Treatment initiation for hormone-sensitive metastatic prostate cancer should include the addition of docetaxel to androgen deprivation therapy (ADT) as standard of care.
Claire L. Vale, MD
Treatment initiation for hormone-sensitive metastatic prostate cancer should include the addition of docetaxel to androgen deprivation therapy (ADT) as standard of care. This recommendation is based on a meta-analysis1of three large, relatively recent, randomized trials showing that docetaxel improves survival and failure-free survival (FFS) in metastatic hormone-sensitive prostate cancer. These findings move docetaxel up to the hormone-sensitive setting from its previous role as upfront treatment in the castrate-resistant setting.
In men with metastatic hormone-sensitive prostate cancer, docetaxel added to ADT improved 4-year survival by an absolute value of 9% and reduced FFS by an absolute value of 16%.
According to the findings in men with nonmetastatic hormone-sensitive prostate cancer, docetaxel improves FFS, but more evidence is needed to show a survival benefit in this setting. Vale and co-authors plan to do an individual-participant analysis of men enrolled in the trials included in the meta-analysis to find more reliable evidence about the effect of docetaxel on survival and prostate cancer-specific survival in the nonmetastatic setting. The addition of docetaxel to ADT is not recommended in nonmetastatic high-risk hormone-sensitive prostate cancer at this time.
The meta-analysis also evaluated the addition of zoledronic acid to ADT and found little or no benefit for this bisphosphonate in high-risk localized or metastatic hormone-sensitive disease.
"This meta-analysis provides substantial and reliable evidence that adding docetaxel to standard of care improves the survival of men with metastatic hormone-sensitive prostate cancer. The addition of docetaxel to androgen deprivation therapy is the new standard of care, and this combination should be offered to men who are fit to receive chemotherapy," wrote lead author Claire L. Vale, MD, MRC Clinical Trials Unit at UCL, London, UK, and co-authors. "We found no evidence that zoledronic acid improves survival."
Survival data for docetaxel were based on results from the CHAARTED, GETUG-15, and STAMPEDE trials in a total of 2292 (93%) of 3206 men with metastatic disease initiating treatment for the first time. At the time of the publication of results, 1271 deaths had occurred. The authors assumed a 4-year survival of 40% with standard of care; the hazard ratio (HR) of 0.77 (95% CI, 0.68-0.87) for the meta-analysis showed a significant benefit in survival with the addition of docetaxel to standard of care (P<.0001). There was no evidence of variation among trial results.
FFS was defined similarly in all three trials. FFS results were based on the same group of 2292 men as in the survival analysis; 2204 events signaling failure were recorded. Assuming a baseline 4-year FFS of 20% with standard therapy, the FFS HR was 0.64 (95% CI, 0.58-0.70;P<.0001), an improvement from 80% to 64%, which represents an absolute benefit of 16% for the addition of docetaxel.
Across the three trials, docetaxel was associated with an increase in grade 3 to 4 toxicities, most notably neutropenia. Overall, 16 deaths were deemed treatment related in patients treated with docetaxel.
The authors state that despite these risks, docetaxel should be considered the new standard of care and offered to "men with metastatic disease starting on long-term androgen deprivation therapy for the first time who are fit enough to receive chemotherapy and willing to accept these risks. Future trials in this setting should also consider this as an appropriate control group."