TY - JOUR
T1 - Burden of Metastatic Castrate Naive Prostate Cancer Patients, to Identify Men More Likely to Benefit from Early Docetaxel
T2 - Further Analyses of CHAARTED and GETUG-AFU15 Studies
AU - Gravis, Gwenaelle
AU - Boher, Jean Marie
AU - Chen, Yu Hui
AU - Liu, Glenn
AU - Fizazi, Karim
AU - Carducci, Michael A.
AU - Oudard, Stephane
AU - Joly, Florence
AU - Jarrard, David M.
AU - Soulie, Michel
AU - Eisenberger, Mario J.
AU - Habibian, Muriel
AU - Dreicer, Robert
AU - Garcia, Jorge A.
AU - Hussain, Maha H.M.
AU - Kohli, Manish
AU - Vogelzang, Nicholas J.
AU - Picus, Joel
AU - DiPaola, Robert
AU - Sweeney, Christopher
N1 - Funding Information:
The combined analyses of the CHAARTED and GETUG-AFU15 data support the observation that HV and LV behaved differently in terms of OS with ADT alone and impact of D. It is also clear that some patients benefit from D in the setting of mCNPC, namely, those with a poorer prognosis such as a high tumor burden, which is still to be better defined. At the other end of the spectrum, patients with LV disease, slow-growing tumors, have less benefit with early chemotherapy, and the toxicity may often exceed the benefits. However, going forward, we need to develop better tools than volume of metastases on conventional imaging and explore modern technologies to identify better molecular or novel imaging parameters, and accurately characterize each patient's disease so we can optimize treatment allocation to D-based and/or abiraterone-based and/or possibly other biologically directed therapy combinations with ADT for mCNPC. Author contributions: Gwenaelle Gravis had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Gravis, Boher, Chen, Liu, Fizazi, Carducci, Jarrard, Dreicer, Garcia, Hussain, DiPaola, Sweeney. Acquisition of data: All authors. Analysis and interpretation of data: All authors. Drafting of the manuscript: All authors. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Boher, Chen. Obtaining funding: Gravis, Liu, Carducci, Jarrard, Eisenberger, Habibian, Dreicer, Garcia, Hussain, Kohli, Vogelzang, Picus, Sweeney. Administrative, technical, or material support: None. Supervision: None. Other: None. Financial disclosures: Gwenaelle Gravis certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Gwenaelle Gravis: travel, accommodations, expenses—Janssen Oncology, Pfizer, and Roche. Jean-Marie Boher, Yu-Hui Chen, Glenn Liu: no relationships to disclose. Karim Fizazi: honoraria—Astellas Pharma, Janssen, Sanofi, and Takeda; consulting or advisory role—Astellas Pharma, AstraZeneca, Bayer, Curevac, ESSA, Janssen Oncology, Orion Pharma GmbH, Roche/Genentech, and Sanofi; travel, accommodations, expenses—Amgen. Michael Anthony Carducci: consulting or advisory role—Astellas Pharma, AstraZeneca, Clovis Oncology, Medivation, and Merck. Stephane Oudard: honoraria—Astellas Pharma, Bayer, Janssen, and Sanofi; consulting or advisory role—Astellas Pharma, Bayer, Janssen Oncology, and Sanofi. Florence Joly: consulting or advisory role—AstraZeneca, Bristol-Myers Squibb, Novartis, Pfizer, Roche, Sanofi, and Tesaro; research funding—Astellas Medivation; expert testimony—Roche and Sanofi. David Frazier Jarrard and Michel Soulie: no relationships to disclose. Mario A. Eisenberger: honoraria—Sanofi; consulting or advisory role—Astellas Pharma, Bayer, Ipsen, Sanofi; research funding—Genentech, Sanofi, and Tokai Pharmaceuticals; travel, accommodations, expenses—Astellas Pharma, Bayer, and Sanofi. Muriel Habibian: no relationships to disclose. Robert Dreicer: honoraria—Astellas Pharma; consulting or advisory role—Asana Biosciences, Astellas Pharma, Exelixis, Ferring, Janssen Oncology, Medivation, and Roche; research funding—Asana Biosciences (Inst) and Genentech (Inst). Jorge A. Garcia: consulting or advisory role—Bayer, Eisai, Exelixis, Genentech/Roche, Medivation, Pfizer, and Sanofi; speakers’ bureau—Bayer, Genentech/Roche, Medivation/Astellas, and Sanofi; research funding—Astellas Pharma (Inst), Bayer (Inst), Genentech/Roche (Inst), Janssen Oncology (Inst), Lilly (Inst), Orion Pharma GmbH (Inst), and Pfizer (Inst); travel, accommodations, expenses—Bayer, Eisai, Exelixis, Genentech/Roche, Medivation/Astellas, Pfizer, and Sanofi. Maha Hussain: consulting or advisory role—AstraZeneca, Essa, Johnson & Johnson, and Synthon; research funding—Astellas Pharma (Inst), Bayer (Inst), Genentech (Inst), Medivation (Inst), and Pfizer (Inst); patents, royalties, other intellectual property—title: Dual Inhibition of MET and VEGF for the treatment of castration resistant prostate cancer and osteoblastic bone metastases, applicant/proprietor Exelexis, Inc., application no./patent no. 11764665.4-1464 Application No/Pat; title: Method of treating cancer, docket no.: serial number: 224990/10-016P2/311733 61/481/671, application filed on: 5/2/2011; title: Systems and methods for tissue imaging, 3676, our file: serial number: UM-14437/US-1/PRO 60/923,385 UM-14437/US-2/ORD 12/101,753. Manish Kohli: no relationships to disclose. Nicholas J. Vogelzang: employment—US Oncology; stock and other ownership interests—Caris Life Sciences; honoraria—Abbvie, Bavarian Nordic, DAVA Oncology, Dendreon, Endocyte, Janssen Oncology, Mannkind, Pfizer, and UpToDate; consulting or advisory role—Amgen, AVEO, Bayer, BIND Biosciences, Cerulean Pharma, Churchill Pharmaceuticals, Genentech/Roche, HERON, Janssen Biotech, Labceutics, and Pfizer; speakers’ bureau—Bayer, Bristol-Myers Squibb, Caris MPI, Dendreon, Genentech/Roche, GlaxoSmithKline, Medivation, Millennium, Pfizer, and Sanofi; research funding—Endocyte (Inst), Exelixis (Inst), GlaxoSmithKline (Inst), Merck (Inst), Parexel (Inst), Progenics (Inst), US Oncology (Inst), and Viamet Pharmaceuticals (Inst); travel, accommodations, expenses—Bayer/Onyx, Celgene, Dendreon, Exelixis, Genentech/Roche, Novartis, Pfizer, and US Oncology. Joel Picus: consulting or advisory role—Novo Nordisk; research funding—Agensys, Altor BioScience, Astex Pharmaceuticals, BioClin Therapeutics, Mirati Therapeutics, Novartis, and Oncogenex. Robert S. DiPaola: research funding—Abbvie (Inst). Christopher Sweeney: stock and other ownership interests—Leuchemix; consulting or advisory role—Astellas Pharma, AstraZeneca, Bayer, Genentech/Roche, Janssen Biotech, Pfizer, and Sanofi; research funding—Astellas Pharma (Inst), Bayer (Inst), Exelixis (Inst), Janssen Biotech (Inst), and Sanofi (Inst); patents, royalties, other intellectual property—Leuchemix: parthenolide, dimethylaminoparthenolide; Exelixis: abiraterone plus cabozantinib combination. Funding/Support and role of the sponsor: Partial financial support and drug supply by Sanofi. For the E3805: CHAARTED: Sanofi provided docetaxel for early use and financial grant support; NCI-CTEP and ECOG-ACRIN; Public Health Service Grants CA180794, CA180820, CA23318, CA66636, CA21115, CA49883, CA16116, CA21076, CA27525, CA13650, CA14548, CA35421, CA32102, CA31946, CA04919, CA107868, and support from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. For the GETUG-AFU15: trial was supported by grants from The French Health Ministry (PHRC), Sanofi-Aventis, Astra-Zeneca, and AMGEN. Appendix A
Publisher Copyright:
© 2018 European Association of Urology
PY - 2018/6
Y1 - 2018/6
N2 - Background: Docetaxel (D) at the time of starting androgen deprivation therapy (ADT) for metastatic castrate naive prostate cancer shows a clear survival benefit for patients with high-volume (HV) disease. It is unclear whether patients with low-volume (LV) disease benefit from early D. Objective: To define the overall survival (OS) of aggregate data of patient subgroups from the CHAARTED and GETUG-AFU15 studies, defined by metastatic burden (HV and LV) and time of metastasis occurrence (at diagnosis or after prior local treatment [PRLT]). Design, setting, and participants: Data were accessed from two independent phase III trials of ADT alone or ADT + D—GETUG-AFU15 (N = 385) and CHAARTED (N = 790), with median follow-ups for survivors of 83.2 and 48.2 mo, respectively. The definition of HV and LV disease was harmonized. Outcome measurements and statistical analysis: The primary end point was OS. Results and limitations: Meta-analysis results of the aggregate data showed significant heterogeneity in ADT + D versus ADT effect sizes between HV and LV subgroups (p = 0.017), and failed to detect heterogeneity in ADT + D versus ADT effect sizes between upfront and PRLT subgroups (p = 0.4). Adding D in patients with HV disease has a consistent effect in improving median OS (HV-ADT: 34.4 and 35.1 mo, HV-ADT + D: 51.2 and 39.8 mo in CHAARTED and GETUG-AFU15, respectively; pooled average hazard ratio or HR (95% confidence interval [CI]) 0.68 ([95% CI 0.56; 0.82], p < 0.001). Patients with LV disease showed much longer OS, without evidence that D improved OS (LV-ADT: not reached [NR] and 83.4; LV-ADT + D: 63.5 and NR in CHAARTED and GETUG-AFU15, respectively; pooled HR (95% CI) 1.03 (95% CI 0.77; 1.38). Aggregate data showed no evidence of heterogeneity of early D in LV and HV subgroups irrespective of whether patients had PRLT or not. Post hoc subgroup analysis was based on aggregated data from two independent phase III randomized trials. Conclusions: There was no apparent survival benefit in the CHAARTED and GETUG-AFU15 studies with D for LV. Across both studies, early D showed consistent effect and improved OS in HV patients. Patient summary: Patients with a higher burden of metastatic prostate cancer starting androgen deprivation therapy (ADT) have a poorer prognosis and are more likely to benefit from early docetaxel. Low-volume patients have longer overall survival with ADT alone, and the toxicity of docetaxel may outweigh its benefits. The aggregate data of two phase 3 trials show that patients with a high volume of metastatic castrate naive prostate cancer have poorer overall survival (OS) and benefit from androgen deprivation therapy (ADT) + docetaxel. Low-volume patients have longer OS with ADT alone and no clear benefit with adding docetaxel.
AB - Background: Docetaxel (D) at the time of starting androgen deprivation therapy (ADT) for metastatic castrate naive prostate cancer shows a clear survival benefit for patients with high-volume (HV) disease. It is unclear whether patients with low-volume (LV) disease benefit from early D. Objective: To define the overall survival (OS) of aggregate data of patient subgroups from the CHAARTED and GETUG-AFU15 studies, defined by metastatic burden (HV and LV) and time of metastasis occurrence (at diagnosis or after prior local treatment [PRLT]). Design, setting, and participants: Data were accessed from two independent phase III trials of ADT alone or ADT + D—GETUG-AFU15 (N = 385) and CHAARTED (N = 790), with median follow-ups for survivors of 83.2 and 48.2 mo, respectively. The definition of HV and LV disease was harmonized. Outcome measurements and statistical analysis: The primary end point was OS. Results and limitations: Meta-analysis results of the aggregate data showed significant heterogeneity in ADT + D versus ADT effect sizes between HV and LV subgroups (p = 0.017), and failed to detect heterogeneity in ADT + D versus ADT effect sizes between upfront and PRLT subgroups (p = 0.4). Adding D in patients with HV disease has a consistent effect in improving median OS (HV-ADT: 34.4 and 35.1 mo, HV-ADT + D: 51.2 and 39.8 mo in CHAARTED and GETUG-AFU15, respectively; pooled average hazard ratio or HR (95% confidence interval [CI]) 0.68 ([95% CI 0.56; 0.82], p < 0.001). Patients with LV disease showed much longer OS, without evidence that D improved OS (LV-ADT: not reached [NR] and 83.4; LV-ADT + D: 63.5 and NR in CHAARTED and GETUG-AFU15, respectively; pooled HR (95% CI) 1.03 (95% CI 0.77; 1.38). Aggregate data showed no evidence of heterogeneity of early D in LV and HV subgroups irrespective of whether patients had PRLT or not. Post hoc subgroup analysis was based on aggregated data from two independent phase III randomized trials. Conclusions: There was no apparent survival benefit in the CHAARTED and GETUG-AFU15 studies with D for LV. Across both studies, early D showed consistent effect and improved OS in HV patients. Patient summary: Patients with a higher burden of metastatic prostate cancer starting androgen deprivation therapy (ADT) have a poorer prognosis and are more likely to benefit from early docetaxel. Low-volume patients have longer overall survival with ADT alone, and the toxicity of docetaxel may outweigh its benefits. The aggregate data of two phase 3 trials show that patients with a high volume of metastatic castrate naive prostate cancer have poorer overall survival (OS) and benefit from androgen deprivation therapy (ADT) + docetaxel. Low-volume patients have longer OS with ADT alone and no clear benefit with adding docetaxel.
KW - Androgen deprivation therapy
KW - Chemotherapy
KW - Docetaxel
KW - High volume
KW - Low volume
KW - Metastatic castrate naive prostate cancer
KW - Metastatic prostate cancer
KW - Prostate cancer
KW - Volume disease
UR - http://www.scopus.com/inward/record.url?scp=85042143303&partnerID=8YFLogxK
U2 - 10.1016/j.eururo.2018.02.001
DO - 10.1016/j.eururo.2018.02.001
M3 - Article
C2 - 29475737
AN - SCOPUS:85042143303
VL - 73
SP - 847
EP - 855
JO - European Urology
JF - European Urology
SN - 0302-2838
IS - 6
ER -