Dataset Information

Comparison of Joint and Landmark Modeling for Predicting Cancer Progression in Men With Castration-Resistant Prostate Cancer: A Secondary Post Hoc Analysis of the PREVAIL Randomized Clinical Trial.

ABSTRACT:

Importance

Dynamic prediction models may help predict radiographic disease progression in advanced prostate cancer.

Objective

To assess whether dynamic prediction models aid prognosis of radiographic progression risk, using ongoing longitudinal prostate-specific antigen (PSA) assessments.

Design, setting, and participants

This prognostic study used data from the PREVAIL study to compare dynamic models for predicting disease progression. The PREVAIL study was a phase 3, multinational, double-blind, placebo-controlled randomized clinical trial of enzalutamide for prostate cancer conducted from September 2010 to September 2012. A total of 773 men with metastatic castration-resistant prostate cancer (CRPC) who had never received chemotherapy and had no baseline visceral disease were treated with enzalutamide. For illustration, 4 patients were selected based on PSA kinetics or PSA response in case studies. Data were analyzed from July 2018 to September 2019.

Main outcomes and measures

Landmark and joint models were applied to dynamically predict radiographic progression-free survival (PFS) using longitudinal PSA profile, baseline PSA, lactate dehydrogenase, and hemoglobin levels. The main outcome was radiographic PFS as predicted using landmark and joint models. Current PSA and PSA change were considered longitudinal biomarkers possibly associated with radiographic PFS. Predictive performance was evaluated using Brier score for overall prediction errors (PEs) and area under the curve (AUC) for model discriminative capability. Case studies were illustrated using dynamic prediction plots.

Results

A total of 763 men with metastatic CRPC treated with enzalutamide (mean [SD] age, 71.2 [8.5] years; mean [SD] body mass index [calculated as weight in kilograms divided by height in meters squared], 28.4 [4.6]) were included in the analysis. Current PSA and PSA change were associated with radiographic PFS in all models. Adding the PSA slope, compared with the landmark models using current PSA alone, improved the prediction of 5-month prospect of radiographic progression, with relative gains of 5.7% in prediction (PE [SE], 0.132 [0.008] vs 0.140 [0.008]) and 7.7% in discrimination (AUC [SE], 0.800 [0.018] vs 0.743 [0.018]) at month 10. In joint models with linear vs nonlinear PSA, prediction of 5-month risk of radiographic progression was improved when PSA trajectories were not assumed to be linear, with 8.0% relative gain in prediction (PE [SE], 0.150 [0.006] vs 0.138 [0.005]) and 19.4% relative gain in discrimination (AUC [SE], 0.653 [0.022] vs 0.780 [0.016]) at month 10. Predictions were affected by amount of marker information accumulated and prespecified assumptions. PSA changes affected progression risk more strongly at later vs earlier follow-up.

Conclusions and relevance

This prognostic study found that prediction of radiographic PFS was improved when longitudinal PSA information was added to baseline variables. In a population of patients with metastatic CRPC, dynamic predictions using landmark or joint models may help identify patients at risk of progression.

SUBMITTER: Finelli A

PROVIDER: S-EPMC8207237 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceFor men with metastatic castration-resistant prostate cancer (mCRPC) whose condition is responding to enzalutamide, new unconfirmed bone lesions detected at posttreatment scinitigraphy may reflect an osteoblastic reaction that represents healing, known as pseudoprogression, which can lead to premature discontinuation of therapy.ObjectiveTo determine the association between new unconfirmed lesions detected on a follow-up bone scintigram (bone scan) and outcomes in enzalutamide-treated men with mCRPC.Design, setting, and participantsThis post hoc, retrospective secondary analysis of 1672 enzalutamide-treated men from 2 phase 3, randomized mCRPC studies (PREVAIL and AFFIRM) before or after treatment with docetaxel was conducted from April 12, 2018, to July 25, 2019. Participants were men from the enzalutamide groups of the 2 studies with a decrease in prostate-specific antigen level at any time or with stable disease or soft-tissue disease responding to treatment based onradiologic findings.InterventionEnzalutamide, 160 mg once daily.Main outcomes and measuresThe clinical significance of new lesions detected on the first (early) or second (late) posttreatment bone scan, without an unfavorable change in prostate-specific antigen level or soft-tissue progression, was investigated. Associations of new unconfirmed lesions with radiographic progression-free survival, overall survival, decrease in prostate-specific antigen level, objective response in soft tissue, and quality of life were evaluated.ResultsAmong the 643 men (median age, 72 years [range, 43-93 years]) in PREVAIL, early and late unconfirmed lesions were observed in 177 men (27.5%) with stable disease or disease responding to enzalutamide. Among the 404 men (median age, 70 years [range, 41-88 years]) in AFFIRM, early and late unconfirmed lesions were observed in 73 men (18.1%) with stable disease or disease responding to enzalutamide. In PREVAIL, men with new unconfirmed lesions had median radiographic progression-free survival (hazard ratio [HR], 1.37 [95% CI, 0.81-2.30]; P = .23) and median overall survival (HR, 1.25 [95% CI, 0.85-1.83]) in the chemotherapy-naive setting similar to men those of men without such new lesions. In AFFIRM, the median overall survival (HR, 1.94 [95% CI, 1.10-3.44]) was reduced among men with unconfirmed bone lesions, but the median radiographic progression-free survival was not reduced (HR, 1.21 [95% CI, 0.83-1.75]; P = .32). Quality of life over time was similar regardless of the presence of new unconfirmed lesions detected on a follow-up bone scan in either setting.Conclusions and relevanceThese results suggest that new unconfirmed lesions detected on follow-up bone scans may represent pseudoprogression in men with mCRPC and are indicative of a favorable treatment response to enzalutamide. The detection of new unconfirmed bone lesions in men with mCRPC that responded to treatment with enzalutamide after docetaxel appears to be associated with worse overall survival and may represent true progression, thus highlighting the need for improved functional bone metastasis imaging.Trial registrationClinicalTrials.gov Identifiers: NCT01212991 and NCT00974311.

Project description:Enzalutamide is an androgen receptor (AR) inhibitor that acts on different steps in the AR signaling pathway. In PREVAIL, an international, phase III, double-blind, placebo-controlled trial, enzalutamide significantly reduced the risk of radiographic progression by 81% (hazard ratio [HR], 0.19; P?<?.0001) and reduced the risk of death by 29% (HR, 0.71; P?<?.0001) compared with placebo in chemotherapy-naïve men with metastatic castration-resistant prostate cancer.To evaluate treatment effects, safety, and pharmacokinetics of enzalutamide in East Asian patients from the PREVAIL trial, we performed a post hoc analysis of the Japanese, Korean, and Singaporean patients. PREVAIL enrolled patients with asymptomatic or mildly symptomatic chemotherapy-naïve metastatic castration-resistant prostate cancer who had progressed on androgen deprivation therapy. During the study, patients received enzalutamide (160?mg/d) or placebo (1:1) until death or discontinuation because of radiographic progression or skeletal-related event and initiation of subsequent therapy. Centrally assessed radiographic progression-free survival (rPFS) and overall survival (OS) were coprimary endpoints. The secondary endpoints of the PREVAIL trial were investigator-assessed rPFS, time to initiation of chemotherapy, time to prostate-specific antigen (PSA) progression, and PSA response (?50% decline).Of 1717 patients, 148 patients were enrolled at sites in East Asia (enzalutamide 73, placebo 75). Treatment effect of enzalutamide versus placebo was consistent with that for the overall population as indicated by the HRs (95% confidence interval) of 0.38 (0.10-1.44) for centrally assessed rPFS, 0.59 (0.29-1.23) for OS, 0.33 (0.19-0.60) for time to chemotherapy, and 0.32 (0.20-0.50) for time to PSA progression. In East Asian patients, PSA responses were observed in 68.5% and 14.7% of enzalutamide- and placebo-treated patients, respectively. The enzalutamide plasma concentration ratio (East Asian:non-Asian patients) was 1.12 (90% confidence interval, 1.05-1.20) at 13 weeks. Treatment-related adverse events grade ??3 occurred in 1.4% and 2.7% of enzalutamide- and placebo-treated East Asian patients, respectively.Treatment effects and safety of enzalutamide in East Asian patients were generally consistent with those observed in the overall study population from PREVAIL. CLINICALTRIALS.NCT01212991.

Project description:BackgroundMen with nonmetastatic, castration-resistant prostate cancer and a rapidly rising prostate-specific antigen (PSA) level are at high risk for metastasis. We hypothesized that enzalutamide, which prolongs overall survival among patients with metastatic, castration-resistant prostate cancer, would delay metastasis in men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level.MethodsIn this double-blind, phase 3 trial, we randomly assigned, in a 2:1 ratio, men with nonmetastatic, castration-resistant prostate cancer and a PSA doubling time of 10 months or less who were continuing androgen-deprivation therapy to receive enzalutamide (at a dose of 160 mg) or placebo once daily. The primary end point was metastasis-free survival (defined as the time from randomization to radiographic progression or as the time to death without radiographic progression).ResultsA total of 1401 patients (median PSA doubling time, 3.7 months) underwent randomization. As of June 28, 2017, a total of 219 of 933 patients (23%) in the enzalutamide group had metastasis or had died, as compared with 228 of 468 (49%) in the placebo group. The median metastasis-free survival was 36.6 months in the enzalutamide group versus 14.7 months in the placebo group (hazard ratio for metastasis or death, 0.29; 95% confidence interval, 0.24 to 0.35; P<0.001). The time to the first use of a subsequent antineoplastic therapy was longer with enzalutamide treatment than with placebo (39.6 vs. 17.7 months; hazard ratio, 0.21; P<0.001; such therapy was used in 15% vs. 48% of patients) as was the time to PSA progression (37.2 vs. 3.9 months; hazard ratio, 0.07; P<0.001; progression occurred in 22% vs. 69% of patients). At the first interim analysis of overall survival, 103 patients (11%) receiving enzalutamide and 62 (13%) receiving placebo had died. Adverse events of grade 3 or higher occurred in 31% of the patients receiving enzalutamide, as compared with 23% of those receiving placebo.ConclusionsAmong men with nonmetastatic, castration-resistant prostate cancer with a rapidly rising PSA level, enzalutamide treatment led to a clinically meaningful and significant 71% lower risk of metastasis or death than placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, NCT02003924 .).

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