Dataset Information

Adjusting Overall Survival Estimates for Treatment Switching in Metastatic, Castration-Sensitive Prostate Cancer: Results from the LATITUDE Study.

ABSTRACT: BACKGROUND:LATITUDE was the first phase 3 trial examining the survival benefit of adding abiraterone acetate (AA)?+?prednisone (P) to androgen-deprivation therapy (ADT) in newly diagnosed metastatic, castration-sensitive prostate cancer (mCSPC). Due to significant improvement in overall survival after the first interim analysis, patients in the placebos?+?ADT arm could switch to AA?+?P?+?ADT during an open-label extension. As in other studies where switching is allowed, statistical adjustments are needed to assess the real benefit of new drugs. PATIENTS AND METHODS:This was a post hoc analysis to estimate the true survival benefit of AA?+?P?+?ADT in patients with newly diagnosed mCSPC by applying statistical adjustments commonly used to adjust for treatment switching. RESULTS:Of 112 patients still receiving placebos?+?ADT at the first interim analysis, 72 switched to AA?+?P?+?ADT during the open-label extension. Final analysis was conducted after median follow-up of 51.8 months. Compared to the placebos?+?ADT arm, the risk of death in the AA?+?P?+?ADT arm was 34% lower [hazard ratio (HR)?=?0.663 (95% confidence interval 0.566-0.778)] by unadjusted intent-to-treat analysis, 37% lower [HR?=?0.629 (95% confidence interval 0.526-0.753)] by rank preserving structure failure time modeling, and 38% lower [HR?=?0.616 (95% confidence interval 0.524-0.724)] by inverse probability of censoring weights. CONCLUSIONS:Analyses adjusting for treatment switching using two different statistical approaches confirm the improved survival benefit of adding AA?+?P to ADT in patients with newly diagnosed mCSPC. TRIAL REGISTRATION:ClinicalTrials.gov identifier NCT01715285.

SUBMITTER: Feyerabend S

PROVIDER: S-EPMC6875513 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Adjusting Overall Survival Estimates for Treatment Switching in Metastatic, Castration-Sensitive Prostate Cancer: Results from the LATITUDE Study.

Feyerabend Susan S Saad Fred F Perualila Nolen Joy NJ Van Sanden Suzy S Diels Joris J Ito Tetsuro T De Porre Peter P Fizazi Karim K

Targeted oncology 20191201 6

<h4>Background</h4>LATITUDE was the first phase 3 trial examining the survival benefit of adding abiraterone acetate (AA) + prednisone (P) to androgen-deprivation therapy (ADT) in newly diagnosed metastatic, castration-sensitive prostate cancer (mCSPC). Due to significant improvement in overall survival after the first interim analysis, patients in the placebos + ADT arm could switch to AA + P + ADT during an open-label extension. As in other studies where switching is allowed, statistical adjus ...[more]

PMID: 31754962

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Project description:IntroductionEvaluating overall survival in randomized controlled trials (RCTs) can often be confounded by bias introduced by treatment switching. SERAPHIN was a large RCT that evaluated the effects of long-term treatment with the endothelin receptor antagonist macitentan in patients with pulmonary arterial hypertension. In an intent-to-treat (ITT) analysis, a non-significant decrease in the risk of all-cause mortality up to study closure was reported with macitentan 10 mg versus placebo. As patients could switch treatment when experiencing symptoms of disease progression, this analysis attempts to adjust for the confounding effects on overall survival.MethodsThe inverse probability of censoring weighted (IPCW) and rank-preserving structural failure time (RPSFT) models were used to estimate the treatment effect on overall mortality had there been no treatment switching in SERAPHIN. Time to all-cause death was evaluated up to study closure. Treatment switching was defined as patients in the placebo group switching to open-label macitentan 10 mg, and patients in the macitentan 10 mg group prematurely discontinuing macitentan.ResultsBy study closure, 73.2% (183/250) of patients in the placebo group had switched to macitentan 10 mg. Among these patients, exposure time to macitentan 10 mg represented 28.2% of total study treatment exposure (cumulative exposure 134.6 patient-years). At study closure, 24.8% (60/242) of patients in the macitentan 10 mg group were not receiving open-label macitentan; mean time not receiving macitentan was 44.3 weeks. The adjusted hazard ratios (HR) for overall survival using the IPCW and RPSFT methods were lower (HR 0.42, 95% confidence interval [CI] 0.22, 0.81; p = 0.009, and HR 0.33, 95% CI 0.04, 2.83, respectively) than the ITT unadjusted HR (0.80, 95% CI 0.51, 1.24).ConclusionThese results from the current analyses indicate that in SERAPHIN, the standard ITT analysis was confounded by treatment switching resulting in an underestimation of the benefit of macitentan 10 mg on overall survival. By adjusting for switching, the IPCW and RPSFT models estimated a 58% and 67% reduction in risk of mortality, respectively, with macitentan 10 mg versus placebo.Trial registrationClinicalTrials.gov identifier: NCT00660179.

Project description:ObjectiveRecently, hormonal therapy using abiraterone acetate, a second-generation androgen receptor axis-targeted agent, was reported to improve overall survival and progression-free survival in men with LATITUDE-high-risk metastatic castration-sensitive prostate cancer. This observational multicenter study aimed to assess the efficacy of upfront abiraterone acetate in Japanese patients with LATITUDE-high-risk metastatic castration-sensitive prostate cancer.MethodsThe present study included 112 Japanese patients with LATITUDE-high-risk metastatic castration-sensitive prostate cancer who received upfront abiraterone acetate at four institutions belonging to the Tokai Urologic Oncology Research Seminar group, between January 2018 and September 2020. Progression-free survival and overall survival were assessed, and Cox regression analyses were carried out to evaluate the prognostic significance of upfront abiraterone acetate for progression-free survival.ResultsWithin a median follow-up period of 13 months, the progression-free survival and overall survival rates were 76.8% and 89.3%, respectively. Both univariate and multivariable Cox regression analyses showed that the presence of Gleason pattern 5, performance status and hemoglobin were independent predictors of progression-free survival. The patients were subsequently divided into three groups as follows: group 1, 17 patients negative for these three independent progression-free survival predictors; group 2, 49 patients with one positive independent progression-free survival predictor; and group 3, 45 patients with two or three independent progression-free survival predictors. Progression-free survival was significantly different among these three groups (P < 0.001).ConclusionUpfront abiraterone acetate might provide satisfactory outcomes for Japanese patients with LATITUDE-high-risk metastatic castration-sensitive prostate cancer. Gleason pattern 5, performance status and hemoglobin are potential predictors of progression-free survival in Japanese patients with LATITUDE-high-risk metastatic castration-sensitive prostate cancer who received upfront abiraterone acetate.

Project description:BackgroundAbiraterone acetate plus prednisone with androgen deprivation therapy is a standard treatment option for patients with high-risk metastatic castration-sensitive prostate cancer (mCSPC). However, no data are available on the optimal subsequent treatment option in patients treated with abiraterone acetate plus prednisone for high-risk mCSPC.ObjectiveWe aimed to compare the clinical outcomes of subsequent therapy after discontinuation of abiraterone acetate plus prednisone in patients with high-risk mCSPC.MethodsOverall survival and time to treatment failure from initiation of subsequent therapies were estimated by applying a marginal structural Cox proportional hazards model using inverse probability of treatment weighting with a change of time scale to time on treatment.ResultsA total of 217 patients received subsequent therapies: 127 received chemotherapy, 49 received non-chemotherapy, and 41 received other treatments. For overall survival, when adjusted with the marginal structural Cox proportional hazards model using inverse probability of treatment weighting, the hazard ratio was 1.212 (95% confidence interval [CI] 0.742-1.979) for chemotherapy versus non-chemotherapy, 0.534 (95% CI 0.267-1.066) for non-chemotherapy versus other treatments, and 0.635 (95% CI 0.317-1.271) for chemotherapy versus other treatments. For time to treatment failure, the hazard ratio was 1.287 (95% CI 0.832-1.989) for chemotherapy versus non-chemotherapy, 0.785 (95% CI 0.486-1.269) for non-chemotherapy versus other treatments, and 0.898 (95% CI 0.612-1.318) for chemotherapy versus other treatments.ConclusionsNo differences were observed between the treatment effects of chemotherapy and non-chemotherapy in patients with high-risk mCSPC after abiraterone acetate plus prednisone. These findings suggest that life-extending subsequent therapy after abiraterone acetate plus prednisone for mCSPC should be chosen at the physician's discretion and patient's preference.Clinical trial registrationClinicalTrials.gov, NCT01715285, registered 26 October, 2012.

Project description:ImportanceThe adrenal-restrictive HSD3B1(1245A) allele limits extragonadal dihydrotestosterone synthesis, whereas the adrenal-permissive HSD3B1(1245C) allele augments extragonadal dihydrotestosterone synthesis. Retrospective studies have suggested an association between the adrenal-permissive allele, the frequency of which is highest in white men, and early development of castration-resistant prostate cancer (CRPC).ObjectiveTo examine the association between the adrenal-permissive HSD3B1(1245C) allele and early development of CRPC using prospective data.Design, setting, and participantsThe E3805 Chemohormonal Therapy vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) was a large, multicenter, phase 3 trial of castration with or without docetaxel treatment in men with newly diagnosed metastatic prostate cancer. From July 28, 2006, through December 31, 2012, 790 patients underwent randomization, of whom 527 had available DNA samples. In this study, the HSD3B1 germline genotype was retrospectively determined in 475 white men treated in E3805 CHAARTED, and clinical outcomes were analyzed by genotype. Data analysis was performed from July 28, 2006, to October 17, 2018.InterventionsMen were randomized to castration plus docetaxel, 75 mg/m2, every 3 weeks for 6 cycles or castration alone.Main outcomes and measuresTwo-year freedom from CRPC and 5-year overall survival, with results stratified by disease volume. Patients were combined across study arms according to genotype to assess the overall outcome associated with genotype. Secondary analyses by treatment arm evaluated whether the docetaxel outcome varied with genotype.ResultsOf 475 white men with DNA samples, 270 patients (56.8%) inherited the adrenal-permissive genotype (≥1 HSD3B1[1245C] allele). Mean (SD) age was 63 (8.7) years. Freedom from CRPC at 2 years was diminished in men with low-volume disease with the adrenal-permissive vs adrenal-restrictive genotype: 51.0% (95% CI, 40.9%-61.2%) vs 70.5% (95% CI, 60.0%-80.9%) (P = .01). Overall survival at 5 years was also worse in men with low-volume disease with the adrenal-permissive genotype: 57.5% (95% CI, 47.4%-67.7%) vs 70.8% (95% CI, 60.3%-81.3%) (P = .03). Hazard ratios were 1.89 (95% CI, 1.13-3.14; P = .02) for CRPC and 1.74 (95% CI, 1.01-3.00; P = .045) for death. There was no association between genotype and outcomes in men with high-volume disease. There was no interaction between genotype and benefit from docetaxel.Conclusions and relevanceInheritance of the adrenal-permissive HSD3B1 genotype is associated with earlier castration resistance and shorter overall survival in men with low-volume metastatic prostate cancer and may help identify men more likely to benefit from escalated androgen receptor axis inhibition beyond gonadal testosterone suppression.

Project description:BackgroundEmerging data suggest that metastasis is a spectrum of disease burden rather than a binary state, and local therapies, such as radiation, might improve outcomes in oligometastasis. However, current definitions of oligometastasis are solely numerical.ObjectiveTo characterize the somatic mutational landscape across the disease spectrum of metastatic castration-sensitive prostate cancer (mCSPC) to elucidate a biological definition of oligometastatic CSPC.Design, setting, and participantsThis was a retrospective study of men with mCSPC who underwent clinical-grade sequencing of their tumors (269 primary tumor, 25 metastatic sites). Patients were classified as having biochemically recurrent (ie, micrometastatic), metachronous oligometastatic (≤5 lesions), metachronous polymetastatic (>5 lesions), or de novo metastatic (metastasis at diagnosis) disease.Outcome measurements and statistical analysisWe measured the frequency of driver mutations across metastatic classifications and the genomic associations with radiographic progression-free survival (rPFS) and time to castrate-resistant prostate cancer (CRPC).Results and limitationsThe frequency of driver mutations in TP53 (p = 0.01), WNT (p = 0.08), and cell cycle (p = 0.04) genes increased across the mCSPC spectrum. TP53 mutation was associated with shorter rPFS (26.7 vs 48.6 mo; p = 0.002), and time to CRPC (95.6 vs 155.8 mo; p = 0.02) in men with oligometastasis, and identified men with polymetastasis with better rPFS (TP53 wild-type, 42.7 mo; TP53 mutated, 18.5 mo; p = 0.01). Mutations in TP53 (incidence rate ratio [IRR] 1.45; p = 0.004) and DNA double-strand break repair (IRR 1.61; p < 0.001) were associated with a higher number of metastases. Mutations in TP53 were also independently associated with shorter rPFS (hazard ratio [HR] 1.59; p = 0.03) and the development of CRPC (HR 1.71; p = 0.01) on multivariable analysis. This study was limited by its retrospective nature, sample size, and the use of commercially available sequencing platforms, resulting in a limited predefined set of genes examined.ConclusionsSomatic mutational profiles reveal a spectrum of metastatic biology that helps in redefining oligometastasis beyond a simple binary state of lesion enumeration.Patient summaryOligometastatic prostate cancer is typically defined as less than three to five metastatic lesions and evidence suggests that using radiation or surgery to treat these sites improves clinical outcomes. As of now, treatment decisions for oligometastasis are solely defined according to the number of lesions. However, this study suggests that tumor mutational profiles can provide a biological definition of oligometastasis and complement currently used numerical definitions.

Dataset Information

Adjusting Overall Survival Estimates for Treatment Switching in Metastatic, Castration-Sensitive Prostate Cancer: Results from the LATITUDE Study.

Publications

Adjusting Overall Survival Estimates for Treatment Switching in Metastatic, Castration-Sensitive Prostate Cancer: Results from the LATITUDE Study.

Similar Datasets

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