Meta-analyses of patients with low-volume metastatic hormone-sensitive prostate cancer will likely be required to attain sufficient power to address the role of docetaxel in this setting.
Docetaxel traditionally has been given to men with metastatic castration-resistant prostate cancer (mCRPC) after the failure of front-line hormonal therapy (androgen deprivation therapy [ADT]). Docetaxel is now also frequently deferred until after the failure of immunotherapy with sipuleucel-T and the failure of novel hormonal therapies, such as abiraterone acetate or enzalutamide, based on the positive results from multiple phase III trials of these agents in the chemotherapy-naive setting.[1-3] The reasons for the deferral of docetaxel are multiple and include a desire by patients and providers to delay the toxic effects of chemotherapy on quality of life, and the relatively modest impact of docetaxel on overall survival (OS) in mCRPC.
In the TAX 327 study, the hazard ratio (HR) for improved OS with every-3-week docetaxel and prednisone in the mCRPC setting was 0.76 based on the original dataset, and 0.79 based on the updated dataset, indicating a relative improvement in the risk of death over time of 24% (original dataset; P = .009) to 21% (updated dataset; P = .004).[4,5] While the activity of docetaxel following progression on either enzalutamide or abiraterone acetate is not well described to date, TAX 327 does provide level 1 evidence supporting the use of docetaxel in this setting; the median survival benefit conferred is around 2.5 months. In the mCRPC setting, docetaxel provides a much greater survival benefit in some men (those who achieve a prostate-specific antigen [PSA] decline or radiographic response or who have pain palliation,[6,7] and appears to produce a greater absolute survival advantage in men who are minimally symptomatic and perhaps in those men with higher-grade tumors.[4,8]
In the Eastern Cooperative Oncology Group (ECOG) phase III CHAARTED trial, a more substantial OS benefit was observed for the addition of docetaxel in the setting of metastatic hormone-sensitive prostate cancer (mHSPC). In this 790-patient trial of 6 cycles of every-3-week docetaxel (without prednisone) plus ADT vs ADT alone, the HR for OS was 0.61 (95% confidence interval [CI], 0.47–0.80; P = .0003), with a median improvement in OS of 13.6 months, from 44.0 to 57.6 months. The improved HR for OS in mHSPC (0.61) in the CHAARTED trial was surprisingly better than the HR for OS in mCRPC seen in the TAX 327 trial (0.76).
Why might this be? There are emerging data that docetaxel may act as a hormonal agent, interfering with androgen receptor (AR) nuclear translocation on microtubules. Certain AR variants that lack the microtubule binding domain (eg, AR-v7) are more docetaxel-resistant, and have also been shown to emerge during CRPC progression on ADT and novel hormonal therapies.[10,11] ADT may thus select for AR variants that confer cross-resistance to taxanes; thus, the optimal use of docetaxel may be prior to the development of such variants. These AR variants have been linked to stemness and invasive traits, including the epithelial-to-mesenchymal transition,[12-14] which has also been shown to promote chemoresistance in multiple studies.[15,16] This hypothesis of improved chemosensitivity in the hormone-sensitive setting warrants further prospective study of taxanes. Another possibility could be the engagement of the glucocorticoid receptor by the prednisone used in the castration-resistant setting, which may promote prostate cancer progression in a subset of men. The results of future and ongoing studies, such as Radiation Therapy and Oncology Group 0521 (NCT00288080; radiation and ADT ± docetaxel in high-risk localized prostate cancer), TAX 3503 (NCT01813370; ADT± docetaxel in hormone-naive patients with high-risk, rising PSA M0 prostate cancer), and the STAMPEDE trial (NCT00268476) may address these important questions, as may studies of the early use of cabazitaxel in the setting of high-risk localized or recurrent disease.
Whatever the reasons for the improvement in OS with docetaxel seen in the CHAARTED trial, the question remains: do these results mean that docetaxel should now be given to all patients with mHSPC? It is important to keep in mind that the CHAARTED trial initially was for men with high-volume mHSPC, defined as visceral metastases or more than four bone metastases and at least one bone metastasis beyond the pelvis and vertebral column; around two-thirds of the men in the final analysis had high-volume disease. While men with both high-volume and low-volume disease had similar relative improvements in OS (HRs, 0.60 and 0.63, respectively), the overall favorable outcomes for men with low-burden disease and the small number of men in this subgroup led to the inability to show a statistically significant survival difference (P = .14) in this subset, and no difference in median survival, which was not yet reached in the study.
This low-risk subset of men is similar to the population included in the GETUG-AFU 15 phase III trial, in which 192 men with mHSPC were randomly assigned to ADT ± every-3-week docetaxel without prednisone for up to 9 cycles. In this smaller trial, no survival benefit was seen with early docetaxel (HR, 1.01; 95% CI, 0.75–1.36), with estimated median survival times of 54.2 vs 58.9 months, slightly favoring docetaxel plus ADT. In this study, visceral disease was uncommon, with only 13% to 16% of patients having liver or lung metastases, and only around 20% considered as having poor-risk mHSPC by the Glass prognostic scale.
Why did the CHAARTED trial succeed while in the GETUG study, early docetaxel failed to improve survival? One reason could be power and sample size, which was more than threefold higher in the US cooperative group study; thus, the ability to find a difference-if one was present-was greater. In addition, the CHAARTED trial was enriched for men who presented with high-risk, high-volume disease, and in these men, the median PSA level was about twice that of the men in the GETUG study (50–56 ng/mL vs 25–26 ng/mL). In both trials, a similar number of men presented with metastatic disease and had no local therapy (around 70% in each study), so the main difference appears to be the intentional selection of men with higher-burden disease in the CHAARTED trial. Men with high-volume, visceral disease may represent a unique biology that is more sensitive to docetaxel, or they may tend to have such poor outcomes that an adequately powered study is more able to discern a difference in survival. However, there are also high-risk/poor-prognosis men who are within the “low-volume” category as defined by the ECOG study, and it will be critical to identify other subsets of men with mHSPC who also have a clear survival advantage beyond the trial-defined high volume subset.
Meta-analyses of patients with low-volume mHSPC will likely be required to attain sufficient power to address the role of docetaxel in this setting. For now, however, I would recommend 6 cycles of docetaxel only to men with high-volume disease (as defined in the CHAARTED study), since these are the men across two major phase III trials who clearly had the survival advantage of 17 months, which cannot be ignored.
Financial Disclosure:Dr. Armstrong receives research support from and is a consultant and advisor to Sanofi Aventis, Janssen, and Medivation/Astellas.
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