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Docetaxel for hormone-naïve prostate cancer: results from long-term follow-up of metastatic (M1) patients in the STAMPEDE randomised trial NCT00268476 and sub group analysis by metastatic burden

  • N.W. Clarke 1,
  • A. Ali 1,
  • F.C. Ingleby 2,
  • A. Hoyle 3,
  • J. Calvert 2,
  • G. Attard 4,
  • S. Chowdhury 5,
  • D. Dearnaley 6,
  • H. Douis 7,
  • S. Gillessen 3,
  • R. Jones 8,
  • Z. Malik 9,
  • M.D. Mason 10,
  • R. Millman 2,
  • C. Parker 6,
  • H.L. Rush 2,
  • A.G. Omlin 11,
  • M.R. Sydes 2,
  • M.K.B. Parmar 2,
  • N.D. James 12
1 The departments of surgery and urology, the christie and salford royal hospitals, Manchester, UK 2 Institute of clinical trials & methodology, MRC clinical trials unit at UCL, London, UK 3 Department of oncology/hematology, the christie NHS foundation trust, Manchester, UK 4 Ucl cancer institute, University College London, London, UK 5 Medical oncology, Guy's and St. Thomas' hospital NHS trust, London, UK 6 Department of urology, the institute of cancer research/royal marsden NHS foundation trust, Sutton, UK 7 Department of radiology, University Hospital Birmingham, Birmingham, UK 8 Beatson west of scotland cancer centre, University of Glasgow, Glasgow, UK 9 Royal Liverpool University Hospital, University of Liverpool, Liverpool, UK 10 Velindre cancer centre, Velindre Hospital, Cardiff, UK 11 Medical oncology and haematology, Kantonsspital St. Gallen, St. Gallen, Switzerland 12 Clinical trials unit, Queen Elizabeth-University Hospital Birmingham NHS Foundation Trust, Birmingham, UK

Background

STAMPEDE has previously reported that upfront docetaxel (Doc) improved overall survival (OS) for patients (pts) starting long-term androgen deprivation therapy (ADT). We report the long-term outcomes for M1 pts using OS as the primary outcome measure. We also assessed if benefit of Doc depended on metastatic burden, as suggested by previous trials, using the CHAARTED definition of high burden (HB) and low burden (LB) baseline disease.

Methods

724 SOC and 362 SOC+Doc pts were recruited with a 2:1 randomised stratified allocation. Analysis used Cox regression models, adjusted for all stratification factors, with emphasis on restricted mean survival time if hazards were non-proportional. Retrospectively-collected imaging data, blinded to trial arm, was used to categorise pts as having LB or HB disease.

Results

Median follow-up was ∼6.5yr, compared to ∼3.5yr when last reported. There were 494 deaths on SOC (41% increase in deaths compared to previous report), with median OS = 43.1 months (m). There was good evidence of benefit of SOC+Doc on OS (median = 59.1m, HR = 0.81, 95% CI 0.69-0.95, P = 0.009). Metastatic burden was assessable for 830/1086 (76%) pts; subgroups were representative of the full M1 cohort in terms of stratification factors. There was no evidence of heterogeneity of Doc effect between the LB and HB subgroups (interaction P = 0.827; LB HR = 0.76, 95%CI 0.54-1.07, P = 0.107; HB HR = 0.81, 95%CI 0.64-1.02, P = 0.064). Analysis of other outcomes also found evidence of benefit of SOC+Doc over SOC in failure-free survival (FFS; HR = 0.66, 95% CI 0.57-0.76, P < 0.001) and progression-free survival (PFS; HR = 0.69, 95% CI 0.59-0.81, P < 0.001), and no evidence of heterogeneity of Doc effect between metastatic burden subgroups for either outcome (FFS: P = 0.792; PFS: P = 0.855). There was no evidence that SOC+Doc resulted in late (after 1yr) G3-5 toxicity compared to SOC (27% vs 28% respectively).

Conclusions

The clinically significant benefit in survival for upfront Doc persists after longer follow-up, with no evidence that the benefit differed dependent on disease burden. We advocate that upfront Doc is considered for both LB and HB M1 pts.

Commented by Prof. Tsaur

The results of the trial support utilization of docetaxel in metastatic hormone-sensitive prostate cancer irrespectively of disease volume. This is conflicting to the findings of the CHAARTED trial demonstrating no overall survival benefit from the upfront cytotoxic treatment for low volume disease. This might be attributable to a higher proportion of relapsed as compared to primary metastatic patients in the CHAARTED trial, since they might not have such a biologically aggressive cancer as the latter ones thus not benefitting from aggressive treatment regimen. Taken together, upfront docetaxel is a sensible treatment option for primary metastatic hormone-sensitive prostate cancer regardless of disease burden. If it is a reasonable option for high volume recurrent cancer, still needs to be clarified.