CHICAGO, IL USA (UroToday.com) - Maha Hussain, Professor of Medicine and Urology at the University of Michigan, and Howard Scher, Chief of the Genitourinary Oncology Service at Memorial Sloan Kettering Cancer Center artfully presented point and counterpoint debating the timing of docetaxel chemotherapy in advanced prostate cancer given the changing therapeutic landscape.
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Dr. Hussain argued for earlier treatment with docetaxel, and Dr. Scher argued the counterpoint supporting later incorporation of chemotherapy into the treatment algorithm.
Early treatment with docetaxel chemotherapy
Dr. Hussain reviewed clinical trial data to discuss early use of docetaxel chemotherapy in various disease states, including micrometastatic disease, metastatic castration-resistant prostate cancer (mCRPC), and metastatic hormone-sensitive prostate cancer. She argued that treating prostate cancer with chemotherapy when it is still micrometastatic disease may allow the earliest treatment possible, and may have the greatest impact on disease trajectory. She mentioned three studies that will provide insight into best treatment practices, including GETUG 12, RTOG-0521, and SWOG 9921, but noted that overall survival data remains outstanding for all three. In the GETUG 12 study, 413 patients with high risk prostate cancer (Gleason ≥ 8, PSA >20, T3, pN+/N-) were randomized to treatment with ADT (3 years) and radiation therapy with or without docetaxel/estramustine (4 cycles) up front. Progression-free survival appears to be prolonged with the addition of chemotherapy, with a hazard ratio (HR) of 0.71 (95% CI 0.54-0.94; p=0.017), though overall survival data is outstanding. She cautioned that although this data suggests a possible benefit from early treatment with chemotherapy in the high-risk/micrometastatic disease setting, overall survival data are needed to make final recommendations.
In terms of mCRPC, Dr. Hussain argued that early treatment with docetaxel chemotherapy may provide superior outcomes for several reasons. First she referenced a report by Azad and colleagues in European Urology earlier this year that demonstrated that the use of sequential androgen receptor (AR) targeted agents may not maximize efficacy of therapy, making earlier use of cytotoxic therapy a potential avenue to improve outcomes. She also described that patients who are subjected to multiple AR targeted and other therapies may experience progressive frailty, making them poor candidates for treatment with docetaxel later in the disease course. Most importantly, she acknowledged that the field must appropriately identify a group of patients who would attain the most benefit from chemotherapy, and have an acceptable rate of side effects. She noted that doing this requires the use of biomarkers to identify an appropriate treatment group, and suggested that the use of disease burden as defined by imaging may be an appropriate way to do this, though current systems to define disease burden remain varied.
In addition to mCRPC, Dr. Hussain discussed the early use of chemotherapy in men with hormone-sensitive metastatic prostate cancer. She discussed CHAARTED, the ECOG study describing the use of standard androgen deprivation therapy with or without 6 cycles of docetaxel chemotherapy in men with high-risk hormone sensitive metastatic prostate cancer. The statistical analysis for this study stratified men by disease burden, with high volume disease defined as visceral metastases or ≥ 4 bone metastases (with ≥ 1 outside of the axial skeleton). Men were allowed 4 months of treatment with ADT before initiating docetaxel chemotherapy. Approximately 2/3 of patients in the study had high-volume disease. Treatment with early chemotherapy was well tolerated, with most men (87.5%) completing all 6 cycles of chemotherapy and a very tolerable safety profile. Importantly, Dr. Hussain notes that a majority of patients in the ADT-alone arm were treated with chemotherapy and/or hormonal therapies later in the treatment course, and had similar exposure to standard therapies as patients in the docetaxel up-front arm. Ultimately there was a 15.6 month improvement in median overall survival (OS) associated with early treatment with docetaxel in this population overall (HR = 0.61 (95% CI 0.47-0.80); p=0.0003). She also noted that patients with high-volume disease appeared to have an increase in median OS by 17 months (HR = 0.60 (95% CI 0.45-0.81); p=0.0006), while patients with low-volume disease did not have a significant improvement in median OS (HR 0.63 (95% CI 0.34-1.17); p=0.1398). Secondary endpoints were also better with early use of docetaxel, including achieving a PSA < 0.2 at 6 and 12 months, delaying median time to CRPC, and prolonging median time to clinical progression.
In addition to CHAARTED, Dr. Hussain discussed the GETUG-AFU 15 phase III study of ADT with or without docetaxel chemotherapy for men with hormone-sensitive metastatic prostate cancer performed in Europe. Many have interpreted this study as contradicting the findings of CHAARTED because GETUG-AFU 15 did not find a significant improvement in overall survival associated with the early use of chemotherapy. Dr. Hussain noted that the study was smaller (790 patients in CHAARTED, 385 in GETUG-AFU 15), had fewer high-volume disease patients (514 in CHAARTED, 183 in GETUG-AFU 15)), and had a lower median PSA than CHAARTED. She questioned whether GETUG-AFU 15 may have had outcomes more consistent with CHAARTED if the study had enriched for high-volume disease and had higher numbers overall. She supported this possibility by showing the progression-free survival and survival curves side by side, and demonstrating that the trajectories appeared to be somewhat similar between studies.
Lastly Dr. Hussain presented docetaxel outcomes data from the STAMPEDE study, a complicated trial that randomized men with hormone-sensitive metastatic or biochemical recurrent prostate cancer to one of a number of different treatment combinations. In a comparison of the docetaxel arms from the study, both failure-free survival and overall survival appeared to be superior in the ADT plus docetaxel arm than the ADT alone arm (HR for OS 0.76, p not presented). In a subgroup analysis, men with metastatic disease appeared to have a more substantial benefit from early treatment with docetaxel chemotherapy than men with biochemical recurrence only.
Dr. Hussain summarized her argument for early use of docetaxel chemotherapy in men with prostate cancer in several succinct points. First, in CHAARTED and STAMPED, there was an OS benefit associated with early use of docetaxel with hormonal therapy in men with hormone sensitive prostate cancer. Although the benefit appears to be driven by men with high-volume disease only, continued follow-up of men with low-volume disease may lead to demonstration of benefit in this population also. She postulates that controlling this stage of disease by delaying mCRPC, we will continue to benefit this population with early chemotherapy. Finally, she noted that targeting the AR is helpful, but not the only way to fight this disease. Early treatment with cytotoxic agents may be the best way to provide a “pre-emptive multi-targeted strategy” to contain this disease and best benefit our patients. Ultimately, her argument suggests that early use of chemotherapy appears to improve multiple patient outcomes, including survival, and has a tolerable set of side effects.
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Bottom line: Timing of treatment with docetaxel for men with advanced prostate cancer
Presented by Maha Hussain, MB, ChB at the American Society of Clinical Oncology (ASCO) Annual Meeting - Illumination & Innovation: Transforming Data into Learning - May 29 - June 2, 2015 - Chicago, Illinois USA
Professor of Medicine and Urology at the University of Michigan Health System, Ann Arbor, MI USA
Reported by Alicia K. Morgans, MD, assistant professor of medicine and medical oncologist at Vanderbilt-Ingram Cancer Center, and medical writer for UroToday.com