scholarly journals Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer: Long-Term Survival Analysis of the Randomized Phase III E3805 CHAARTED Trial

2018 ◽  
Vol 36 (11) ◽  
pp. 1080-1087 ◽  
Author(s):  
Christos E. Kyriakopoulos ◽  
Yu-Hui Chen ◽  
Michael A. Carducci ◽  
Glenn Liu ◽  
David F. Jarrard ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Volume ◽  
Phase Iii ◽  
Cancer Trial ◽  
Term Survival ◽  
Chemohormonal Therapy ◽  
Androgen Ablation ◽  
Hormone Sensitive ◽  
Low Volume

Purpose Docetaxel added to androgen-deprivation therapy (ADT) significantly increases the longevity of some patients with metastatic hormone-sensitive prostate cancer. Herein, we present the outcomes of the CHAARTED (Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) trial with more mature follow-up and focus on tumor volume. Patients and Methods In this phase III study, 790 patients with metastatic hormone-sensitive prostate cancer were equally randomly assigned to receive either ADT in combination with docetaxel 75 mg/m2 for up to six cycles or ADT alone. The primary end point of the study was overall survival (OS). Additional analyses of the prospectively defined low- and high-volume disease subgroups were performed. High-volume disease was defined as presence of visceral metastases and/or ≥ four bone metastases with at least one outside of the vertebral column and pelvis. Results At a median follow-up of 53.7 months, the median OS was 57.6 months for the chemohormonal therapy arm versus 47.2 months for ADT alone (hazard ratio [HR], 0.72; 95% CI, 0.59 to 0.89; P = .0018). For patients with high-volume disease (n = 513), the median OS was 51.2 months with chemohormonal therapy versus 34.4 months with ADT alone (HR, 0.63; 95% CI, 0.50 to 0.79; P < .001). For those with low-volume disease (n = 277), no OS benefit was observed (HR, 1.04; 95% CI, 0.70 to 1.55; P = .86). Conclusion The clinical benefit from chemohormonal therapy in prolonging OS was confirmed for patients with high-volume disease; however, for patients with low-volume disease, no OS benefit was discerned.

Impact on overall survival (OS) with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer (mPrCa): An ECOG-led phase III randomized trial.

2014 ◽  
Vol 32 (18_suppl) ◽  
pp. LBA2-LBA2 ◽  
Author(s):  
Christopher Sweeney ◽  
Yu-Hui Chen ◽  
Michael Anthony Carducci ◽  
Glenn Liu ◽  
David Frasier Jarrard ◽  
...  
Keyword(s):  
High Volume ◽  
Phase Iii ◽  
Eligibility Criteria ◽  
Chemohormonal Therapy ◽  
Visceral Metastases ◽  
Skeletal Related Events ◽  
Hormone Sensitive ◽  
Ecog Ps ◽  
Clinical Trial Information

LBA2 Background: Docetaxel (D) improves OS of men with mPrCa who have progressed on androgen deprivation therapy (ADT). We aimed to assess the benefit of upfront chemohormonal therapy for metastatic PrCa. Methods: 1:1 randomization to ADT alone or ADT + D dosed 75mg/m2 every 3 weeks for 6 cycles within 4 month (mos) of starting ADT. Stratification factors: high volume (HV) vs. low volume (LV) disease (HV: visceral metastases and/or 4 or more bone metastases); anti-androgen use beyond 30 days; Age ≥70 vs. < 70 years; ECOG PS 0-1 vs. 2; Prior adjuvant ADT > 12 vs. ≤ 12 mos; FDA approved drug for delaying skeletal related events. Key eligibility criteria: suitable organ and neurological function for D; adjuvant ADT ≤ 24 mos and no progression within 12 mos of adjuvant ADT. OS was the primary endpoint and the study was powered to assess for a 33.3% improvement in median OS (80% power and 1-sided alpha=2.5%). Projected median OS for ADT alone: HV-33 mos; LV-67 mos. Results: 790 men were accrued from 7/28/06 to 11/21/2012: ADT N=393; ADT + D: N=397; balanced for demographic, stratification and disease factors. Median age: 63 years (range: 36 to 91); 98% ECOG PS 0 or 1; 89% Caucasian; 24% prior radiotherapy, 24% prior prostatectomy; HV 64% on ADT and 67% on ADT + D. Data released after 4th interim analysis in Sept 2013 when O’Brien Fleming upper boundary was crossed with 53.1% information. This report reflects 1/16/2014 data with median follow-up of 29 mos with 137 deaths on ADT alone vs. 104 deaths on ADT+D. ADT+D: Grade (G) 3/4 Neutropenic fever: 4%/2%; G3 neuropathy: 1% sensory, 1% motor; 1 death due to treatment (no deaths due to treatment on ADT). Efficacy data is in the table below. After disease progression, 123 pts on ADT alone and 45 pts on ADT + D received docetaxel. Conclusions: ADT + D improves OS over ADT alone in men with HV mPrCa. Longer follow-up is needed for men with LV mPrCa. Clinical trial information: NCT00309985. [Table: see text]

scholarly journals Seven-Month Prostate-Specific Antigen Is Prognostic in Metastatic Hormone-Sensitive Prostate Cancer Treated With Androgen Deprivation With or Without Docetaxel

2018 ◽  
Vol 36 (4) ◽  
pp. 376-382 ◽  
Author(s):  
Lauren C. Harshman ◽  
Yu-Hui Chen ◽  
Glenn Liu ◽  
Michael A. Carducci ◽  
David Jarrard ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Prostate Specific Antigen ◽  
Multivariable Analysis ◽  
Specific Antigen ◽  
Androgen Deprivation ◽  
Androgen Ablation ◽  
Hormone Sensitive ◽  
Low Volume

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.

scholarly journals Genomic Profiles of De Novo High- and Low-Volume Metastatic Prostate Cancer: Results From a 2-Stage Feasibility and Prevalence Study in the STAMPEDE Trial

2020 ◽  
pp. 882-897 ◽  
Author(s):  
Clare Gilson ◽  
Fiona Ingleby ◽  
Duncan C. Gilbert ◽  
Marina A. Parry ◽  
Nafisah B. Atako ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Chromatin Remodeling ◽  
Metastatic Prostate Cancer ◽  
De Novo ◽  
High Volume ◽  
Pi3k Pathway ◽  
Mismatch Repair Gene ◽  
Copy Number Loss ◽  
Hormone Sensitive ◽  
Low Volume

PURPOSE The STAMPEDE trial recruits men with newly diagnosed, high-risk, hormone-sensitive prostate cancer. To ascertain the feasibility of targeted next-generation sequencing (tNGS) and the prevalence of baseline genomic aberrations, we sequenced tumor and germline DNA from patients with metastatic prostate cancer (mPCa) starting long-term androgen-deprivation therapy (ADT). METHODS In a 2-stage approach, archival, formalin-fixed, paraffin-embedded (FFPE) prostate tumor core biopsy samples were retrospectively subjected to 2 tNGS assays. Prospective enrollment enabled validation using tNGS in tumor and germline DNA. RESULTS In stage 1, tNGS data were obtained from 185 tumors from 287 patients (65%); 98% had de novo mPCa. We observed PI3K pathway aberrations in 43%, due to PTEN copy-number loss (34%) and/or activating mutations in PIK3 genes or AKT (18%) and TP53 mutation or loss in 33%. No androgen receptor ( AR) aberrations were detected; RB1 loss was observed in < 1%. In stage 2, 93 (92%) of 101 FFPE tumors (biopsy obtained within 8 months) were successfully sequenced prospectively. The prevalence of DNA damage repair (DDR) deficiency was 14% (somatic) and 5% (germline). BRCA2 mutations and mismatch repair gene mutations were exclusive to high-volume disease. Aberrant DDR (22% v 15%), Wnt pathway (16% v 4%), and chromatin remodeling (16% v 8%) were all more common in high-volume compared with low-volume disease, but the small numbers limited statistical comparisons. CONCLUSION Prospective genomic characterization is feasible using residual diagnostic tumor samples and reveals that the genomic landscapes of de novo high-volume mPCa and advanced metastatic prostate cancer have notable similarities (PI3K pathway, DDR, Wnt, chromatin remodeling) and differences ( AR, RB1). These results will inform the design and conduct of biomarker-directed trials in men with metastatic hormone-sensitive prostate cancer.

scholarly journals Stratification of Prognoses based on Criteria from Clinical Trials of Metastatic Hormone-sensitive Prostate Cancer

2021 ◽  
Author(s):  
Hyun Kyu Ahn ◽  
Jeong Woo Yoo ◽  
Kyo Chul Koo ◽  
Byung Ha Chung ◽  
Kwang Suk Lee
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Liver Metastasis ◽  
Bone Metastasis ◽  
High Volume ◽  
Classification Systems ◽  
Oncologic Outcomes ◽  
Visceral Metastasis ◽  
Hormone Sensitive ◽  
Low Volume

Abstract Background: Oncologic outcomes in metastatic hormone-sensitive prostate cancer (mHSPC) are extremely heterogeneous. We aimed to (1) stratify the prognosis in mHSPC patients according to criteria for high-volume disease, as defined in clinical trials, and (2) identify the combinations of unfavorable risk factors.Methods: This retrospective study reviewed 623 patients who were diagnosed with mHSPC between 1996 and 2014. The prognoses of mHSPC patients were stratified by criteria from the GETUG15, CHAARTED, STAMPEDE, and LATITUDE trials. The exclusion criteria were incomplete clinical data, docetaxel chemotherapy with upfront options, and metastatic disease without proper management after initial diagnosis.Results: All 485 patients (median follow-up=36.1 months) were categorized according to stage: M1a (70, 14.4%), M1b (367, 75.7%), and M1c (48, 9.9%). Significant differences in overall survival (OS) and cancer-specific survival (CSS) were found among the groups with low-volume disease, as classified by four clinical trials (log-rank p=0.001 and p<0.001, respectively). Bone metastasis volume and liver metastasis were independent predictors of prognosis. According to disease classification under NCCN guidelines, the prognosis of CSS between low-volume disease patients and M1c patients (no bone metastasis and low-volume bone metastasis) was not significantly different. Additionally, the prognosis of CSS did not significantly differ between M1c (high-volume bone metastasis and visceral metastasis, except liver) and M1b (high-volume bone metastasis) patients.Conclusions: The prognoses of patients with low-volume disease, based on several classification systems, were heterogeneous. Except for lung or liver metastasis, the combination of visceral metastasis with no/low-volume bone disease should be considered as a proxy of less aggressive disease in patients presenting with mHSPC.

Why Chemotherapy Should be Given Early for Men with Metastatic Prostate Cancer

2015 ◽  
pp. e263-e269 ◽  
Author(s):  
Leonel F. Hernandez-Aya ◽  
Maha Hussain
Keyword(s):  
Prostate Cancer ◽  
De Novo ◽  
High Volume ◽  
High Response Rate ◽  
Phase Iii ◽  
Incurable Disease ◽  
Castration Resistant ◽  
Castrate Resistant Prostate Cancer ◽  
Hormone Sensitive ◽  
Castrate Resistant

Metastatic hormone-sensitive prostate cancer (mHSPC) is an incurable disease, and despite a high response rate to androgen-deprivation therapy (ADT), outcomes have not significantly changed for many decades. Earlier attempts at multitargeted strategies with the addition of cytotoxic chemotherapy to ADT did not affect survival. As more effective therapies are emerging, including cytotoxic therapy for patients with metastatic castrate-resistant prostate cancer (mCRPC), there is increasing interest for testing these drugs earlier in the disease course. The premise is that agents with clinical benefit in advanced mCRPC may have a better effect if used preemptively before the development of significant resistance and to attack earlier de novo androgen resistant/independent clones. The recent results of the phase III clinical trial E3805 investigating ADT with or without docetaxel in mHSPC provide compelling support for this strategy. Docetaxel combined with ADT significantly improved overall survival from 44 to 57.6 months (p = 0.0003), particularly in patients with high-volume disease (from 32.2 to 49.2 months; p = 0.0006). Longer follow-up is needed to assess the effect on patients with low disease burden. Further studies are needed to further maximize the antitumor effect in patients with mHSPC and to investigate the effects of advancing therapy to this disease setting on the efficacy of respective agents in the castration-resistant setting.

Androgen deprivation therapy (ADT) plus docetaxel (D) versus ADT alone for hormone-naïve metastatic prostate cancer (PCa): Long-term analysis of the GETUG-AFU 15 phase III trial.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 140-140 ◽  
Author(s):  
Gwenaelle Gravis ◽  
Jean-Marie Boher ◽  
Florence Joly ◽  
Stephane Oudard ◽  
Laurence Albiges ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
High Volume ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Intention To Treat ◽  
Original Analysis ◽  
Definition Of

140 Background: ADT is standard treatment for metastatic PCa. Recently, the E3805 trial reported a survival benefit for (ADT+D) in high volume disease (HVD) patients, whereas the GETUG-15 trial did not demonstrate a survival improvement among a less selected group of patients (pts) with hormone-naïve metastatic PCa. We report an updated analysis of overall survival (OS) of the GETUG 15 trial and aligned the definition of HVD and low volume disease (LVD) subgroups. Methods: Long-termOS was analyzed in the intention-to-treat population (n=385 pts). Additionally, we retrospectively assessed the tumor volume as defined per E3805criteria in all patients enrolled in GETUG 15. Results: See Table. With a median follow-up of 82.9 months (95%CI [80.5-84.3]) (vs 50 months (95%CI [80.5-84.3] in the original analysis), 212 patients (55%) have died. The median OS is 46.5 [39.1-60.6] and 60.9 months [46.1-71.4] in the ADT and in the ADT + D arms, respectively (HR: 0.9 [95%CI: 0.7-1.2]). In HVD patients (n=183, 47.5%), median OS rates were 35.1 months [29.9-44.2] in the ADT alone arm and 39 months [28-52.6] in the ADT+D arm (HR: 0.8 [0.6-1.2]). Conclusions: With longer follow-up, the addition of docetaxel to ADT did not significantly improve OS in patients with hormone-naïve metastatic prostate cancer. In the retrospective analysis using aligned definition of volume of metastasis as E3805, the HVD outcomes were similar to E3805 for ADT alone and there was a non-significant 4 months increase in OS with ADT+D, in this underpowered subset. Clinical trial information: 00104715. [Table: see text]

Influence of CHAARTED, STAMPEDE, and LATITUDE eligibility criteria on utilization of abiraterone (A) and docetaxel (D).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 301-301
Author(s):  
Shruti Parshad ◽  
Urban Emmenegger
Keyword(s):  
Prostate Cancer ◽  
Treatment Duration ◽  
Medical Oncology ◽  
High Volume ◽  
Patient Characteristics ◽  
Phase Iii ◽  
Eligibility Criteria ◽  
Drug Access ◽  
Low Volume ◽  
Phase Iii Studies

301 Background: A and D improve the survival of men with high-risk localized or metastatic hormone-naïve prostate cancer (HNPC) when combined with androgen deprivation therapy (ADT). However, the two drugs differ regarding side effects, treatment duration, and associated costs. Furthermore, different eligibility criteria were used in the seminal phase III studies. Since the latter may impact on drug access in many constituencies, we decided to study how applying the eligibility criteria of CHAARTED, STAMPEDE and LATITUDE for drug funding purposes might influence the utilization of A versus D. Methods: 102 men with HNPC were referred from 06/2014 to 09/2017 to the medical oncology service at Odette Cancer Centre (Toronto/ON, Canada) for consideration of additional systemic therapy secondary to ADT. After extraction of baseline patient characteristics, we applied the eligibility criteria of CHAARTED (both high-volume [HV] and low-volume [LV] definition), STAMPEDE, and LATITUDE to determine the rate of men qualifying for treatment with A, D, or either of the two agents. Results: 98.0, 69.6, 28.4, and 47.1 percent of all 102 men fulfilled the STAMPEDE, CHAARTED-HV, CHAARTED-LV, and LATITUDE criteria, respectively. Considering that A funding for HNPC therapy is pending in Ontario, and that D funding is limited to men with CHAARTED-HV disease, the rate of D therapy was 62.0, 69.0, and 77.1 percent of patients conforming to STAMPEDE, CHAARTED-HV, and LATITUDE, respectively. 42 of 48 men (87.5%) conforming to LATITUDE would also be candidates for D, whereas 42 of 71 CHAARTED-HV patients (59.2%) would be eligible for A as alternative treatment. Hence, while all men fulfilling the STAMPEDE criteria (100 of 102, 98%) could be considered for either A or D, only 42 of 102 patients (41.2%) would be candidates for both of the drugs if the CHAARTED-HV and LATITUDE criteria were applied. Conclusions: In our patient population, applying the more restrictive CHAARTED-HV and LATITUDE criteria - as opposed to STAMPEDE - would result in around 30% or 50% fewer men offered D or A secondary to ADT, respectively. In addition, only around 40% of men would conform to both CHAARTED-HV and LATITUDE, and thus be candidates for both drugs.

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