Effect of Adding Docetaxel to Androgen-Deprivation Therapy in Patients With High-Risk Prostate Cancer With Rising Prostate-Specific Antigen Levels After Primary Local Therapy

Abstract

IMPORTANCE Androgen-deprivation therapy (ADT) plus docetaxel is the standard of care in hormone-naive metastatic prostate cancer but is of uncertain benefit in a nonmetastatic, high-risk prostate cancer setting.OBJECTIVE To assess the benefit of ADT plus docetaxel in patients presenting with rising prostate-specific antigen (PSA) levels after primary local therapy and high-risk factors but no evidence of metastatic disease. DESIGN, SETTING, AND PARTICIPANTSThis open-label, phase 3, randomized superiority trial comparing ADT plus docetaxel vs ADT alone enrolled patients from 28 centers in France between June 4, 2003, and September 25, 2007; final follow-up was conducted April 12, 2017, and analysis was performed May 2 to July 31, 2017. Patients had undergone primary local therapy for prostate cancer, were experiencing rising PSA levels, and were considered to be at high risk of metastatic disease. Stratification was by prior local therapy and PSA-level doubling time (Յ6 vs >6 months), and intention-to-treat analysis was used.INTERVENTIONS Patients were randomly assigned to receive ADT (1 year) plus docetaxel, 70 mg/m 2 (every 3 weeks [6 cycles]), or ADT alone (1 year). MAIN OUTCOMES AND MEASURESThe primary outcome was PSA progression-free survival (PSA-PFS). Secondary end points were PSA response, radiologic PFS, overall survival, safety, and quality of life. RESULTS Overall, 254 patients were randomized (1:1) to the trial; median age, 64 years in the ADT plus docetaxel arm, 66 years in the ADT alone arm. At a median follow-up of 30.0 months, the median PSA-PFS was 20.3 (95% CI, 19.0-21.6) months in the ADT plus docetaxel arm vs 19.3 (95% CI, 18.2-20.8) months in the ADT alone arm (hazard ratio [HR], 0.85; 95% CI, 0.62-1.16; P = .31). At a median follow-up of 10.5 years, there was no significant between-arm difference in radiologic PFS (HR, 1.03; 95% CI, 0.74-1.43; P = .88). Overall survival data were not mature. The most common grade 3 or 4 hematologic toxic effects in the ADT plus docetaxel arm were neutropenia (60 of 125 patients [48.0%]), febrile neutropenia (10 [8.0%]), and thrombocytopenia (4 [3.0%]). There was no significant between-arm difference in overall quality of life.CONCLUSIONS AND RELEVANCE Compared with ADT alone, combined ADT plus docetaxel therapy with curative intent did not significantly improve PSA-PFS in patients with high-risk prostate cancer and rising PSA levels and no evidence of metastatic disease. TRIAL REGISTRATION French Health Products Safety Agency identifier: 030591; ClinicalTrials.gov identifier: NCT00764166

The Impact of Whole Genome Data on Therapeutic Decision-Making in Metastatic Prostate Cancer: A Retrospective Analysis

“…Firstly, studies of neoadjuvant or adjuvant docetaxel in men with high-risk localized disease undertaking radical prostatectomy or definitive radiotherapy with ADT have had conflicting results [4,46,71] but a subgroup of men appear to benefit. Poor prognostic genomic findings, such as TP53 deletions or deleterious BRCA2 alterations at baseline may be useful in selecting men for additional treatment.…”

“…In practice, knowledge of this patient's genomic landscape at baseline may have prompted his treating clinician to escalate his treatment with combination systemic therapy such as the rucaparib arm of the STAMPEDE trial. The loss of NCOR1 and NCOR2 and the poorer prognosis conferred by his TP53 and BRCA2 status represent potential indications for early chemohormonal therapy (ADT with docetaxel chemotherapy) despite him having low-volume, node only metastases [3,4,46,71]. BRCA2 alterations may also sensitize this patient to radiotherapy due to impaired DDR.…”

“…Knowledge of these molecular features may have triggered more aggressive treatment upfront. Within current treatment paradigms, this may have included radiotherapy with ADT and docetaxel [5,71]. Additionally, the number of alterations in multiple targetable pathways, particularly PI3K (PI3K/AKT inhibitors) and MAPK/ERK (BRAF/MEK inhibitors), highlights the need to contextualise genomic events rather than viewing them in isolation.…”

Green Nanotechnology of MGF-AuNPs for Immunomodulatory Intervention in Prostate Cancer Therapy

“…The latest epidemiological investigation (spanning January 1, 2008-March 31, 2018) of patients with castration-resistant prostate cancer (mCRPC) has concluded high mortality suggesting a significant unmet clinical need in prolonging life span of human population inflicted with this deadly disease globally. [1][2][3][4] There is an emerging consensus that current therapies are poorly effective for patients with castration-resistant prostate cancer (CRPC), where the disease manifests from asymptomatic or minimally symptomatic, non-metastatic disease to symptomatic or highly metastatic condition, depending on the time of diagnosis with significant interpatient variation. [5][6][7] The United States Food and Drug Administration (FDA) has approved several chemotherapeutic agents including docetaxel, cabazitaxel, abiraterone, and enzalutamide for treating such patients.…”

Adjuvant Chemotherapy in High-Risk Prostate Cancer Patients after Primary Local Therapy: Recurrence, Metastasis, and Survival – A Meta-Analysis

“…There is no specific guideline recommendation and clinical consensus [11]. It is hoped that this meta-analysis can clarify whether adjuvant chemotherapy can improve the prognosis of the patients [12].…”