Defining new standards of care for men with prostate cancer
Authors: Howard I Scher
Journal: The Lancet (2016)

Improving the outcomes of medical or surgical castration for men with prostate cancer has been an elusive goal since the approach was first reported in the 1940s.1Huggins C Effect of orchiectomy and irradiation of cancer of the prostate.Ann Surg. 1942; 115: 1192-1200Crossref PubMed Google Scholar However, this situation changed at the annual American Society of Clinical Oncology meeting in 2014, when results reported from the ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease (CHAARTED) showed that addition of six cycles of docetaxel to standard of care (testosterone lowering hormone therapy) prolonged the survival of men with metastatic disease at the time of diagnosis relative to treatment with hormones alone.2Sweeney C Chen Y-H Carducci MA et al.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.J Clin Oncol. 2014; 32 (abstr LBA2).: 5sCrossref PubMed Scopus (165) Google Scholar, 3Sweeney CJ Chen YH Carducci M et al.Chemohormonal therapy in metastatic hormone-sensitive prostate cancer.N Engl J Med. 2015; 373: 737-746Crossref PubMed Scopus (1779) Google Scholar The result contrasted with a trial of similar design, GETUG-AFU 15, that did not show a survival benefit.4Gravis G Fizazi K Joly F et al.Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial.Lancet Oncol. 2013; 14: 149-158Summary Full Text Full Text PDF PubMed Scopus (514) Google Scholar In The Lancet, Nicholas James and colleagues5James ND Sydes MR Clarke NW et al.for the STAMPEDE investigatorsAddition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.Lancet. 2016; 387: 1163-1177Summary Full Text Full Text PDF PubMed Scopus (1352) Google Scholar report on the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) study, a multinational trial of unparalleled scope and size designed to establish new standards of care for prostate cancer patients starting first-line hormone therapy. The report includes 2962 men with high-risk localised, node-only disease, and metastatic disease that was newly diagnosed or that relapsed after local therapy, who were randomised to one of four treatment groups: standard of care (SOC) alone, standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care plus zoledronic acid plus docetaxel (SOC + ZA + Doc). Overall, relative to SOC alone, SOC + Doc reduced mortality by 22% (hazard ratio 0·78 [95% CI 0·66–0·93]), prolonged median overall survival by 10 months (81 months vs 71 months), and increased absolute 5-year survival by 8% (63% vs 55%). For the subset of patients with metastatic disease, the relative reduction in mortality was 24% (hazard ratio 0·76 [95% CI 0·62–0·92]), median survival increased by 15 months (60 months vs 45 months), and absolute 5-year survival increased by 11% (50% vs 39%). Favourable effects on failure-free survival—defined as time from randomisation to evidence of at least one of the following: biochemical failure; local, nodal, or metastatic progression; or death from prostate cancer—were also reported. No survival benefit, prolongation of failure-free survival, or reduction in the frequency of skeletal-related events was seen for adding zoledronic acid to either SOC alone or SOC + Doc. However, the addition of docetaxel did delay the time to the first skeletal-related event. Safety and tolerance were as anticipated for docetaxel and, although the frequency of grade 3 or higher adverse events was increased in the first 6 months, the overall frequencies at 1 year were similar for the docetaxel and non-docetaxel treatment groups. James and colleagues' results5James ND Sydes MR Clarke NW et al.for the STAMPEDE investigatorsAddition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.Lancet. 2016; 387: 1163-1177Summary Full Text Full Text PDF PubMed Scopus (1352) Google Scholar provide further unequivocal level 1 evidence of a meaningful clinical benefit for early docetaxel relative to the potential risks and harms, leading the study authors to conclude that the “standard of care should be updated to include docetaxel chemotherapy in suitable patients with metastatic disease”, similar to the group shown to benefit in CHAARTED, and that it “may be considered for men with high-risk non-metastatic” disease. Adding zoledronic acid to standard of care was not recommended.5James ND Sydes MR Clarke NW et al.for the STAMPEDE investigatorsAddition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.Lancet. 2016; 387: 1163-1177Summary Full Text Full Text PDF PubMed Scopus (1352) Google Scholar Based on the results of STAMPEDE and CHAARTED, should all men with newly diagnosed or recurrent metastatic disease receive chemotherapy? No. Even though over 100 sites participated in STAMPEDE and accrual was not restricted to academic high volume centres, the patients enrolled were not representative of a general prostate cancer population in that 97% had no cardiovascular history, 99% no cerebrovascular history, 100% no history of congestive heart failure, and over 90% no history of diabetes. Few had performance status 1 or greater. In a Canadian study,6Templeton AJ Vera-Badillo FE Wang L et al.Translating clinical trials to clinical practice: outcomes of men with metastatic castration resistant prostate cancer treated with docetaxel and prednisone in and out of clinical trials.Ann Oncol. 2013; 24: 2972-2977Crossref PubMed Scopus (112) Google Scholar use of docetaxel in patients with metastatic castration-resistant prostate cancer by the same physicians at the same institution, at the same dose and schedule, off-protocol resulted in higher morbidity and inferior outcomes relative to patients treated on-protocol strictly on the basis of demographics. The non-castrate metastatic disease state includes patients with one or two lesions, 20 or more lesions, bone marrow entirely replaced by tumour, and those with or without symptoms. Tolerance and safety are unlikely to be the same in the two settings. The non-castrate metastatic state also includes patients metastatic at diagnosis and those who develop metastases after failing local therapy for whom median survival times are inherently longer,7Gravis G Boher JM Foly F et al.Androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in metastatic non castrate prostate cancer: impact of metastatic burden and long-term survival analysis of the randomized phase 3 GETUG-AFU15 trial.Eur Urol. 2015; (published online Nov 20.)https://doi.org/10.1016/j.eururo.2015.11.005Summary Full Text Full Text PDF Scopus (292) Google Scholar and, although there was no evidence of heterogeneity across subgroups, patients older than 70 years did not appear to benefit.5James ND Sydes MR Clarke NW et al.for the STAMPEDE investigatorsAddition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.Lancet. 2016; 387: 1163-1177Summary Full Text Full Text PDF PubMed Scopus (1352) Google Scholar Hidden factors might have affected survival outcomes in favour of the groups treated with chemotherapy relative to those not treated with chemotherapy. Reported are the specific therapies received and how long after a failure event was documented. Most failures were biochemical, and about 80% of patients in each group received a new treatment within 6 months. Most treatments were not life prolonging. During the course of STAMPEDE,5James ND Sydes MR Clarke NW et al.for the STAMPEDE investigatorsAddition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.Lancet. 2016; 387: 1163-1177Summary Full Text Full Text PDF PubMed Scopus (1352) Google Scholar four additional therapies proven to prolong life in metastatic castration-resistant prostate cancer became available, which were also given at a similar time and frequency to the four treatment groups after the failure event. Not surprisingly, a higher percentage of patients in the SOC alone and SOC + ZA groups received docetaxel and a lower percentage abiraterone, enzalutamide, or cabazitaxel relative to the SOC + Doc and SOC + Doc + ZA groups. A concern is that 40% of patients in the non-docetaxel containing groups had not received docetaxel or any other life-prolonging therapy. These imbalances could have affected the survival outcome in favour of early chemotherapy. Notable here is that the relative percentage of patients receiving a newly approved life-prolonging therapy and docetaxel in the SOC + Doc group relative to the standard of care groups in CHAARTED which showed a survival benefit was 25% and 50% greater than GETUG-AFU 15, a trial that largely accrued before these therapies were available and showed no survival benefit.7Gravis G Boher JM Foly F et al.Androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in metastatic non castrate prostate cancer: impact of metastatic burden and long-term survival analysis of the randomized phase 3 GETUG-AFU15 trial.Eur Urol. 2015; (published online Nov 20.)https://doi.org/10.1016/j.eururo.2015.11.005Summary Full Text Full Text PDF Scopus (292) Google Scholar Showing the post-failure survival of the four groups, although not definitive, could shed some light. An additional question that has not been formally addressed by either STAMPEDE or CHAARTED, and which remains open, is whether chemotherapy given early versus chemotherapy given later at the time of failure or progression would have produced similar overall survival times.8Scher HI Chemotherapy should be given late for men with metastatic disease. Presented at the education session: Debate on Chemotherapy and Radium 223 for the Optimal Treatment of Advanced Prostate Cancer. 2015. 2015 ASCO Annual Meeting; Chicago, IL, USA; May 29–June 2, 2015.http://am.asco/org/timing-chemotherapy-ra-223-advanced-prostate-cancerGoogle Scholar For patients with non-metastatic disease, the hazard ratio for the reduction in mortality was similar to that observed in metastatic patients, but the results are not definitive due to the short follow-up and insufficient number of events. An important amendment to the STAMPEDE trial in 2011 was to require radiation therapy to the primary tumour, previously shown to improve survival relative to standard of care hormone therapy or radiation therapy alone.9Widmark A Klepp O Solberg A et al.for the Scandinavian Prostate Cancer Group Study 7 and the Swedish Association for Urological Oncology 3Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial.Lancet. 2009; 373: 301-308Summary Full Text Full Text PDF PubMed Scopus (688) Google Scholar, 10Warde P Mason M Ding K et al.Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial.Lancet. 2011; 378: 2104-2111Summary Full Text Full Text PDF PubMed Scopus (460) Google Scholar For these patients, failure rates and overall prostate cancer-specific death rates are lower than for men with metastatic disease and the net benefit of early chemotherapy is less certain. For those not at risk of dying of prostate cancer, or who have tumours that can be successfully treated with standard of care hormones and local therapy alone, or who have tumours that are insensitive to docetaxel, any chemotherapy is overtreatment. Additionally, in The Lancet Oncology, Claire Vale and colleagues11Vale CL Burdett S Rydzewska H et al.for the STOpCaP Steering GroupAddition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: a systematic review and meta-analyses of aggregate data.Lancet Oncol. 2016; 17: 243-256Summary Full Text Full Text PDF PubMed Scopus (312) Google Scholar have reported a meta-analysis that considers ongoing trials that might affect outcomes, based solely on completed studies. The conclusions for metastatic (M1) disease were based on the results of CHAARTED,3Sweeney CJ Chen YH Carducci M et al.Chemohormonal therapy in metastatic hormone-sensitive prostate cancer.N Engl J Med. 2015; 373: 737-746Crossref PubMed Scopus (1779) Google Scholar GETUG-AFU 15,4Gravis G Fizazi K Joly F et al.Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial.Lancet Oncol. 2013; 14: 149-158Summary Full Text Full Text PDF PubMed Scopus (514) Google Scholar and STAMPEDE5James ND Sydes MR Clarke NW et al.for the STAMPEDE investigatorsAddition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.Lancet. 2016; 387: 1163-1177Summary Full Text Full Text PDF PubMed Scopus (1352) Google Scholar representing 2992 (93%) of the 3206 patients enrolled in the relevant trials. The combined analysis showed an absolute 9% (95% CI 5–14) improvement in survival at 4 years, and makes it essential that the role of docetaxel in combination with hormones be discussed. However, for an individual patient careful consideration must be given to comorbidities that might compromise tolerance and the ability to give chemotherapy safely. For patients with locally advanced (M0) disease, failure-free survival was consistently prolonged with docetaxel (hazard ratio 0·70 [95% CI 0·61–0·81]) but an effect on survival has not been firmly established (0·87 [0·69–1·09]). For these patients, prognostic models that can define the risk of developing metastatic disease, symptoms, and death from prostate cancer, and, for all cohorts, biomarkers that predict which tumours are likely to be sensitive to docetaxel, are needed to better inform management for the individual patient. Participation in protocols designed to address these questions is strongly encouraged. Overall, the STAMPEDE results5James ND Sydes MR Clarke NW et al.for the STAMPEDE investigatorsAddition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.Lancet. 2016; 387: 1163-1177Summary Full Text Full Text PDF PubMed Scopus (1352) Google Scholar mandate a discussion of the proven benefit of early chemotherapy in combination with standard of care hormone therapy for men with metastatic disease at diagnosis, or who develop metastatic disease after local therapy with consideration to patient factors that might affect tolerance and safety. Longer follow-up, as noted by the authors, is required before the benefit-to-risk ratio is definitively established in earlier disease states. Needed now is a biological understanding of which tumours will be sensitive to docetaxel, which will not, and which might be more responsive to a next-generation agent directed to the androgen receptor or androgen receptor signalling, or another class of drug. Doing so will spare patients potentially ineffective treatment. Equally important is the drug assessment paradigm established by STAMPEDE that enables new systemic and combined modality approaches to be assessed at a more rapid pace than could have been achieved with more traditional research designs.12James ND Sydes MR Mason MD et al.Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial.Lancet Oncol. 2012; 10: 549-558Summary Full Text Full Text PDF Scopus (95) Google Scholar The trial has already, and will continue to provide, a treasure trove of data that directly affects the management and outcomes for men with different states of prostate cancer. HIS reports non-financial support from AstraZeneca, Bristol-Myers Squibb, Celgene, Endocyte, Genentech, Medivation, Novartis, Pfizer, Takeda Millennium, personal fees from Astellas, BIND Pharmaceuticals, Blue Earth Diagnostics, Chugai Academy for Advanced Oncology, Elsevier's PracticeUpdate Website, Ferring Pharmaceuticals, Med IQ, Oncology STAT, Roche, Sanofi-Aventis, WCG Oncology, and grants from BIND Therapeutics, Innocrin Pharma, Medivation, and Janssen, outside the submitted work. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trialZoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. Full-Text PDF Open Access