Two large randomized trials have now shown a robust and clinically meaningful survival benefit by the addition of docetaxel to ADT in men with mHSPC [7, 8]. The magnitude of the OS in the CHAARTED and STAMPEDE trials is remarkable (13.6 and 15 months in the metastatic patient population, respectively) and much larger than obtained with the use of chemotherapeutic or novel hormonal agents in the setting of mCRPC. A meta-analysis of the available data, also incorporating a smaller study by the French Genitourinary Tumor Group (GETUG-15) that showed a similar trend but did not reach statistical significance, is reported by Vale et al.  in the current issue of The Lancet Oncology. The meta-analysis revealed a robust 9 % absolute OS benefit at 4 years by the use of docetaxel plus ADT in men with mHSPC . Consequently, these results should be considered as practice changing in the daily treatment of men with prostate cancer. Men with newly diagnosed mHSPC, who are considered fit to receive chemotherapy, should be offered six cycles of docetaxel in addition to ADT.
However, some questions remain unsolved. Which patients precisely benefit from six cycles of docetaxel? Should docetaxel be administered with or without prednisone? And what is the explanation for the magnitude of the benefit by applying docetaxel early?
The CHAARTED study stratified for high- versus low-volume disease and only showed a statistically significant OS benefit in the high-volume subgroup. For men with low-volume disease, the number of events was too small at the time of reporting and therefore longer follow-up is awaited. The STAMPEDE trial, on the other hand, did not stratify for volume of metastatic disease and demonstrated clinical benefit for the entire patient population. These findings, in by far the largest study, in combination with the results from the meta-analysis incorporating low-volume metastatic patients, demonstrate that docetaxel plus ADT should be considered in all men with mHSPC regardless of disease burden.
Whereas the benefit of docetaxel is clearly visible in metastatic patients, longer follow-up will be needed to draw conclusions for non-metastatic patients. Likewise, since the vast majority of men included in both STAMPEDE and CHAARTED studies presented with newly diagnosed metastatic prostate cancer, conclusions regarding the use of docetaxel in men previously treated for local disease are also limited. To date, the recommendation of docetaxel plus ADT thus reflects the setting of newly diagnosed metastatic disease. For those patients, however, in whom metastatic disease becomes apparent within months after local treatment and the true extent of disease may have been missed upfront, treatment decisions should be individualized and preferably weighed in the multidisciplinary setting of modern patient care.
The reasons that underlie the greater benefit by using six cycles of docetaxel in the hormone-naïve setting as compared to the castrate-resistant setting might be sought in the early kill of hormone-resistant cell clones, as previously suggested by Sweeney et al. . An alternative or additional explanation could lie in different docetaxel pharmacokinetics. The incidence of neutropenic fever in TAX 327 was 2.7 %, whereas the incidence in all three mHSPC studies ranged from 6 to 12 %. These findings may suggest different docetaxel exposure in mCRPC as compared with mHSPC patients. Franke et al.  have shown that the clearance of docetaxel is affected by a castrate status. In their study, the clearance of docetaxel was increased by 100 % in castrated as compared to non-castrated men, resulting in a significantly higher area under the curve.
Steroids are CYP3A4 inducers and may therefore influence taxane pharmacokinetics. A recent Danish report suggested a higher incidence of neutropenic fever in patients receiving docetaxel alone as compared to docetaxel with prednisone . In the CHAARTED trial, docetaxel was given without prednisone. However, STAMPEDE produced similar survival benefit as observed in CHAARTED despite docetaxel being co-administered with prednisone. Although it is conceivable that prednisone might impact docetaxel clearance and may reduce docetaxel exposure, the addition of prednisone clearly enhances the efficacy of the regimen. To substantiate, the recently reported study on orteronel plus prednisone versus prednisone alone in chemotherapy-naïve men with mCRPC showed a 28 % prostate-specific antigen (PSA) response rate and 25 % circulating tumor cell conversion rate at 12 weeks in men receiving prednisone alone . Considering these data, the recommendation is to co-administer docetaxel with prednisone.