The current study demonstrates the safety and anti-tumor activity of neoadjuvant docetaxel plus bevacizumab in patients with high-risk localized prostate cancer. Specifically, this study shows that this combination can be administered with rare grade > 2 toxicities and uncommon intra-operative or peri-operative complications. Furthermore, the majority of patients achieved a reduction in tumor volume by erMRI (with 29% patients achieving a reduction of > 50%, meeting the study’s primary endpoint) and decrease PSA (with 22% patients achieving a reduction of 50%). Unfortunately, similar to other reported neoadjuvant studies, no complete pathologic responses were observed.
The role of neoadjuvant single-agent docetaxel in high-risk localized prostate cancer is in evolution and a large randomized phase III trial (CALGB 90203) is ongoing.21
We previously demonstrated that single-agent docetaxel was associated with a reduction of tumor volume of >50% in 21% of patients12
compared with 29% of patients in the current study of docetaxel plus bevacizumab. However, the small sample sizes of these studies and problems inherent in cross-study comparisons make conclusions regarding incremental improvements problematic. Furthermore, while tumor down-staging by MRI represents a non-invasive intermediate endpoint obtainable in the vast majority of patients on the current study, whether or not erMRI response correlates with progression-free survival or overall survival has not yet been established and is the subject of ongoing work. Also of note, in the current study, erMRI responses did not directly correlate with post-treatment declines in PSA, a finding that also warrant further evaluation, and correlation with long-term clinical outcomes, in an effort to define an optimal intermediate endpoint for neoadjuvant prostate studies. Though complete pathologic responses to neoadjuvant therapy have been associated with improved long term outcomes in other solid tumors, complete pathologic responses have been an extremely rare event in neoadjuvant prostate cancer studies. Ultimately, the results of CALGB 90203 will be required to determine if the responses achieved with docetaxel-based neoadjuvant therapy in prostate cancer are sufficient to improve clinical outcomes.
The results of the current study must be interpreted in the context of additional clinical data regarding the use of bevacizumab that has emerged since the conduct of this trial. CALGB 90401 was a randomized phase III trial of docetaxel versus docetaxel plus bevacizumab in patients with castration-resistant metastatic prostate cancer.18
While CALGB 90401 demonstrated that the combination regimen was associated with a statistically significant improvement in response rate and progression-free survival, there was no significant improvement in overall survival with the addition of bevacizumab. Despite these findings, the mechanism of action of antiangiogenic therapy in patients with bulky established metastatic disease (e.g., vascular normalization and improved chemotherapy delivery) may be quite different than the mechanism in patients at high risk for micrometastatic disease (e.g., preventing metastases through inhibition of recruitment of the neovasculature). In this regard, the results of National Surgical Adjuvant Breast and Bowel Project (NSABP) C-08 and the AVANT study are more concerning. Both of these randomized phase III trials, exploring the use of adjuvant chemotherapy plus bevacizumab in high-risk localized colon cancer, failed to demonstrate an improvement in relapse-free survival with the addition of adjuvant anti-angiogenic therapy.22
The results of ongoing randomized studies exploring perioperative bevacizumab in other solid tumors will be helpful in determining if docetaxel plus bevacizumab warrants further evaluation as neoadjuvant therapy in prostate cancer.
The role of integration of ADT into neoadjuvant regimens is also worthy of discussion. Several randomized trials have explored varying durations of neoadjuvant androgen-deprivation therapy prior to prostatectomy.5–9
These trials have generally revealed improved tumor down-staging and a lower rate of positive surgical margins with the use of neoadjuvant hormonal therapy, though no significant impact on long-term clinical outcomes. Prostate cancer xenograft studies have demonstrated conflicting findings regarding the impact of treatment sequence on combination chemotherapy plus hormonal therapy with one study suggesting improved activity with simultaneous administration and another demonstrating optimal growth inhibition with docetaxel followed by ADT.23–24
Phase II studies have demonstrated the feasibility and activity of docetaxel plus ADT as neoadjuvant therapy prior to prostatectomy with one study demonstrating 2 complete pathologic responses.10
The combined chemohormonal approach is being explored in the ongoing CALGB 90203.
In summary, the current study demonstrates the safety and activity of docetaxel plus bevacizumab as neoadjuvant therapy prior to prostatectomy in patients with high-risk localized prostate cancer. Given that subsets of patients will likely benefit preferentially from both docetaxel and bevacizumab, molecular correlates of response to treatment on the current trial are being analyzed and will be reported separately. The role of neoadjuvant chemotherapy in prostate cancer, and perioperative antiangiogenic therapy in solid tumors, requires further elucidation through the results of ongoing randomized clinical trials.