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Androgen deprivation therapy in nonmetastatic prostate cancer patients: Indications, treatment effects, and new predictive biomarkers

Abstract Men with prostate cancer with positive margins, extraprostatic extension, positive lymph nodes, high prostate‐specific antigen, or high Gleason Score are at high risk of recurrence following primary therapy. Androgen deprivation therapy (ADT), which includes medical/surgical castration, antiandrogen therapy, and combined androgen blockade, can be combined with primary therapy to shrink the tumor, reduce margin positivity, and reduce the risk of recurrence. However, many problems still remain, such as optimizing the application of ADT in the treatment of prostate cancer, for example, ideal patient population and optimal timing and duration of therapy. To investigate these problems, we searched PubMed for relevant publications on clinical studies of deprivation therapy for nonmetastatic prostate cancer. In this review, we discuss our findings on the role of ADT in the treatment of castrate‐sensitive nonmetastatic prostate cancer and the adverse effects associated with ADT. We also examine the recent advances in new predictive biomarkers for ADT, many of which are currently in the exploratory phase. Overall, the addition of ADT to primary therapy improves outcomes for patients with intermediate‐ or high‐risk prostate cancer.


INTRODUCTION
Prostate cancer is the second most common cancer affecting men, with an estimated 1.1 million new cases in the world in 2012. 1,2 Primary therapy consists of radical prostatectomy or radiotherapy. However, patients with a positive margin, extraprostatic extension, lymph node involvement, high prostate-specific antigen (PSA), or high Gleason Score (GS) are at high risk of prostate cancer recurrence following primary therapy. In these patients, androgen deprivation therapy (ADT) can be given as neoadjuvant therapy prior to primary therapy to shrink the tumor and reduce margin positivity. Radiotherapy, ADT, or a combination of the two can also be given as adjuvant treatment following primary therapy to reduce the risk of recurrence.
There are several different ADT modalities, which aim to deplete androgen levels by suppressing testicular androgen secretion or by inhibiting circulating androgens through targeting the androgen receptor. Consequently, ADT can be delivered by medical or surgical This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. castration, antiandrogen therapy, and combined androgen blockade (CAB). 3,4 Although ADT monotherapy is not appropriate for clinically localized prostate cancer, the addition of ADT to primary therapy has been shown to improve outcomes significantly for certain men with intermediate-or high-risk prostate cancer. 4 However, many questions still remain unanswered, including the ideal patient population and optimal timing and duration of therapy. Exploring these questions is complicated by long survival and observation times, leading to fewer opportunities to conduct ideal randomized clinical trials. Furthermore, diverse study endpoints make comparisons difficult and a standard comparator is lacking. A need to address this challenge in prostate cancer patients has been exemplified by the Intermediate Clinical Endpoints in Cancer of the Prostate (ICECap) working group in the development of an intermediate clinical endpoint to serve as a robust surrogate for overall survival (OS). 5 This review, therefore, discusses the current findings on the role of ADT in the treatment of castrate-sensitive nonmetastatic prostate cancer. We also propose a treatment roadmap for ADT in this setting based on the available evidence.

METHODS
A PubMed search of all prospective and retrospective studies or meta-analyses evaluating the outcomes of men treated with ADT for nonmetastatic prostate cancer published since 2000 was conducted.
Findings on the use of neoadjuvant and adjuvant therapy in combination with radical prostatectomy or radiotherapy, and ADT at the time of biochemical recurrence were reviewed.
Based on existing publications, long-term ADT treatment has been defined as treatment duration ≥18 months. 6

ADT for patients who received radical prostatectomy as a primary treatment
Radical prostatectomy is typically used for patients with localized disease who have an estimated life expectancy of over 10 years, and in patients with locally advanced disease.

Neoadjuvant ADT plus radical prostatectomy
Men with early-stage prostate cancer with intermediate or high risk of recurrence may be considered for neoadjuvant ADT prior to primary treatment. Neoadjuvant ADT before prostatectomy has been shown to provide long-term progression-free survival (PFS) 2 and to significantly reduce the risk of recurrence (Table 1)

Adjuvant ADT following radical prostatectomy
A number of studies have demonstrated that adjuvant ADT following radical prostatectomy results in excellent PFS, OS, and diseasespecific survival in patients with high-risk localized or locally advanced prostate cancer (Table 1). [15][16][17][18] Several of these studies investigated the optimal timing and duration of ADT following radical prostatectomy. A matched cohort study (N = 8290) compared outcomes of patients with lymph node-negative Although ADT has been shown to significantly improve OS following radical prostatectomy, patients with high-risk prostate cancer still experience worse disease progression and shorter OS than patients with lower-risk disease. Chemotherapy may improve outcomes in a number of solid tumors, and the addition of chemotherapy to adjuvant ADT following radical prostatectomy was investigated in the SWOG S9921 study. Patients with high-risk features at radical prostatectomy (N = 961) received 2 years of CAB alone or in combination with mitoxantrone chemotherapy and prednisone. 17,20 Survival results were greater than expected and similar for both treatment regimens.
Ten-year disease-free survival was 72% in both treatment groups (HR,

Adjuvant radiotherapy plus ADT following radical prostatectomy
Radiotherapy as adjuvant therapy following radical prostatectomy was also reported to improve outcomes in a number of studies. [22][23][24] Compared with radical prostatectomy alone, adjuvant radiotherapy has been shown to significantly improve biochemical PFS (10-year PFS: 56% vs 35%; P < 0.0001), 22-24 median metastasis-free survival (14.7 years vs 12.9 years; HR, 0.71; P = 0.016), 25 and median OS (15.2 years vs 13.3 years; HR, 0.72; P = 0.023). 25 The combination of adjuvant ADT plus adjuvant radiotherapy following radical prostatectomy was analyzed in a retrospective study (N = 132), which found that men with high-risk prostate cancer who received adjuvant radiotherapy plus ADT following prostatectomy had excellent outcomes (Table 1). 26 Five-year biochemical relapse-free, metastasis-free, disease-specific, and OS rates were 90.5, 95.9, 100, and 90.6%, respectively. The median duration of ADT was 24 months . Further investigation into this combination regimen is therefore warranted.

Summary of findings for adjuvant radiotherapy plus ADT following radical prostatectomy
A strong level of evidence supports combining adjuvant ADT with adjuvant radiotherapy following radical prostatectomy, which metaanalysis has shown to improve outcomes compared with radical prostatectomy alone, particularly in men with high-risk prostate cancer. Five-year biochemical relapse-free, metastasis-free, diseasespecific, and OS rates were >90% with long-term ADT in combination with adjuvant radiotherapy.

Biochemical recurrence following radical prostatectomy
The standard of care for patients with biochemical recurrence is ADT.
However, the optimal timing of ADT (early or late) and the optimal adjuvant regimen remain controversial. Three phase 3 trials have investigated these issues ( Table 1).
The timing of antigen deprivation (TOAD) study (n = 293) investigated immediate treatment with ADT versus delayed ADT for men with PSA relapse following radical prostatectomy or radiotherapy, and men with incurable prostate cancer. 27 The investigated timing of delayed ADT was ≥2 years after biochemical recurrence, unless earlier treatment was clinically indicated. Immediate ADT significantly improved OS (5-year OS was 91.2% vs 86.4%; P = 0.047) compared with delayed ADT.
The RTOG 9601 study (n = 760) investigated long-term ADT plus salvage radiotherapy versus salvage radiotherapy alone in patients with rising PSA following radical prostatectomy. 29

Summary of findings for biochemical recurrence following radical prostatectomy
ADT with or without radiotherapy at the time of biochemical relapse significantly improved outcomes for patients who previously received radical prostatectomy as a primary therapy, which is strongly supported by three phase 3, randomized, prospective trials. Among the salvage treatment options that have been studied, radiotherapy plus longterm ADT provided an OS benefit. Thus, radiotherapy plus long-term ADT is recommended at the time of biochemical recurrence, especially for men with GS ≥7, PSA = 0.7-4.0 ng/mL, or positive surgical margins.

ADT for patients who received radiotherapy as a primary treatment
Radiotherapy, either external beam or brachytherapy, can be administered alone, following radical prostatectomy, or in combination with ADT to patients with prostate cancer. In patients with low-risk localized prostate cancer, radiotherapy alone has been shown to provide durable control, with 73% each disease-free survival rates at 15, 20, and 25 years. 30 Many studies have shown that radiotherapy plus adjuvant ADT provides a benefit for patients with intermediate-risk, high-risk, or locally advanced disease (Table 2). Results from a meta-analysis indicated that adjuvant ADT following radiotherapy significantly improves 5-year OS (odds ratio [OR], 1.46; P = 0.0009), disease-specific survival (OR, 2.10; P = 0.00001), and disease-free survival (OR, 2.53; P < 0.00001). 7 In the phase 3 RTOG 94-08 study (n = 1979), short-term CAB for 4 months before and during radiotherapy was associated with a decreased disease-specific mortality and increased OS. 33

Radiotherapy plus ADT for high-risk localized and locally advanced prostate cancer
For high-risk disease, several studies have investigated various lengths of ADT therapy in combination with radiotherapy. The results demonstrate better outcomes with long-term use of ADT, which has become the standard of care.
The TROG 96.01 study (N = 818) compared three different treatment groups: radiotherapy preceded by 6 months of neoadjuvant ADT, radiotherapy plus 3 months of neoadjuvant ADT, and radiotherapy alone in patients with high-risk, localized prostate cancer. 35 The study showed that 6 months of ADT significantly improved outcomes compared with radiotherapy alone, and also improved outcomes compared with 3 months of ADT.
In the phase 3 DART01/05 GICOR study (N = 355), men with intermediate-or high-risk prostate cancer were treated with 4 months of neoadjuvant plus concurrent ADT combined with radiotherapy (short-term ADT), or with the same treatment followed by 24 months of adjuvant ADT (long-term ADT). 36 Long-term ADT plus radiotherapy improved biochemical control and OS compared with short-term ADT. For locally advanced disease, many studies have demonstrated that the addition of long-term adjuvant therapy following radiotherapy improved outcomes. The phase 3 RTOG 8610 study (N = 456) investigated 2 months of neoadjuvant CAB plus 2 months of ADT during external beam radiotherapy versus radiotherapy alone for men with locally advanced prostate cancer with or without lymph node involvement. 38 The addition of ADT improved 10-year disease-free survival, disease-specific mortality, distant metastases, and biochemical failure. There was also a trend toward improved OS.  ADT, androgen deprivation therapy; BFS, biochemical progression-free survival; CAB, combined androgen blockade; DFS, disease-free survival; DSM, disease-specific mortality; DSS, disease-specific survival; EBRT, external beam radiation therapy; GS, Gleason score; LHRH, luteinizing hormone-releasing hormone; NR, not reported; OS, overall survival; PFS, progression-free survival; PSA, prostate-specific antigen; RP, radical prostatectomy; RT, radiotherapy. a Level of evidence determined by study design: 1, meta-analysis or systematic review and 2, randomized controlled trial.

Biochemical recurrence following radiotherapy
The SWOG-JPR7 study investigated intermittent versus continuous ADT in men with elevated PSA following primary or salvage radiotherapy (N = 1386; Table 2). 43

New predictive biomarkers for ADT and personalized therapy
Prognostic and predictive biomarkers have the potential for optimizing therapy through personalization of treatment regimens. The use of blood or urine-based prognostic markers, present a minimally invasive method for determining treatment response, allowing more responsive adjustments to therapy when necessary.
Inactivating phosphate and tensin homolog (PTEN) mutations are commonly detected in prostate cancers and are associated with a poorer prognosis. PTEN expression may also be able to predict response to ADT; this is currently being investigated in patients with intermediate-and high-risk prostate cancer (Clinicaltrials.gov identifier NCT01542021). What's more, subtyping based on luminal and basal lineage could also potentially serve as a predictive biomarker. 56 Results from an analysis of 1567 prostate cancer samples from high-risk patients treated with prostatectomy showed that luminal B prostate cancers were significantly associated with response to ADT: 10-year metastasis occurred in 33% for those treated with ADT versus 55% for those untreated (P = 0.006), suggesting that luminal/basal subtyping may be useful in the selection of patient treatment. 56 Circulating tumor cells (CTCs) are increasingly investigated prognostic biomarkers in many cancers, including prostate cancer. High compared to 11 months [EGFR−]; P < 0.05). 59 By using a blood test instead of radiographic imaging, monitoring can be performed more frequently, allowing prompt treatment before metastatic tumors become clinically detectable.
Currently, ongoing clinical trials are investigating the use of urine metabolomic profiling, as well as the expression of tumor markers in CTCs as biomarkers for predicting response to therapy. These studies are being explored in small populations and will require further validation before they can be applied in a clinical setting.

CONCLUSIONS
The addition of ADT to primary therapy significantly improves outcomes for certain men with intermediate-or high-risk prostate cancer and is recommended in these settings in our proposed roadmap for treatment ( Figure 1). Among men who undergo radical prostatectomy as primary therapy, neoadjuvant ADT is feasible in those with localized or locally advanced prostate cancer and warrants further exploration.
Long-term adjuvant ADT is recommended immediately following radical prostatectomy for men with high-risk localized or locally advanced prostate cancer, particularly those with positive lymph nodes. Radiotherapy plus long-term ADT provided an OS benefit and is recommended at the time of biochemical recurrence, particularly for men with GS ≥7, PSA 0.7-4.0 ng/mL, or positive surgical margins.
ADT with an LHRHa and an antiandrogen is recommended for 4-6 months following radiotherapy as a primary therapy, for patients with intermediate-risk disease, while ADT with an LHRHa with or without an antiandrogen is recommended for 2-3 years in high-risk localized or locally advanced disease. Intermittent ADT was noninferior to continuous therapy following biochemical recurrence but it improved quality of life, particularly during nontreatment phases. Further research is warranted to determine the optimal PSA level at which to begin intermittent ADT; however, the inherent challenges associated with undertaking such studies makes identifying optimal PSA levels an elusive target. Several adverse events are frequently associated with ADT. While they are not dose limiting, some of these events can cause serious morbidity such as death from CVD or bone fractures due to loss of bone mineral density. As such, careful monitoring of patients is required during use of ADT. A predictive biomarker may be helpful to identify patients who would benefit from ADT. It is still at the stage of exploration and research. Further clinical studies are needed to confirm and validate the clinical value of these predictive biomarkers, so as to guide clinical practice in future.