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: A Randomized Clinical Trial

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 participants: This 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 (≤6 vs >6 months), and intention-to-treat analysis was used.

Interventions: Patients were randomly assigned to receive ADT (1 year) plus docetaxel, 70 mg/m2 (every 3 weeks [6 cycles]), or ADT alone (1 year).

Main outcomes and measures: The 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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Oudard has received consulting fees, travel support, and honorarium from Sanofi, Astellas, and Janssen during the conduct of the study and consulting fees from Merck outside the submitted work. Laurent Miglianico reports nonfinancial support from Pfizer, Merck, BMS and Pierre Fabre and Roche and personal fees from Novartis, BMS, and Pierre Fabre, outside the submitted work. Dr Mouret has received personal fees from Sanofi, Astellas, Janssen, Pfizer, and Ipsen and reports nonfinancial support from Sanofi, Astellas, Janssen, and Pfizer, outside the submitted work. Dr Culine reports grants from Astellas and Merck Sharp & Dohme and received consulting fees during the meeting with Janssen, Roche, and Astellas, outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram

ITT indicates intention-to-treat.

Figure 2.. Survival

A, Prostate-specific antigen (PSA) progression-free survival in 79 patients receiving androgen-deprivation therapy (ADT) plus docetaxel and 81 receiving ADT alone. Median follow-up, 30.0 months (ADT plus docetaxel, 20.3 [95% CI, 19.0-21.6]; ADT alone: 19.3 months [95% CI, 18.2-20.8]); hazard ratio [HR], 0.85 (95% CI, 0.62-1.16); P = .31. B, Radiologic progression-free survival (including deaths from cancer) in 72 patients receiving ADT plus docetaxel and 69 receiving ADT alone. Median follow-up for ADT plus docetaxel, 8.9 years (7.3-10.2); ADT alone, 9.0 years (range, 7.3-10.4); HR 1.03 (95% CI, 0.74-1.43); P = .88. C, Overall all-cause survival in 40 patients receiving ADT plus docetaxel and 46 receiving ADT alone. Median follow-up, 10.5 years; 25th percentile, ADT plus docetaxel, 8.7 years (6.7-10.2); ADT alone, 7.8 years (6.2-9.3); 12-year survival rate, ADT plus docetaxel, 60% (not reached, 70%); ADT alone, 55% (NR, 65%); HR, 0.86 (95% CI, 0.56-1.31); P = .49. Dashed lines indicate 50% (median) and 75% (25th percentile).

Figure 3.. Subgroup Analysis

A, Prostate-specific antigen (PSA) progression-free survival. Progression defined by 1-ng/mL PSA cutoff level. B, Radiologic progression-free survival. The P value refers to the interaction between therapy arm and subgroup variable. To convert the PSA level to micrograms per liter, multipy by 1. ADT indicates androgen-deprivation therapy; HR, hazard ratio.

Figure 4.. Estimated 10-Year Radiologic Progression-Free Survival (PFS) According to Occurrence of Prostate-Specific Antigen (PSA) Progression

A, At different landmark times (ADT-alone arm vs ADT plus docetaxel arm) for no PSA progression and PSA progression. B, Landmark analysis at 18 months post randomization in ADT-alone arm vs ADT plus docetaxel arm. The dashed horizontal line indicates the median value. Log rank P < .001.