Conflict of Interest
Request Clinical TrialsAssociated Trial(s):
- NCT00638690 - A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Abiraterone Acetate (CB7630) Plus Prednisone in Patients With Metastatic Castration-Resistant Prostate Cancer Who Have Failed Docetaxel-Based Chemotherapy
- NCT00887198 - A Phase 3, Randomized, Double-blind, Placebo-Controlled Study of Abiraterone Acetate (CB7630) Plus Prednisone in Asymptomatic or Mildly Symptomatic Patients With Metastatic Castration-Resistant Prostate Cancer
- NCT02236637 - A Prospective Registry of Patients With a Confirmed Diagnosis of Adenocarcinoma of the Prostate Presenting With Metastatic Castrate-Resistant Prostate Cancer
- 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)
Request Clinical Trials
Data Request StatusStatus: Ongoing
Project Title: Development of a prognostic calculator for patients with metastatic prostate cancer undergoing treatment with androgen receptor axis-targeted therapy.
Androgen deprivation therapy (ADT) intensification with androgen receptor axis targeted therapy (ARAT); abiraterone, enzalutamide, apalutamide, darolutamide) and/or docetaxel is the standard of care for patients with metastatic castration-sensitive prostate cancer (mCSPC).1 However, even with ARATs, 20% patients progress within first year of intensified treatment and suffer poor progression-free survival (PFS) and overall survival (OS).2
In real-world most patients still receive ADT alone3 though its use is no longer recommended for eligible patients.1 These patients tend to get ARAT for mCRPC disease as first-line therapy.3
There is a need to identify clinical, radiological and laboratory factors associated with better or poor prognosis along with an easy-to use risk-calculator [similar to IMDC (International mRCC Database Consortium) calculator in kidney cancer] to help provide survival estimates for these patients.
We hypothesize that these markers of outcomes will be the same for patients receiving first ARAT in the castration-sensitive or castration-resistant setting though duration of PFS and OS will be different as demonstrated in clinical trials.2
Our primary objective is to develop a risk calculator based on baseline clinical, radiological, and laboratory variables to predict PFS, and OS in patients with metastatic prostate cancer receiving ARAT and to compare them between the mCSPC and the mCRPC setting. Our secondary endpoint is to develop a risk score calculator of PFS and OS for patients with metastatic prostate cancer receiving ARAT in mCSPC and mCRPC similar to the International mRCC Database Consortium (IMDC) score.
-Patients with mCSPC treated with ADT +/- abiraterone + prednisone in the LATITUDE trial.
-Patients with mCRPC treated with abiraterone acetate in the COU-AA-301 trial, COU-AA-302 trial, and from the Prospective Registry of Patients With a Confirmed Diagnosis of Adenocarcinoma of the Prostate Presenting With Metastatic Castrate-Resistant Prostate Cancer
Retrospective cohort study
Main Outcome Measures:
PFS, and OS
Baseline clinical variables including age, ethnicity, race, region of study, presence of visceral metastases, site of visceral metastases, presence of bone metastases, number of bone metastases, presence of lymph node metastases, Eastern Cooperative Group performance status, Gleason score, de-novo status and prior treatment will be included in addition to treatment regimen, previous exposure to docetaxel, and laboratory variables including baseline absolute neutrophil count, baseline lymphocyte count, baseline platelet count, baseline albumin, baseline lactate dehydrogenase, baseline PSA, alkaline phosphatase, and hemoglobin. PSA nadir will be evaluated as surrogate for PFS and OS.4-6 With baseline variables prognostic model will be constructed for PFS and OS. Cox proportional hazards regression, followed by bootstrap validation, will be used to identify independent prognostic factors for OS. Additionally, we plan to test the applicability of these factors in the mCRPC setting using a univariate analysis followed by a Cox proportional hazards regression.
Brief Project Background and Statement of Project Significance:
With intensified ADT becoming the standard of care for patients with mCSPC, the use of ADT alone is no longer recommended for eligible patients. ARAT is the preferred intensification modality, however 20% progress within first year of intensified treatment and are prone to worse outcomes and early death. At this point there is an urgent need for identifying markers of poor PFS and OS, and at the same time to guide treatment escalation and clinical trial enrollment. We predict that prognostic factors will be the same if used in the castration-sensitive or castration-resistant setting in patients receiving ARAT.
LATITUDE was one of the first phase III trials to demonstrate the benefit of ARAT in the mCSPC setting. After a median follow-up of 51.8 months, the addition of abiraterone acetate patients with high risk mCSPC receiving ADT plus abiraterone acetate had a significantly longer overall survival (OS) than those who received ADT alone (HR 0.66; 95% CI 056?078; p
Specific Aims of the Project:
- First, we aim to identify clinical, radiological, and laboratory prognostic factors for OS and PFS in patients with metastatic prostate cancer treated with a first ARAT.
- Second, we aim to build a risk calculator involving patients treated with ARAT in the mCSPC setting and test its applicability in patients receiving ARAT in the mCRPC setting.
Study Design: Individual trial analysis
What is the purpose of the analysis being proposed? Please select all that apply.: Research on clinical prediction or risk prediction
Software Used: RStudio
Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study:
Data source: LATITUDE trial dataset, COU-AA-301 trial dataset, COU-AA-302 trial dataset, and the Prospective Registry of Patients With a Confirmed Diagnosis of Adenocarcinoma of the Prostate Presenting With Metastatic Castrate-Resistant Prostate Cancer dataset.
Prognostic model: Patients treated with ADT + abiraterone + prednisone in the LATITUDE trial
Evaluation in the mCRPC setting: patients treated with abiraterone acetate + prednisone in the COU-AA-301 and COU-AA-302 trials as well as the Prospective Registry of Patients With a Confirmed Diagnosis of Adenocarcinoma of the Prostate Presenting With Metastatic Castrate-Resistant Prostate Cancer (NCT02236637)
Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study:
- Overall survival will be defined as the time from randomization to death from any cause
- Progression-free survival as the time from randomization to the occurrence of radiographic progression, clinical progression, PSA progression or death from any cause. Radiographic and clinical progression will be defined according to the definitions established in the LATITUDE trial protocol. PSA progression will be defined as a 25% increase from the baseline value and 2 ng/ml absolute increase after 12 weeks of treatment initiation.
Main Predictor/Independent Variable and how it will be categorized/defined for your study:
- Treatment arm: Categorical
- Ethnicity: Categorical
- Race: Categorical
- Region of study: Categorical
- Age, height, weight: Continuous
- Presence of bone, node, and visceral metastases: yes/no (categorical)
- Site of visceral metastasis: Categorical
- Number of bone metastasis: Ordinal
- Gleason Score: Ordinal
- TNM stage
- Prior surgery or radiation therapy to primary: yes/no
- Duration of prior therapies
- Bone pain
- Opioid use
- ECOG PS: Ordinal (0-2)
- Prior exposure to docetaxel
- Receipt of ADT in the neoadjuvant/adjuvant setting: yes/no
- Duration of neoadjuvant/adjuvant ADT if any (continuous)
- Date of randomization (date format) ? to calculate PFS and OS
- Date of metastatic diagnosis (date format)
- Date of diagnosis (date format)
- Time from ADT to trial treatment start in months Baseline and Post-Baseline Variables:
- PSA: Continuous
- PSA nadir: continuous
- Testosterone: Continuous
- Hemoglobin: Continuous
- Serum albumin: Continuous
- Serum alkaline phosphatase: Continuous
- Serum LDH: Continuous
- Total WBC count with differential counts
- Platelet count
Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study:
- Post-baseline radiographic evaluation (BS/CT scan): categorical
- Last follow-up (date format)
- Censoring information for PFS and OS
- Time of treatment discontinuation
- Time of radiographic progression (date format) ? to calculate PFS
- Time of clinical progression (date format) ? to calculate PFS
- Time of PSA progression (date format) ? to calculate PFS
- Time of death (date format) ? to calculate OS
- Cause of death
- Censoring information for PFS and OS
- Life prolonging therapy received after progression ? (Yes/no) and its details
Statistical Analysis Plan:
Univariate analysis using the log-rank test will be conducted to assess the association between survival and potential risk factors. In the multivariate analysis, step-wise Cox proportional hazard regression with a significance level of 0.15 for entering and removing variables will be conducted to identify prognostic factors. The proportional hazard assumption will be checked by testing Schoenfeld residuals. For interval validation , 300 bootstrap samples will be generated randomly with replacement from the original dataset. Then, the step-wise Cox proportional regression will be conducted on bootstrapped samples to validate risk factors for OS and PFS. Risk factors that are included more than 50% of the time in the final model will be considered as a validated risk factors. After identifying the final model, it will be fitted to the 300 bootstrap samples. Finally, bias-corrected concordance index (C-index) will be calculated by a bootstrap procedure using 500 bootstrap samples to evaluate the predictive accuracy of final models. C-index of 0.5 indicates very poor model, where it is no better than the random model to predict OS or PFS. On the other hand, C-index of 1 means perfect concordance.
To test the risk calculator in the mCRPC dataset, univariate analysis using the log-rank test will be conducted to assess the association between survival and potential risk factors. In the multivariate analysis, Cox proportional hazard regression with a significance level of 0.15 for entering and removing variables will be conducted to identify prognostic factors. The proportional hazard assumption will be checked by testing Schoenfeld residuals.
ARAT is the most common intensification therapy for patients with mCSPC.1 However, even with ARATs, 20% patients progress within first year of treatment and suffer poor outcomes.2 In patients treated with androgen deprivation therapy alone for mCSPC, ARAT is the most common treatment for castration-resistant stage.3
There is an urgent need to identify markers of poor outcomes, to help prognosticate in clinics, personalize treatment and clinical trial enrollment. Herein we aim to develop an easy-to-use prognostic calculator for busy clinics based on clinical, radiological, and laboratory factors for patients with metastatic prostate cancer treated with ARAT.
Day 0: Approval of the project
Day 30: Data transfer
Day 60: Data processing (data re-coding/formatting)
Day 90: Data analysis
Day 120: Manuscript writing
Day 180: Manuscript submission
- Abstract presentation in ASCO Annual Meeting 2023
- Submission of manuscript first-quartile oncology journals: Journal of Clinical Oncology, JAMA Oncology, European Urology, Annals of Oncology
1. National Comprehensive Cancer Network: Prostate Cancer (Version 4.2022),
2. Sayegh N, Swami U, Agarwal N: Recent Advances in the Management of Metastatic Prostate Cancer. JCO Oncol Pract:OP2100206, 2021
3. Swami U, Sinnott JA, Haaland B, et al: Treatment Pattern and Outcomes with Systemic Therapy in Men with Metastatic Prostate Cancer in the Real-World Patients in the United States. Cancers (Basel) 13, 2021
4. Goldkorn A, Tangen C, Plets M, et al: Baseline Circulating Tumor Cell Count as a Prognostic Marker of PSA Response and Disease Progression in Metastatic Castrate-Sensitive Prostate Cancer (SWOG S1216). Clin Cancer Res 27:1967-1973, 2021
5. Hussain M, Tangen CM, Berry DL, et al: Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med 368:1314-25, 2013
6. Chi KN, Saad F, Chowdhury S, et al: Pd34-11Prostate-Specific Antigen Kinetics in Patients with Advanced Prostate Cancer Treated with Apalutamide: Results from the Titan and Spartan Studies. Journal of Urology 206, 2021
7. Fizazi K, Tran N, Fein L, et al: Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med 377:352-360, 2017
8. Labe SA, Wang X, Lehrer EJ, et al: Identification and Validation of the Prognostic Impact of Metastatic Prostate Cancer Phenotypes. Clin Genitourin Cancer 20:371-380, 2022
9. Roy S, Sun Y, Wallis CJD, et al: Development and validation of a multivariable prognostic model in de novo metastatic castrate sensitive prostate cancer. Prostate Cancer Prostatic Dis, 2022