Sweeney et al reported on the results of a seminal phase III trial (E3805) of chemohormonal therapy vs androgen-deprivation therapy in metastatic hormone-sensitive prostate cancer in a recent issue of The New England Journal of Medicine,1 and the study is summarized in this issue of The ASCO Post.
This open-label trial randomized 790 men with metastatic hormone-sensitive disease within 120 days of starting androgen-deprivation therapy to either androgen-deprivation therapy plus docetaxel every 3 weeks for 6 cycles or androgen-deprivation therapy alone. The primary endpoint of the study was overall survival, with secondary endpoints including nadir prostate-specific antigen < 0.2 ng/mL and biochemical, clinical, or radiographic time to development of castration-resistant prostate cancer. Overall, combined treatment was well tolerated, with 86% of patients completing all 6 cycles of docetaxel.
Patient Population and Clinicopathologic Implications
The patients in this study were younger than typical patients with prostate cancer, reflecting the predominance of aggressive disease in a younger population and limiting the applicability of the study to older populations. However, it should be noted that based on a subgroup analysis, a clinical benefit was retained for men ≥ 70 years of age (hazard ratio [HR] = 0.43).
Of the 789 patients randomized, 575 (72.8%) had not received prior local therapies. The majority of the patients on this study, 65.7%, had high-volume metastatic disease. Almost three-quarters of the patients in both arms had not received prior treatment for prostate cancer, indicative of de novo presentation in both arms. As noted, the patients were about 5 years younger (63 to 64 years) than those typically presenting with prostate cancer, suggesting a potentially more aggressive biology. The use of prior adjuvant androgen-deprivation therapy was around 4% in both arms, concordant with its primary use in conjunction with definitive radiation, which was received by approximately 7% in the combined arm and approximately 8% in the androgen-deprivation therapy–alone arm.
Taken together, these data suggest that the patients on this study had an inherently more aggressive biology associated with their disease and that chemohormonal therapy may be more applicable to these men. The use of combined androgen blockade for more than 30 days did not impact outcomes based on the subgroup analysis.
Treatment Rationale and Mechanistic Implications
Metastatic prostate cancer is unique among human cancers in that its natural history is profoundly influenced by therapy, in this case androgen-deprivation therapy. Although the clinical benefit of androgen-deprivation therapy is pronounced, with a 90% to 95% response rate—among the highest of all human cancer therapies—its effects are short-lived, with progression typically seen within 18 to 24 months of therapy. The tumor burden is usually reduced significantly on the order of 1 to 2 log10 units.
Hypothetically, if more of these cells could be eliminated upfront, progression-free survival, time to castration-resistant prostate cancer, and overall survival would increase, and this could be accomplished by the addition of therapies that impact the tumor burden in a noncross-resistant additive, or ideally, synergistic manner. The data from the E3805 trial indicate the lack of cross-resistance between docetaxel and androgen-deprivation therapy.
In comparing the clinical benefit of docetaxel in hormone-sensitive prostate cancer (in E3805) vs its U.S. Food and Drug Administration–approved use in castration-resistant prostate cancer (based on the TAX 3272 and SWOG 99163 trials), early use of docetaxel imparts a longer median overall survival benefit (13 months vs about 3 months in castration-resistant prostate cancer). This is true despite the fact that almost 40% (137 of 393) of the men randomized to androgen-deprivation therapy alone in E3805 received subsequent docetaxel.
Predominance of Benefit in High-Volume Disease
Although a survival benefit was observed in all subgroups, the benefit was most pronounced in the high-volume subgroup, defined as those patients with extensive osseous or visceral metastatic disease. This, together with a delayed time to castration-resistant prostate cancer, argues that the cytoreduction resulting from docetaxel administration specifically targets the biologically aggressive disease compartment that ultimately gives rise to lethal castration-resistant prostate cancer. However the median overall survival was not reached in the low-volume subgroup, limiting the power of this subgroup analysis.
Impact of Subsequent Therapies
Delivery of subsequent therapies was fairly well balanced between the groups, with the predictable exceptions of more docetaxel given to the androgen-deprivation therapy–alone group and more cabazitaxel (Jevtana) given to the combination arm. There was, however, about 20% more use of life-prolonging therapy in the androgen-deprivation therapy–alone arm. Although not prospectively validated, these findings suggest that docetaxel administration has the potential to be cost-effective in that it may reduce the need for subsequent therapies without compromising survival benefit.
Future Directions and Conclusions
Docetaxel delivered as chemohormonal therapy is well tolerated and provides a greater clinical benefit than when it is delivered in the setting of castration-resistant prostate cancer. This therapy should be considered for all patients with newly diagnosed metastatic prostate cancer initially, particularly those with high-volume disease. ■
Disclosure: Dr. Goodman reported no potential conflicts of interest.
References
1. Sweeney CJ, Chen YH, Carducci M, et al: Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 373:737-746, 2015.
2. Tannock IF, de Wit R, Berry WR, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502-1512, 2004.
3. Petrylak DP, Tangen CM, Hussain MH, et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351:1513-1520, 2004.
Dr. Goodman is an oncologist at Comprehensive Cancer Centers of Nevada and US Oncology.
