br Neoadjuvant androgen deprivation therapy ADT represents one of

Neoadjuvant androgen-deprivation therapy
ADT represents one of the original targeted therapies for cancer (Fig. 1). Two decades of trials testing neoadjuvant ADT alone or combined with chemotherapy have demonstrated that this treatment can induce measureable changes in the local disease burden at the time of surgery (recent, prospective, randomized controlled trials are summarized in Table 1). Though end points differed between studies, they generally included higher rates of organ-confined disease, reduced rates of extracapsular extension, and reduced rates of positive surgical margins. Affected systemic end points included reduced incidence of SW033291 node involvement, reduced testosterone levels, and PSA responses. Unfortunately, improved local control rates obtained in these trials did not translate into OS benefits; granted, the majority of these studies were underpowered to detect statistically significant differences in biochemical relapse-free survival.
Schulman and colleagues were among the first to report on both progression-free survival (PFS) and OS in a large, randomized trial of neoadjuvant ADT [6]. This study randomized 402 men with clinical T2 or T3 localized prostate cancer to receive either 3 months of total androgen deprivation with neoadjuvant goserelin plus flutamide before RP or RP alone. The rates of pathologic downstaging in the neoadjuvant ADT group compared with the prostatectomy alone group were 15% and 7% (P<0.01), and the positive surgical margin rates were 47.5% and 26.3% (P<0.05), respectively. After 4 years of follow-up, there were no significant differences in biochemical progression-free survival (67% vs. 76%, P = 0.18) or OS (95% vs. 94%, P =0.64) between the 2 treatment groups. Kumar et al. [7] performed a systematic review and meta-analysis of neoadjuvant hormone therapy in localized or locally advanced prostate cancer. Overall, 10 randomized clinical trials testing the role of hormonal therapy given before prostatectomy between 1966 and 2006 were included. Only 3 of the trials provided OS data, and 5 provided biochemical progression-free survival data. The authors showed that neoadjuvant hormonal therapy before prostatectomy did not improve OS (OR = 1.11; 95% CI: 0.67–1.85; P = 0.69) despite significant reductions in the positive surgical margin rates (OR = 0.34; 95% CI: 0.27–0.42; P<0.00001) and significant improvements in other clinical outcome measures including lymph node involvement, pathologic staging, and organ-confined rates. Neoadjuvant treatment resulted in a borderline significant reduction in disease recurrence rates (OR = 0.74; 95% CI: 0.55–1.0; P = 0.05). The authors concluded that neoadjuvant hormone therapy given before prostatectomy is associated with significant clinical benefits in the form of improved local control but does not result in improved OS. As a result, neoadjuvant ADT before prostatectomy is not considered the standard of care. One possible reason for the lack of survival benefit was the short 3-month duration of treatment used in most of the studies. We now know from the neoadjuvant-EBRT experience in high-risk prostate cancer that longer duration (3y) of androgen suppression is associated with improved outcomes [4]. In the study by Gleave, 8 months of preoperative ADT was compared with 3 months (Table 1) and showed a significant reduction in the rate of positive surgical margins from 23% to 12% (P = 0.0106) with longer duration of ADT; mean serum PSA decreased by 98% after 3 months, with a further 57% decrease from 3 to 8 months. Although this suggested that 3 months of ADT was insufficient to achieve optimal local control, survival data were not reported, so conclusions regarding the ideal length of preoperative ADT could not be determined from this study [8].
The reasons for the failure of neoadjuvant ADT to improve survival are unclear and complex. However, the biology of castration-resistant prostate cancer (CRPC), defined as progressive disease despite castrate levels of testosterone (less than 50ng/dl), has taught us that despite maximum suppression of androgen synthesis and activity using LHRH agonists/antagonists and antiandrogens, residual levels of testosterone are sufficient to drive continued growth of prostate cancer left behind with surgery. It is possible that the degree of androgen suppression achieved with these medications was not profound enough to ultimately affect survival rates. Abiraterone is a novel first-in-class inhibitor of 17α-hydroxylase/C17, 20-lyase (CYP17), a critical enzyme in testicular, adrenal, and tumor androgen biosynthesis (Fig. 1). By suppressing androgen synthesis beyond what is achievable using LHRH agonists and antagonists, abiraterone was shown to increase PFS and OS in men with metastatic CRPC in both the pre– and post–docetaxel administration patient populations [9,10]. A neoadjuvant trial combining abiraterone with leuprolide has since been performed [11]. Overall, 58 men with high-risk prostate cancer (cT3–T4, Gleason score greater than or equal to 7, PSA greater than or equal to 20ng/ml, or PSA velocity greater than 2ng/ml/y) were randomized to receive treatment with abiraterone plus prednisone in combination with leuprolide or leuprolide alone for the first 12 weeks. All patients then subsequently received an additional 12 weeks of combined abiraterone plus prednisone with leuprolide before prostatectomy for 24 weeks of treatment. The primary end point of the study was a comparison of intraprostatic testosterone (and DHT) levels in interim prostate biopsies obtained at 12 weeks. The secondary end points of PSA, pathologic complete response (pCR), and near pCR (less than or equal to 5mm of residual tumor) were assessed on the surgical specimen. Patients receiving the 24 weeks of abiraterone treatment had a trend toward improved combined pCR/near pCR rates (34% vs. 15%, P = 0.0894) compared with those treated with abiraterone for only the final 12 weeks. These results suggest that abiraterone may enhance the potency of traditional androgen deprivation in early prostate cancer and provide a rationale to further study this combination in that disease setting.