Phase II trial of short-term neoadjuvant docetaxel and complete androgen blockade in high-risk prostate cancer

Abstract

BACKGROUND: The low probability of curing high-risk prostate cancer (PC) with local therapy suggests the need to study modality of therapeutic approaches. To this end, a prospective phase II trial of neoadjuvant docetaxel (D) and complete androgen blockade (CAB) was carried out in high-risk PC patients. The primary end point was to detect at least 10% of pCRs after chemohormonal treatment. METHODS: Patients with T1c -T2 clinical stage with prostate-specific antigen (PSA) 420 ng ml À1 and/or Gleason score X7 (4 þ 3) and T3 were included. Treatment consisted of three cycles of D 36 mg m À2 on days 1, 8 and 15 every 28 days concomitant with CAB, followed by radical prostatectomy (RP). RESULTS: A total of 57 patients were included. Clinical stage was T1c, 11 patients (19.3%); T2, 30 (52.6%) and T3, 16 (28%) patients. Gleason score was X7 (4 þ 3) in 44 (77%) patients and PSA 420 ng ml À1 in 15 (26%) patients. Treatment was well tolerated with 51 (89.9%) patients completing neoadjuvant therapy together with RP. The rate of pCR was 6% (three patients). Three (6%) additional patients had microscopic residual tumour (near pCR) in prostate specimen. With a median follow-up of 35 months, 18 (31.6%) patients presented PSA relapse. CONCLUSION: Short-term neoadjuvant D and CAB induced a 6% pCR rate, which is close to what would be expected with ADT alone. The combination was generally well tolerated.

Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer

“…Our data are in concordance with these reports. We observed that the expression of AR and several AR-regulated genes (i.e., ZEB1, IL6, TGFBR3, KLF9) increased in treated tumors, even though serum PSA levels decreased under therapy in most cases, as we previously reported (17). Moreover, high levels of AR correlated with high risk of clinical relapse.…”

“…The study included 28 patients with high-risk localized prostate cancer from a previously published, multicenter, phase II trial of neoadjuvant docetaxel plus androgen deprivation followed by radical prostatectomy (17) and 36 control patients with high-risk prostate cancer treated with radical prostatectomy without neoadjuvant treatment. Of the 57 participants in the clinical trial (17), 29 were not included in this study: 23 patients did not consent to participation in the molecular substudy and insufficient material for molecular analysis was available for 6 patients, 3 of whom had a pathologic complete response (pCR) and 3 had microscopic residual tumor (near pCR) in the prostate specimen.…”

“…In the present study, 73 genes from that study together with 20 genes from the literature were tested in tumor specimens of patients with high-risk localized prostate cancer included in a clinical trial of neoadjuvant hormone chemotherapy (17), and compared with nontreated specimens with similar clinical characteristics. This approach was based on the notion that residual tumor cells in prostatectomy specimens after neoadjuvant systemic therapy are likely enriched for resistant tumor cells and their molecular characterization may provide important information on mechanisms of resistance (18).…”

Integrating chemohormonal therapy and surgery in known or suspected lymph node metastatic prostate cancer

“…Unfortunately, the results of studies of taxanes as single agents or in combination with ADT in previously untreated high-risk patients have suggested no enhanced benefit over the use of ADT alone concerning pathologic as well as long-term outcomes, even when the docetaxel was administered every 3 weeks and at doses higher than that in our trial. 22–26 Consistently, >75% and approximately 50% of our patients had evidence of respectively residual locally advanced and pelvic LN–metastatic disease after completing treatment, and 9 have died of progressive prostate cancer. Very recent data from a randomized phase III clinical trial (CHAARTED) suggests that, among patients newly diagnosed with metastatic hormone sensitive prostate cancer, those presenting with visceral disease and/or ≥4 bone lesions are the ones that benefit the most from the early use of docetaxel.…”

Beyond Castration—Defining Future Directions in the Hormonal Treatment of Prostate Cancer

“…This strategy certainly has not been beneficial in breast cancer [39,40], but there is the theoretical potential that exposure to a highly androgen-deficient state, either prior to or simultaneous with chemotherapy, may reduce the efficacy of subsequent taxane-based chemotherapy as taxanes may exert part if not all of their effect [41] by blocking AR nuclear translocation, an effect that may be lost [42] with alternative AR growth pathways activated. To date, this concept has been most closely modelled in the neoadjuvant studies of androgen withdrawal and docetaxel which to date indicate that clinically relevant disease remains despite combination therapies [43,44], and to date, the histological outcomes are no different from neoadjuvant hormonal therapy alone. Nevertheless, this concept will likely require assessment in prospective wellcontrolled studies, although it will be difficult to perceive how such a hypothesis will be practically tested given the suggestion that significant numbers of men will start taking abiraterone prior to chemotherapy in the near future and potential crossover will limit an effect on overall survival.…”