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SWOG S0925: A Randomized Phase II Study of Androgen Deprivation Combined With Cixutumumab Versus Androgen Deprivation Alone in Patients With New Metastatic Hormone-Sensitive Prostate Cancer.

ABSTRACT: Cixutumumab, formerly IMC-A12, is a recombinant human monoclonal immunoglobulin G1 antibody that targets insulin-like growth factor I receptor (IGF-IR). Cixutumumab was synergistic with castration in a hormone-sensitive prostate cancer xenograft model.Patients with new metastatic prostate cancer were randomly assigned within 30 days of initiating androgen deprivation (AD) to cixutumumab added to a luteinizing hormone-releasing hormone agonist with bicalutamide versus AD alone. With 180 patients and one-sided alpha of 0.10, there would be 90% power to detect an absolute 20% difference in undetectable prostate-specific antigen (PSA; ? 0.2 ng/mL) rate at 28 weeks (relative risk, 1.44); this end point was previously strongly correlated with survival. Secondary end points included the proportion of patients with PSA > 4.0 ng/mL, safety and tolerability, circulating tumor cell (CTC) levels, and seven plasma IGF-IR biomarkers. Fisher's exact test was used for the primary end point, and extended Mantel-Haenszel ?(2) test was used for three PSA response categories.The trial accrued 210 eligible patients (105 randomly assigned to each arm). Patient characteristics were similar in both arms. Undetectable PSA rate was 42 (40.0%) of 105 for cixutumumab plus AD and 34 (32.3%) of 105 for AD alone (relative risk, 1.24; one-sided P = .16). Lower baseline CTCs (0 v 1 to 4 v ? 5/7.5 mL whole blood) were associated with higher rate of PSA response (three categories; P = .036) in 39 evaluable patients. IGF-IR biomarkers were not correlated with PSA outcome, and cixutumumab did not significantly change these biomarker levels.Cixutumumab plus AD did not significantly increase the undetectable PSA rate in men with new metastatic hormone-sensitive prostate cancer. CTCs at baseline may carry prognostic value.

SUBMITTER: Yu EY

PROVIDER: S-EPMC4417730 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Project description:BackgroundCixutumumab, a monoclonal antibody targeting insulin-like growth factor I receptor, did not improve undetectable prostate-specific antigen (PSA) rate at 28 weeks when combined with androgen deprivation in the randomized phase II SWOG S0925 trial for patients with new metastatic hormone-sensitive prostate cancer. We now present mature survival analyses, along with pre-specified secondary and exploratory endpoints.MethodsWe randomized 210 patients to androgen deprivation with or without cixutumumab, 105 per treatment arm. We used Kaplan-Meier curves to analyze overall survival, radiographic progression-free survival, and castration resistance-free survival by treatment arm, disease volume, and risk group. We explored differences in survival by treatment arm via covariate-adjusted Cox proportional hazards models adjusted for disease volume and risk.ResultsNo difference was seen between treatment arms in overall survival (HR 1.01 [0.70-1.45]; p = 0.97), radiographic progression-free survival (HR 1.17 [0.85-1.60]; p = 0.35), or castration resistance-free survival (HR 1.02 [0.75-1.41]; p = 0.88). At baseline, 105/198 (53.0%) patients had high-risk features and 119/210 (56.7%) had high-volume disease; 16.7% of patients had discordant classifications of high or low category for risk and volume. Adjusting for risk or volume yielded no differences in overall survival between arms. Inferior survival was observed in high-risk (HR 1.89 [1.29-2.80]; p = 0.001) and high-volume (HR 2.75 [1.84-4.10]; p < 0.0001) disease. Disease volume was a better fit to survival data than risk group (AIC 878.3 vs. 889.2). Compared to patients achieving undetectable PSA at 28 weeks, inferior survival was observed in patients whose PSA was >0.2 to ≤4.0 ng/mL (HR 3.72 [1.99-6.95]; p < 0.0001) or >4.0 ng/mL (HR 7.13 [4.24-11.9]; p < 0.0001).ConclusionsIn new metastatic hormone-sensitive prostate cancer, addition of cixutumumab to androgen deprivation did not improve survival. Baseline risk and disease volume carried prognostic value for this distinct trial population, although disease volume added more prognostic information. PSA treatment response was a strong intermediate endpoint for survival.

Project description:ImportanceBlack patients have been underrepresented in prospective clinical trials of advanced prostate cancer. This study evaluated the efficacy of enzalutamide compared with bicalutamide, with planned subset analysis of Black patients with metastatic hormone-sensitive prostate cancer (mHSPC), which is a disease state responsive to androgen deprivation therapy (ADT).ObjectiveTo compare the efficacy of enzalutamide vs bicalutamide in combination with ADT in men with mHSPC, with a subset analysis of Black patients.Design, setting, and participantsIn this randomized clinical trial, a phase 2 screening design enabled a nondefinitive comparison of the primary outcome by treatment. Patients were stratified by race (Black or other) and bone pain (present or absent). Accrual of at least 30% Black patients was required. This multicenter trial was conducted at 4 centers in the US. Men with mHSPC with no history of seizures and adequate marrow, renal, and liver function were eligible. Data analysis was performed from February 2019 to March 2020.InterventionsParticipants were randomized 1:1 to receive oral enzalutamide (160 mg daily) or bicalutamide (50 mg daily) in addition to ADT.Main outcomes and measuresThe primary end point was the 7-month prostate-specific antigen (PSA) response (SMPR) rate, a previously accepted surrogate for overall survival (OS) outcome. Secondary end points included adverse reactions, time to PSA progression, and OS.ResultsA total of 71 men (median [range] age, 65 [51-86] years) were enrolled; 29 (41%) were Black, 41 (58%) were White, and 1 (1%) was Asian. Thirty-six patients were randomized to receive enzalutamide, and 35 were randomized to receive bicalutamide. Twenty-six patients (37%) had bone pain and 37 patients (52%) had extensive disease. SMPR was achieved in 30 of 32 patients (94%; 95% CI, 80%-98%) taking enzalutamide and 17 of 26 patients (65%; 95% CI, 46%-81%) taking bicalutamide (P = .008) (difference, 29%; 95% CI, 5%-50%). Among Black patients, the SMPR was 93% (95% CI, 69%-99%) among those taking enzalutamide and 42% (95% CI, 19%-68%) among those taking bicalutamide (P = .009); among non-Black patients, the SMPR was 94% (95% CI, 74%-99%) among those taking enzalutamide and 86% (95% CI, 60%-96%) among those taking bicalutamide. The 12-month PSA response rates were 84% with enzalutamide and 34% with bicalutamide.Conclusions and relevanceThe findings of this randomized clinical trial comparing enzalutamide with bicalutamide suggest that enzalutamide is associated with improved outcomes compared with bicalutamide, in terms of the rate and duration of PSA response, in Black patients with mHSPC.Trial registrationClinicalTrials.gov Identifier: NCT02058706.

Project description:Background: Recent randomized clinical trials have examined the efficacy of different combinations of systemic and local treatment approaches for metastatic hormone-sensitive prostate cancer (mHSPC). We compared the efficacy of these combined regimens in order to identify the optimal therapy for specific patient subgroups. Methods: The treatments were abiraterone (ABI), apalutamide (APA), docetaxel (DOC), enzalutamide (ENZ), and radiotherapy (RT) combined with androgen-deprivation therapy (ADT). Five electronic databases were searched up to May 7, 2020 for relevant trials. The risk of bias in the included trials was evaluated with the Cochrane tool. The hazard ratio (HR) with 95% confidence interval (CI) was determined for the included trials and indirect comparisons were performed using the R software. Results: In total, 10 randomized, controlled trials with 11,194 patients were included in the meta-analysis. ADT + RT was superior to ADT monotherapy in terms of overall survival (HR = 0.96, 95% CI: 0.85-1.1) and conferred a survival benefit in a subgroup of low-volume patients (HR = 0.68, 95% CI: 0.54-0.87). Combined systemic treatments were significantly superior to ADT monotherapy in comparisons of survival and prostate-specific antigen response, including in the high-volume subgroup; meanwhile, in the low-volume subgroup only ADT + ENZ (HR = 0.38, 95% CI 0.21-0.69) showed a significant clinical benefit. In the Gleason score <8 subgroup, all combined systemic treatments were superior to ADT monotherapy, but the results were only significant for ADT + APA (HR = 0.56, 95% CI: 0.33-0.95) and ADT + DOC (HR = 0.71, 95% CI: 0.54-0.92). In the Gleason score ≥8 subgroup, ADT monotherapy was inferior (albeit not significantly) to combined treatments. In a ranking of performed comparisons, ADT + ENZ was the optimal regimen, although this was non-significant. Combined therapies also demonstrated superiority in quality-of-life indicators such as time to skeletal events and pain progression. Conclusion: ADT + radiotherapy led to superior outcomes in mHSPC patients with low-volume disease. While all combined systemic regimens confer a survival advantage over ADT monotherapy, the optimal treatment approach for certain mHSPC patient subgroups remains to be determined.

Project description:Purpose We evaluated the relationship between prostate-specific antigen (PSA) and overall survival in the context of a prospectively randomized clinical trial comparing androgen-deprivation therapy (ADT) plus docetaxel with ADT alone for initial metastatic hormone-sensitive prostate cancer. Methods We performed a landmark survival analysis at 7 months using the E3805 Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) database ( ClinicalTrials.gov identifier: NCT00309985). Inclusion required at least 7 months of follow-up and PSA levels at 7 months from ADT initiation. We used the prognostic classifiers identified in a previously reported trial (Southwest Oncology Group 9346) of PSA ≤ 0.2, > 0.2 to 4, and > 4 ng/mL. Results Seven hundred nineteen of 790 patients were eligible for this subanalysis; 358 were treated with ADT plus docetaxel, and 361 were treated with ADT alone. Median follow-up time was 23.1 months. On multivariable analysis, achieving a 7-month PSA ≤ 0.2 ng/mL was more likely with docetaxel, low-volume disease, prior local therapy, and lower baseline PSAs (all P ≤ .01). Across all patients, median overall survival was significantly longer if 7-month PSA reached ≤ 0.2 ng/mL compared with > 4 ng/mL (median survival, 60.4 v 22.2 months, respectively; P < .001). On multivariable analysis, 7-month PSA ≤ 0.2 and low volume disease were prognostic of longer overall survival (all P < 0.01). The addition of docetaxel increased the likelihood of achieving a PSA ≤ 0.2 ng/mL at 7 months (45.3% v 28.8% of patients on ADT alone). Patients on ADT alone who achieved a 7-month PSA ≤ 0.2 ng/mL had the best survival and were more likely to have low-volume disease (56.7%). Conclusion PSA ≤ 0.2 ng/mL at 7 months is prognostic for longer overall survival with ADT for metastatic hormone-sensitive prostate cancer irrespective of docetaxel administration. Adding docetaxel increased the likelihood of a lower PSA and improved survival.

Project description:ObjectiveProstate cancer is the most common nonskin cancer and second most common cause of cancer mortality in older men in the United States (USA) and Western Europe. Androgen-deprivation therapy alone (ADT) remains the first line of treatment in most cases, for metastatic disease. We performed a systematic review and meta-analysis of all randomized controlled trials (RCT) that compared the efficacy and adverse events profile of a chemohormonal therapy (ADT ± docetaxel) for metastatic hormone-naive prostate cancer (mHNPC).MethodsSeveral databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The primary endpoint was overall survival. Data extracted from the studies were combined by using the hazard ratio (HR) or risk ratio (RR) with their corresponding 95% confidence intervals (95% CI).ResultsThe final analysis included 3 trials comprising 2,264 patients (mHNPC). Patients who received the chemohormonal therapy had a longer clinical progression-free survival interval (HR = 0.64; 95% CI: 0.55 to 0.75; p<0.00001), and no heterogeneity (Chi2 = 0.64; df = 1 [p = 0.42]; I2 = 0%). The biochemical progression-free survival (bPFS) also was higher in patients treated with ADT plus docetaxel (HR = 0.63; 95% CI: 0.57 to 0.69; p<0.00001), also with no heterogeneity noted (Chi2 = 0.48; df = 2 [p = 0.79]; I2 = 0%). Finally, the combination of ADT with docetaxel showed a superior overall survival (OS) compared with ADT alone (HR = 0.73; 95% CI: 0.64 to 0.84; p<0.0001), with moderate heterogeneity (Chi2 = 3.84; df = 2 [p = 0.15]; I2 = 48%). A random-effects model analysis was performed, and the results remained favorable to the use of ADT plus docetaxel (HR = 0.73; 95% CI: 0.60 to 0.89; p = 0.002). In the final combined analysis of the high-volume disease patients, the use of the combination therapy also favored an increased overall survival (HR = 0.67; 95% CI: 0.54 to 0.83; p = 0.0003). Regarding adverse events and severe toxicity (grade ≥3), the group receiving the combined therapy had higher rates of neutropenia, febrile neutropenia and fatigue.ConclusionThe combination of ADT with docetaxel improved the clinical progression-free survival, bPFS and OS of patients with mHNPC. A superior OS was seen especially for patients with metastatic and high-volume disease. This contemporary combination therapy may now be offered as a first-line treatment for selected patients.

Project description:BackgroundThere is a need to synthesise the results of numerous randomised controlled trials evaluating the addition of therapies to androgen deprivation therapy (ADT) for men with metastatic hormone-sensitive prostate cancer (mHSPC). This systematic review aims to assess the effects of adding abiraterone acetate plus prednisone/prednisolone (AAP) to ADT.MethodsUsing our framework for adaptive meta-analysis (FAME), we started the review process before trials had been reported and worked collaboratively with trial investigators to anticipate when eligible trial results would emerge. Thus, we could determine the earliest opportunity for reliable meta-analysis and take account of unavailable trials in interpreting results. We searched multiple sources for trials comparing AAP plus ADT versus ADT in men with mHSPC. We obtained results for the primary outcome of overall survival (OS), secondary outcomes of clinical/radiological progression-free survival (PFS) and grade III-IV and grade V toxicity direct from trial teams. Hazard ratios (HRs) for the effects of AAP plus ADT on OS and PFS, Peto Odds Ratios (Peto ORs) for the effects on acute toxicity and interaction HRs for the effects on OS by patient subgroups were combined across trials using fixed-effect meta-analysis.FindingsWe identified three eligible trials, one of which was still recruiting (PEACE-1 (NCT01957436)). Results from the two remaining trials (LATITUDE (NCT01715285) and STAMPEDE (NCT00268476)), representing 82% of all men randomised to AAP plus ADT versus ADT (without docetaxel in either arm), showed a highly significant 38% reduction in the risk of death with AAP plus ADT (HR = 0.62, 95% confidence interval [CI] = 0.53-0.71, p = 0.55 × 10-10), that translates into a 14% absolute improvement in 3-year OS. Despite differences in PFS definitions across trials, we also observed a consistent and highly significant 55% reduction in the risk of clinical/radiological PFS (HR = 0.45, 95% CI = 0.40-0.51, p = 0.66 × 10-36) with the addition of AAP, that translates to a 28% absolute improvement at 3 years. There was no evidence of a difference in the OS benefit by Gleason sum score, performance status or nodal status, but the size of the benefit may vary by age. There were more grade III-IV acute cardiac, vascular and hepatic toxicities with AAP plus ADT but no excess of other toxicities or death.InterpretationAdding AAP to ADT is a clinically effective treatment option for men with mHSPC, offering an alternative to docetaxel for men who are starting treatment for the first time. Future research will need to address which of these two agents or whether their combination is most effective, and for whom.

Project description:BackgroundAndrogen-deprivation therapy (ADT) historically represented the milestone for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC). Recently, combining androgen receptor-targeted agents (ARTA) or docetaxel with ADT significantly improved clinical outcomes in this setting. The efficacy of the combined use of an ARTA with docetaxel and ADT (triplet), however, was unknown, and often conflicting data derived from subgroup analysis of randomized phase III trials. In order to better define the benefits and risks of the triplet in mHSPC, we carried out a systematic review and meta-analysis of available clinical trials.MethodsA literature search with no data restriction using Medline/PubMed, the Cochrane Library, and American Society of Clinical Oncology/European Society for Medical Oncology (ASCO/ESMO) Meeting abstracts was carried out up to April 2022. The meta-analysis was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statements. Overall survival (OS) was the primary endpoint; progression-free survival (PFS) and safety were secondary endpoints. For OS and PFS, summary hazard ratios (HRs) were calculated; for safety, risk ratio (RR) was assessed. Random- or fixed-effects models were used, depending on studies heterogeneity.ResultsFive randomized clinical trials fulfilled the prespecified inclusion criteria. The triplet significantly improved OS (fixed-effect, HR = 0.74; P < 0.00001) and PFS (fixed-effect; HR = 0.50 for clinical PFS, HR = 0.49 for radiological PFS; P < 0.0001) compared with docetaxel plus ADT. We did not show heterogeneity between treatment efficacy and the disease burden, metachronous versus synchronous presentation, concomitant versus sequential strategy. Compared with docetaxel + ADT, the triplet did not increase the risk of adverse events (AEs) (RR = 1.00, P = 0.27 for any-grade AEs; RR = 1.13, P = 0.14 for severe AEs), except for severe hypertension (RR = 1.73, P = 0.001).ConclusionsEmerging evidence supports the combination of an ARTA plus docetaxel and ADT in mHSPC patients. Given the availability of several strategies in this setting, clinical characteristics and drug safety profile may help clinicians select the appropriate treatment for mHSPC patients who are more likely to benefit from treatment intensification.

Project description:PurposeEnzalutamide, a potent androgen-receptor inhibitor, has demonstrated significant benefits in metastatic and nonmetastatic castration-resistant prostate cancer. We evaluated the efficacy and safety of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC).MethodsARCHES (ClinicalTrials.gov identifier: NCT02677896) is a multinational, double-blind, phase III trial, wherein 1,150 men with mHSPC were randomly assigned 1:1 to enzalutamide (160 mg/day) or placebo, plus androgen deprivation therapy (ADT), stratified by disease volume and prior docetaxel chemotherapy. The primary end point was radiographic progression-free survival.ResultsAs of October 14, 2018, the risk of radiographic progression or death was significantly reduced with enzalutamide plus ADT versus placebo plus ADT (hazard ratio, 0.39; 95% CI, 0.30 to 0.50; P < .001; median not reached v 19.0 months). Similar significant improvements in radiographic progression-free survival were reported in prespecified subgroups on the basis of disease volume and prior docetaxel therapy. Enzalutamide plus ADT significantly reduced the risk of prostate-specific antigen progression, initiation of new antineoplastic therapy, first symptomatic skeletal event, castration resistance, and reduced risk of pain progression. More men achieved an undetectable prostate-specific antigen level and/or an objective response with enzalutamide plus ADT (P < .001). Patients in both treatment groups reported a high baseline level of quality of life, which was maintained over time. Grade 3 or greater adverse events were reported in 24.3% of patients who received enzalutamide plus ADT versus 25.6% of patients who received placebo plus ADT, with no unexpected adverse events.ConclusionEnzalutamide with ADT significantly reduced the risk of metastatic progression or death over time versus placebo plus ADT in men with mHSPC, including those with low-volume disease and/or prior docetaxel, with a safety analysis that seems consistent with the safety profile of enzalutamide in previous clinical trials in castration-resistant prostate cancer.

Dataset Information

SWOG S0925: A Randomized Phase II Study of Androgen Deprivation Combined With Cixutumumab Versus Androgen Deprivation Alone in Patients With New Metastatic Hormone-Sensitive Prostate Cancer.

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