H, Singh P, Childs DS, Ravi P, Hussain SA, Murad MH, Boorjian SA, Sweeney C, Van Allen EM, Bryce AH. First-line Systemic Treatment Options for Metastatic Castration-Sensitive Prostate Cancer: A Living Systematic Review and Network Meta-analysis. JAMA Oncol. 2023;9(5):635-645. doi: 10.1001/jamaoncol.2022.7762.
 
Roy, S., Morgan, S. C., Wallis, C. J. D., Sun, Y., Spratt, D. E., Malone, J., Grimes, S., Mukherjee, D., Kishan, A. U., Saad, F., & Malone, S. Association of dynamic change in patient-reported pain with survival in metastatic castrate sensitive prostate cancer-exploratory analysis of LATITUDE study. Prostate Cancer and Prostatic Diseases 2023; 26(1): 96–104. https://doi.org/10.1038/S41391-022-00529-2
 
Roy S, Sayyid R, Saad F, Sun Y, Lajkosz K, Ong M, Klaassen Z, Malone S, Spratt DE, Wallis CJD, Morgan SC. Addition of Docetaxel to Androgen Receptor Axis-targeted Therapy and Androgen Deprivation Therapy in Metastatic Hormone-sensitive Prostate Cancer: A Network Meta-analysis. Eur Urol Oncol. 2022 Oct;5(5):494-502. doi: 10.1016/j.euo.2022.06.003.
 
Saad, F., Tombal, B., Hussain, M., Fizazi, K., Sternberg, C. N., Crawford, E. D., Nordquist, L. T., Tutrone, R., Shore, N. D., Belkoff, L., Kapur, S., Jhaveri, J., Ortiz, J., Srinivasan, S., Verholen, F., & Smith, M. R. (2023). MP29-01 Rapid, Durable, And Deep Prostate-Specific Antigen Response Following Addition Of Darolutamide To Androgen-Deprivation Therapy And Docetaxel In Arasens. The Journal of Urology, 2023; 209(Supplement 4). https://doi.org/10.1097/JU.0000000000003257.01
 
Smith MR, Hussain M, Saad F, Fizazi K, Sternberg CN, Crawford ED, Kopyltsov E, Park CH, Alekseev B, Montesa-Pino Á, Ye D, Parnis F, Cruz F, Tammela TLJ, Suzuki H, Utriainen T, Fu C, Uemura M, Méndez-Vidal MJ, Maughan BL, Joensuu H, Thiele S, Li R, Kuss I, Tombal B; ARASENS Trial Investigators. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med. 2022; 386(12): 1132-1142. doi: 10.1056/NEJMoa2119115.
 
VanderWeele TJ. Causal mediation analysis with survival data. Epidemiology 2011; 22: 582. https://doi.org/10.1097/EDE.0B013E31821DB37E.
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