Recent Developments in Androgen Deprivation Therapy for Locally Advanced Prostate Cancer

Oncology & Hematology Review, 2014;10(2):133–8

Abstract:

Locally advanced prostate cancer (LAPC) is often managed with a combination of external beam radiation therapy (EBRT) and androgen deprivation therapy (ADT). Clinical protocols combining ADT and EBRT for the treatment of LAPC were developed based on clinical trials that used conventional-dose EBRT (~70 Gy) and luteinizing hormone-releasing hormone (LHRH) analog monotherapy. However, dose-escalated EBRT (>74 Gy) is in widespread clinical use and potent second-generation agents targeting the androgen axis have recently received US Food and Drug Administration (FDA) approval. These and other recent developments challenge the current standard of care for LAPC. Determining the optimal duration and potency of ADT in combination with dose-escalated EBRT in LAPC is an active area of clinical research seeking to balance the side-effect profile of ADT with its well-established therapeutic benefits. Prospective randomized clinical trials incorporating dose-escalated EBRT and second-generation androgen axis inhibitors are necessary to clarify the role of ADT in this new arena. Further, since biochemical response to neoadjuvant ADT predicts for efficacy of EBRT, new trials should seek to achieve maximal androgen suppression prior to EBRT to increase clinical benefit. Last, recent clinical and preclinical research efforts hold significant promise and seek to provide better predictive markers and expand the therapeutic target spectrum in prostate cancer.

Keywords: Locally advanced prostate cancer (LAPC), androgen deprivation therapy (ADT), androgen receptor (AR), dose-escalation, external beam radiotherapy (EBRT), conformal radiotherapy (CRT), continuous and intermittent ADT (CAD, IAD), prostate specific antigen (P
Disclosure: David A Bader, BS, Jasmina Z Cerne, PhD, and Sean E McGuire, MD, PhD, have no conflicts of interest to declare. No funding was received in the publication of this article.
Received: September 10, 2014 Accepted October 09, 2014 Citation Oncology & Hematology Review, 2014;10(2):133–8
Correspondence: Sean E McGuire, MD, PhD, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, US. E: semcguir@mdanderson.org

Prostate cancer is the most commonly diagnosed noncutaneous cancer and second leading cause of cancer mortality in American men. The lifetime risk for prostate cancer is estimated at one in six; 30,000 men die of the disease annually in the US.1 Prostate cancer is driven by the hormonally responsive transcription factor androgen receptor (AR) and the majority of prostate cancers are detected via serum level increase of the AR target gene prostate-specific antigen (PSA). Localized and low-risk prostate cancer is actively monitored or treated via radical prostatectomy (RP), brachytherapy, or external beam radiation therapy (EBRT).2,3 A small but significant percentage of prostate cancer is locally advanced or metastatic at the time of initial diagnosis. The management of locally advanced prostate cancer (LAPC) is challenging and most often includes the combination of ‘long-term’ (24–36 months) androgen deprivation therapy (ADT) and EBRT. ADT is typically initiated in the neoadjuvant setting, given concurrently with radiotherapy, and continued in the adjuvant setting. Recent studies investigating the duration of androgen deprivation and widespread clinical use of dose-escalated EBRT challenge the role of conventional ADT in LAPC. Further, the consistent finding that biochemical response to neoadjuvant ADT predicts efficacy of subsequent EBRT is supported by recent molecular findings and begs the question as to whether potent second-generation agents targeting the AR axis should be incorporated in the neoadjuvant setting for the treatment of LAPC. However, ADT carries a significant, additive side effect profile and recent efforts to minimize ADT exposure have utilized intermittent ADT and demonstrate that it may be as effective as continuous ADT while reducing ADT-associated side effects in some patients. This review will focus on recent clinical and molecular insights, which will guide management of LAPC in a rational, evidence-based manner. We conclude with a brief section highlighting recent preclinical developments in basic prostate cancer research and novel therapeutic approaches to the treatment of the disease, which may be integrated into future clinical protocols.

Definition of Locally Advanced Prostate Cancer
LAPC has breached the prostatic capsule or invaded the seminal vesicles but has not spread to regional lymph nodes or metastatic sites (T3-4, N0-X, M0). These tumors are often bulky and most risk classification schemes (National Comprehensive Cancer Network,3 Radiation Therapy Oncology Group,4 and D’Amico5) place patients diagnosed with LAPC at high risk for disease recurrence, necessitating the need for aggressive therapeutic approaches up front to maximize the likelihood of a durable response or cure. Since extracapsular extension of the tumor often (not always—see Bonney6 and Stephenson7 for review of RP trials) makes these patients poor surgical candidates, the standard of care at most centers for men diagnosed with LAPC is high-dose conformal EBRT (>74 Gy8) combined with ADT. For these patients, ADT is generally initiated 2–6 months prior to EBRT, given concurrently with EBRT, and continued in the adjuvant setting for a total of 2–3 years.

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Keywords: Locally advanced prostate cancer (LAPC), androgen deprivation therapy (ADT), androgen receptor (AR), dose-escalation, external beam radiotherapy (EBRT), conformal radiotherapy (CRT), continuous and intermittent ADT (CAD, IAD), prostate specific antigen (P