Volume 120, Issue 11 p. 1620-1629
Review Article
Free Access

Current trends for the use of androgen deprivation therapy in conjunction with radiotherapy for patients with unfavorable intermediate-risk, high-risk, localized, and locally advanced prostate cancer

Mack Roach III MD

Corresponding Author

Mack Roach III MD

Department of Radiation Oncology, University of California at San Francisco, San Francisco, California

Department of Urology, University of California at San Francisco, San Francisco, California

Corresponding author: Mack Roach III, MD, Department of Radiation Oncology and Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, 1600 Divisadero St, Suite H 1031, San Francisco, CA 94143-1708; Fax: (415) 353-9883; [email protected]Search for more papers by this author
First published: 03 March 2014
Citations: 27

Editing assistance (funded by Ferring Pharmaceuticals) was provided by Thomas Lavelle of Bioscript Medical.

Abstract

Androgen deprivation therapy (ADT) is now a well-established standard of care in combination with definitive radiotherapy for patients with unfavorable intermediate-risk to high-risk locally advanced prostate cancer. It is also well established that combination modality treatment with ADT and radiotherapy is superior to either of these modalities alone for the treatment of patients with high-risk locally advanced disease. Current treatment guidelines for prostate cancer in the United States are based on the estimated risk of recurrence and death. This review examines the clinical evidence underpinning the use of ADT and radiotherapy among patients with high-risk localized and locally advanced disease in the United States. This review also considers the rationale for moving from traditional luteinizing hormone-releasing hormone agonists to more recently developed gonadotrophin-releasing hormone antagonists. Cancer 2014;120:1620–1629. © 2014 American Cancer Society.

INTRODUCTION

Considered an established treatment of patients with advanced prostate cancer (PCa), androgen deprivation therapy (ADT) is increasingly used in men with earlier (ie, nonmetastatic) disease or recurrent disease after definitive treatment.1 Current US guidelines discourage neoadjuvant ADT for patients undergoing radical prostatectomy (RP)2; however, ADT before, during, or after radiotherapy (RT) is recommended for selected men with unfavorable intermediate-risk and high-risk disease.

PCa is categorized by National Comprehensive Cancer Network guidelines according to recurrence risk.2 Assignment of risk is based primarily on clinical stage of disease, Gleason score, and prostate-specific antigen (PSA) levels. This review addresses the selection of therapy by risk group and the rationale for moving from luteinizing hormone-releasing hormone (LHRH) agonists to recently developed gonadotrophin-releasing hormone (GnRH) antagonists.

The Role of ADT in “Early” (Nonmetastatic) PCa

ADT is not recommended by the National Comprehensive Cancer Network as a primary treatment for patients with localized PCa.2, 3 In patients with locally advanced disease, primary therapy with ADT should only be considered in those who are not candidates for definitive therapy. ADT is now routinely recommended before, during, and/or after definitive RT in patients with unfavorable intermediate-risk and high-risk disease.

Neoadjuvant hormonal therapy (NHT), defined as ADT administered before definitive RT, decreases micrometastatic and macroscopic disease,4-8 and reduces prostate volumes by an average of 25% to 30%.9, 10 In the setting of whole-pelvic RT, there appears to be a sequence-dependent favorable interaction between ADT and RT favoring NHT over adjuvant hormonal therapy (AHT).11

Long-Term AHT Versus RT Alone

Guidelines for the optimal duration of ADT in patients with localized disease remain controversial.12 According to current guidelines,2 long-term ADT is indicated in patients with a high to very high risk of disease recurrence, and typically consists of NHT plus RT followed by AHT (for 2-3 years or longer). In patients with an intermediate risk of disease recurrence, short-term NHT typically is used for a total duration of 4 months to 6 months with RT.

Evidence of the value of long-term ADT was initially derived from Radiation Therapy Oncology Group (RTOG) trial 85-31, which investigated the benefits of adjuvant goserelin in patients with locally advanced PCa and high metastatic risk (T3 disease or regional lymphatic involvement).13 Adjuvant therapy with goserelin reduced the risk of local failure and metastasis, and prolonged overall survival (OS) versus RT alone. Compliance was challenging however, with approximately one-third of patients receiving AHT for < 2 years, one-third receiving AHT for 2 to 5 years, and one-third receiving AHT for > 5 years.

The European Organization for Research and Treatment of Cancer (EORTC) 22863 trial evaluated the effectiveness of long-term ADT (3 years) in patients with locally advanced disease (T1-T2 World Health Organization grade 3 or T3-T4 N0-N1 disease).14, 15 Long-term data demonstrated improved 10-year OS (39.8% with RT alone vs 58.1% with adjuvant ADT; P = .0004).16

Although the value of ADT in the setting of dose-escalated RT has been questioned, to the best of our knowledge, to date the evidence for ADT appears to be stronger than the evidence for dose escalation.17-19 Results have been mixed, with some studies suggesting some value and others no value to adding ADT to brachytherapy.20, 21 Data addressing the use of ADT with stereotactic RT are even more limited. Hopefully, with the completion of the RTOG 08-15 trial, the relative value of ADT in dose-escalated RT for patients with intermediate-risk PCa will be answered.

Long-Term Adjuvant ADT Plus RT Versus ADT Alone

Two recent studies compared RT plus ADT versus ADT alone in patients with locally advanced disease. In the first study, RT and ADT were found to reduce the 10-year PCa-specific and overall mortality in half versus ADT alone.22 The second study also included patients with locally advanced disease (T3/T4 [88%]; T2 and a PSA level > 40 μg/L [10%]; or T2, a PSA level > 20 μg/L, and Gleason score ≥ 8 [2%]). Again, combined long-term ADT and RT was associated with substantial benefits with regard to OS and PCa-specific survival versus ADT alone.23 Thus, it is now established that ADT plus RT is superior to ADT or RT alone for the treatment of patients with high-risk locally advanced PCa.

Long-Term Versus Short-Term ADT In Conjunction With RT

RTOG 92-02 compared ADT for 4 months to ADT for 28 months in men with locally advanced disease (T2c-T4N0 and a PSA level < 150 ng/mL).24, 25 At a median follow-up of 11.3 years, long-term ADT significantly improved local progression, distant metastasis, and biochemical failure rates but not OS.26 However, patients with a Gleason score of 8 to 10 demonstrated improved OS with long-term ADT (45.1% vs 31.9%; P = .0061). In an unpublished subset analysis, patients with T3 disease with a Gleason score of 7 also appeared to benefit from long-term ADT (unpublished data).

In EORTC 22961, RT plus short-term (6 months) or long-term (3 years) ADT were compared among patients with locally advanced PCa.27 Short-term ADT was associated with inferior survival.

Based on these studies, patients with high-grade (Gleason score of 8-10) and/or locally advanced disease who are treated with RT have a survival benefit with long-term compared with short-term ADT, consistent with the meta-analysis of RTOG trials.28

Short-Term NHT In Conjunction With RT: Optimal Duration Of ADT and/or Nadir?

Is There A Threshold For the Duration Of Short-Term NHT?

The evidence for short-term NHT plus RT compared with RT alone is supported by several studies.4-8 In the RTOG 86-10 trial, the combination of goserelin plus flutamide for 2 months before RT and concurrent with RT was evaluated in patients with locally advanced PCa (bulky T2-4 tumors with or without pelvic lymph node involvement).29 NHT significantly improved disease-specific survival versus the use of RT alone. With longer-term follow-up (> 15 years), the median survival (8.7 years vs 7.3 years) and 10-year OS rate (43% vs 34%) favored ADT plus RT (P = .12).8 The failure of this study to demonstrate an OS advantage was most likely due to sample size and the inclusion of very high-risk patients (including those with N+ disease). The RTOG 94-08 trial, which included patients with low-risk and intermediate-risk disease (those with T1b–T2b disease and a PSA level ≤ 20 ng/mL) used the same regimen and confirmed an improvement in OS compared with RT alone (Fig. 1).6

Two randomized controlled trials (RCTs) demonstrated that 6 months of NHT also improved OS compared with RT alone.4, 5 In the first study, the addition of 6 months of NHT/concurrent/adjuvant ADT to RT also conferred an OS benefit versus RT alone.4 In the second RCT, a Trans Tasman Radiation Oncology Group study, NHT (6 months) provided a survival benefit versus RT alone in patients with locally advanced disease.5 However, it is interesting to note that 3 months of ADT was not statistically different from 0 or 6 months of ADT. These findings mirrored those reported by Crook et al, which compared 3 months to 8 months of NHT and demonstrated no difference in survival.30 Two earlier RCTs that included patients with localized PCa who were treated either with RT alone or variable durations of short-term NHT plus RT indicated no advantages to NHT administered for a duration of > 5 months.7 Finally, 2 more recent trials compared 4 months versus 8 months and 4 months versus 9 months of ADT and RT and found no differences in outcome (Fig. 2).6, 31, 32

Details are in the caption following the image
Kaplan-Meier estimates of overall survival (OS) are shown in patients with (A) low-risk and (B) intermediate-risk prostate cancer receiving radiotherapy (RT) plus androgen deprivation therapy (ADT) versus radiotherapy alone. Reprinted from Jones CU, Hunt D, McGowan DG et al. Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med. 2011;365:107-118, with permission from The Publishing Division of the Massachusetts Medical Society.6
Overall, these studies suggest that:
  1. NHT given for 3 months appears to be suboptimal for prolonging survival among patients with intermediate-risk to high-risk PCa.7, 30, 33
  2. NHT given for 4 months appears to be comparable to that given for 8 months to 28 months in patients with intermediate-risk disease treated with conventional-dose RT.24, 31
  3. A large phase 3 randomized trial failed to demonstrated a benefit of 28 weeks of NHT compared with 8 weeks.32

Thus, the optimal duration of NHT appears to be 4 to 6 months for men with intermediate-risk disease who are treated with conventional-dose RT. Might this recommendation be individualized using the biologic (biochemical) response of the patient's tumor (PSA nadir)?

Role for PSA Nadir?

The biochemical response to NHT and/or RT, called the “PSA nadir” (lowest value after treatment), rather than its duration, may be useful in predicting outcome and may help to guide therapy.34, 35 For example, although 8 months of NHT before RT did not improve outcomes compared with 3 months, biochemical disease-free survival was significantly higher for patients with a nearly complete “biochemical response,” as indicated by the pre-RT posthormone therapy PSA level (Fig. 3).31, 34, 35 A similar observation was recently made by Tseng et al.36 D'Amico et al performed a systematic review of 2 RCTs using Prentice criteria to assess whether PSA nadir or PSA end concentrations > 0.5 ng/mL were surrogates for PCa-specific mortality.36, 37 In both trials, men receiving RT and 6 months of ADT were significantly less likely to have PSA end and PSA nadir values > 0.5 ng/mL versus those treated with RT alone (P < .0001). In both trials, the randomized treatment group was no longer associated with PCa-specific mortality when the candidate surrogates were included in the model. Therefore, the authors concluded that both PSA metrics satisfied Prentice criteria for surrogacy. They further concluded that after RT and 6 months of ADT, men with PSA end values > 0.5 ng/mL should be considered for long-term ADT, whereas those with higher-risk disease with a PSA nadir > 0.5 ng/mL should be considered for inclusion in RCTs investigating drugs that have extended survival in patients with castration-resistant metastatic PCa. A potential criticism of these analyses is that PSA response to ADT and RT was assessed post hoc.

Details are in the caption following the image
Overall survival curves are shown for patients randomly assigned to 4 months (127 patients) versus 8 months (134 patients) of neoadjuvant hormonal therapy before radiotherapy (median follow-up duration, 92 months). Reprinted with permission from Elsevier from Armstrong JG, Gillham CM, Dunne MT, et al. A randomized trial (Irish Clinical Oncology Research Group 97-01) comparing short versus protracted neoadjuvant hormonal therapy before radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2011;81:35-45.31

In contrast, a posttreatment PSA response assessment was designed prospectively as part of the RTOG 94-13 trial and the findings appear to be informative.38, 39

In the RTOG 94-13 trial, a PSA complete response (PSA-CR) (a decline in the PSA level to < 0.3 ng/mL)40 at the end of NHT (4 months) was a secondary endpoint in the original protocol. For 1069 evaluable patients, the median PSA value at the end of NHT was 0.2 ng/mL. A total of 744 patients (69.6%) achieved a PSA-CR as per protocol. At a median follow-up of 7.2 years, failure to obtain a PSA-CR was significantly associated with worse disease-specific survival (hazards ratio [HR], 1.95; P = .0006;), disease-free survival (HR, 1.2; P = .003), and a higher incidence of distant metastases (HR, 1.92; P = .0002) and biochemical failure (HR, 1.58; P < .0001;). Failure to obtain a post-NHT and RT PSA-CR (< 0.3 ng/mL) appears to be an independent predictor of unfavorable outcomes, and may help to identify patients who could benefit from an extended course of ADT. It is interesting to note that a GnRH antagonist was associated with a significantly quicker PSA reduction versus the agonist in a large phase 3 study (Fig. 4).34, 41

Details are in the caption following the image
Comparison of biochemical disease-free survival is shown in (A) patients with preradiotherapy posthormone therapy (PRPH) prostate-specific antigen (PSA) levels ≤ 0.1 ng/mL versus PRPH PSA levels > 0.1 ng/mL or (B) in high-risk patients with PRPH PSA levels ≤ 0.1 ng/mL versus PRPH PSA levels > 0.1 ng/mL. Reprinted with permission from Elsevier from Alexander A, Crook J, Jones S, et al. Is biochemical response more important than duration of neoadjuvant hormone therapy before radiotherapy for clinically localized prostate cancer? An analysis of the 3- versus 8-month randomized trial. Int J Radiat Oncol Biol Phys. 2010;76:23-30.34

ADT and RT in the Setting of Salvage Therapy

After RP, most patients with rising PSA appear to be candidates for salvage RT and selected patients may benefit from NHT in addition to RT. The role of NHT in this setting is currently being tested in the RTOG 05-34 trial, but off study at the University of California at San Francisco, we usually recommend adding ADT to the treatment of patients with any unfavorable features. A study comparing outcomes for RT alone versus RT and ADT as “salvage” treatment for patients with biochemical failure after RP demonstrated that “unfavorable” patients benefit most from a combined approach.42 Several other series support the observation that ADT combined with RT in the postoperative setting improves outcomes compared with RT alone.43-45 Stephenson et al45 created a nomogram based on > 1500 patients and provided further evidence to support the use of ADT in the salvage setting (see errata).

A phase 3 trial comparing RT alone versus RT plus ADT favored the latter, with significantly better progression-free survival (PFS), disease-specific survival, and OS with combined modalities in patients with lymph node-positive disease.46 A similar observation was made in the retrospective study of Da Pozzo et al,47 in which combination therapy (ADT plus RT) after RP was found to produce better long-term biochemical recurrence-free and cancer-specific survival versus adjuvant ADT alone.

In summary, as salvage therapy, a combined modality approach using ADT plus RT may be beneficial for high-risk patients, including those with lymph node-positive PCa.

Comorbidity and the Benefits of ADT

Another consideration for men with localized but unfavorable-risk PCa is whether they will actually benefit from the addition of ADT in the face of comorbidity.48 In one report, there did not appear to be a significant decrease in the risk of all-cause mortality among men with moderate or severe comorbidities who received ADT.48 In another study, ADT use was associated with excess all-cause mortality in all patients with a history of congestive heart failure or myocardial infarction, regardless of whether they were revascularized, and in diabetics with low-risk disease.49 The authors concluded that ADT for gland downsizing before brachytherapy should be avoided in these men. However, it is interesting to note that a meta-analysis of RCTs evaluating the impact of ADT on the risk of myocardial infarctions failed to detect a detrimental effect, perhaps because such patients comprise a relatively small percentage of the patients placed on such trials.50 Despite the assurances provided by this meta-analysis, the authors pointed out that it is unknown whether these results can be applied to men with a prior history of congestive heart failure or myocardial infarction, thereby making stratification of future randomized trials by cardiovascular comorbidity necessary. Thus, caution may still be advisable in such patients.

Overview of Current Treatment Options

Treatment options in patients with localized PCa, according to disease risk and current evidence, are summarized in Table 151 It is inappropriate to recommend the routine use of ADT plus RT in low-risk patients. For patients with unfavorable intermediate-risk and high-risk disease, adding ADT to RT is the standard of care. Although some subsets of patients at intermediate risk may benefit from NHT, these patients do not appear to benefit from long-term ADT. At the University of California at San Francisco, most patients treated definitively for high-risk or intermediate-risk disease receive intensity-modulated RT with a brachytherapy boost, as outlined in Table 1.51

Table 1. Guidelines for ADT for Localized Prostate Cancer
Treatment Options Risk
Monotherapya Low risk Favorable intermediate risk
Local ± regionalb RT Unfavorablec low risk Intermediate risk
Local and regional RT ± neoadjuvant ADT Very unfavorable low riskd Unfavorable intermediate risk Favorable high risk
Locoregional RT plus neoadjuvant ADT ± long-terme adjuvant ADT Very unfavorable intermediate riskd High risk
Locoregional RT plus neoadjuvant ADT plus long-term ADT Very unfavorable high riskd
  • Abbreviations: ADT, androgen deprivation therapy; RT, radiotherapy.
  • a Monotherapy indicates intensity-modulated RT or a permanent prostate seed implant.
  • b Regional therapy indicates pelvic RT.
  • c Factors characterized as unfavorable include a percentage of positive biopsies >50%.
  • d Factors that result in characterization as very unfavorable include: 1) all or nearly all biopsies being positive; 2) very bulky disease; 3) seminal vesicle involvement; or 4) a prostate-specific antigen level >50 ng/mL.
  • e Long-term indicates ADT for ≥2 years.
  • Reprinted with permission from Elsevier from Roach M, Wallner K, Hsu I-CJ, et al. Cancer of the prostate. In Hoppe R, Phillips TL, Roach M, eds. Leibel and Phillips Textbook of Radiation Oncology: Expert Consult. 3rd ed. Philadelphia: Elsevier Saunders; 2010: 925-986.51

Future Directions in ADT Options in Patients With Early Prostate Cancer

LHRH agonists

Until recently, LHRH agonists were the only major nonsurgical option for castration in patients with PCa. However, they induce pituitary overstimulation, which produces an initial surge in testosterone for approximately 1 to 2 weeks,1, 52 delaying castration. In addition, “mini” testosterone surges may occur with readministration during long-term treatment. In a 6-month study, > 30% of patients receiving an LHRH agonist with or without bicalutamide recorded a testosterone breakthrough of 0.2 ng/mL to 0.5 ng/mL, whereas 25% recorded breakthroughs of > 0.5 ng/mL.53 It remains to be determined whether “mini” testosterone; surges adversely impact the outcomes of men with localized androgen-sensitive disease receiving short-term ADT.

New hormonal agents

A new class of hormonal therapy, GnRH antagonists, offers a therapeutic alternative to LHRH agonists. In contrast to agonists, antagonists act directly, binding immediately and competitively to pituitary GnRH receptors to produce an immediate blockade of luteinizing hormone and follicle-stimulating hormone (FSH) secretion. This leads to faster testosterone suppression without the initial testosterone surge, microsurges, and clinical flare associated with agonists, thus displaying a pharmacological profile closely matching orchiectomy.55

To the best of our knowledge, the most extensively studied GnRH antagonist is degarelix, which is approved in the United States and other countries for the treatment of patients with hormone-dependent advanced PCa. Degarelix has shown low histamine-releasing potential in comparison with other antagonists,56 and thus a low risk of allergic reaction.

In a 1-year, randomized, phase 3 study,41 degarelix and leuprolide (with or without an antiandrogen as flare protection) displayed similar efficacy in terms of maintaining testosterone levels < 0.5 ng/mL from day 28 until the end of the study. Testosterone surges (an increase ≥ 15% on any 2 days in the first 2 weeks) occurred in 80% of patients treated with leuprolide compared with 0% of patients receiving degarelix. Indeed, degarelix produced fast testosterone suppression: 96.1% of patients treated with degarelix 240/80 mg achieved testosterone levels of ≤ 0.5 ng/mL by day 3 versus 0% with leuprolide.

Decreases in PSA were also more rapid with degarelix: by day 14, the median PSA decreased by 65% with degarelix 240/80 mg versus 18% with leuprolide. Additional analysis indicated that degarelix was also associated with a lower risk of PSA progression or death versus leuprolide in the first treatment year (P = .05).56

Patients completing the phase 3 trial could enter an ongoing 5-year extension study.57 Patients initially receiving degarelix continued with the same monthly maintenance dose whereas those previously receiving leuprolide at a dose of 7.5 mg were rerandomized to degarelix 240/80 mg or 240/160 mg. At a median of 27.5 months of follow-up, there was a significant improvement in PSA recurrence PFS HR in patients crossing over from leuprolide to degarelix 240/80 mg (0.20 events per year vs 0.08 events per year after the switch; P = .003); there was no significant change in the HRs for patients continuing on degarelix 240/80 mg.

Another explanation for the trend toward better PSA control with degarelix may be the more effective suppression of FSH.41 Recent studies have suggested a nearly universal characteristic of tumor-related vasculature is the presence of FSH receptors at the tumor/normal tissue interface.58 FSH receptors are expressed on tumor endothelial cells and overexpressed in PCa.58, 59 FSH also appears to be a potent stimulator of PCa growth in vitro. The activation of FSH pathways in vitro leads to PCa cell progression by stimulating angiogenesis via the vascular endothelial growth factor pathway and may link FSH to cancer progression and metastasis. The link also extends to the activation of multiple oncogenic pathways including phosphatidylinositide 3-kinases (PI3K)/AKT and mitogen-activated protein kinase (MAPK) pathways.60 In contrast to GnRH antagonists, LHRH agonists, antiandrogens, and surgical castration do not reduce FSH levels. The clinical significance of this finding remains to be determined, but it may explain the higher freedom from PSA progression rates observed with the use of degarelix versus leuprolide (Figs. 5A and 5B)41, 56 and the more favorable PFS curve than was expected on crossover from leuprolide to degarelix.57

Details are in the caption following the image
Effect of degarelix 240/80 mg (207 patients) versus leuprolide (201 patients) on the prostate-specific antigen levels in patients with prostate cancer. Data are shown as the median ± the standard error. Adapted with permission from Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008;102:1531-1538.41
Details are in the caption following the image

Probability of being free from prostate-specific antigen recurrence is shown in patients with baseline (A) metastatic disease or (B) a prostate-specific antigen level > 20 ng/mL. Reprinted with permission from Elsevier from Tombal B, Miller K, Boccon-Gibod L, et al. Additional analysis of the secondary end point of biochemical recurrence rate in a Phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol. 2010;57:836-842.56

Degarelix was found to be well tolerated in all clinical trials,41, 57, 61, 62 but injection site reactions were higher with degarelix (40% in pooled degarelix arms vs < 1% with leuprolide; P < .001). These occurred predominantly after the first injection, and may be related to different administration routes (subcutaneously with degarelix vs intramuscularly with leuprolide) and a higher injection volume for degarelix. In contrast, degarelix had a statistically lower risk of musculoskeletal events (17% vs 26%; P < .05) and urinary tract infections (3% vs 9%; P < .01) versus leuprolide in the 1-year phase 3 trial.41, 57 A more recent study appears to provide data consistent with this observation.63

Degarelix may improve relief of lower urinary tract symptoms and quality of life (QoL) compared with LHRH agonists plus antiandrogens in patients with PCa.63 In the current study, due to recruitment issues, only 40 patients were included (27 in the degarelix arm and 13 in the goserelin plus bicalutamide arm). Degarelix induced numerically better improvements in prostate volume and peak urinary flow (Table 2).63 In addition, significantly more patients who were treated with degarelix had improved QoL (International Prostate Symptom Score [IPSS] question) at week 12 (85% vs 46%; P = .01).

Table 2. Results of a Comparative Study of Degarelix and Goserelin/Bicalutamide in Patients with Prostate Cancer and LUTS63
Full Analysis PP Analysis
Mean (SEM) Mean (SEM)
Degarelix, n=27a Agonist Plus AA, n=13a P Degarelix, n=26a Agonist plus AA, n=11a P
IPSS score (primary endpoint)
 Baseline 20.1 (1.1) 21.1 (1.6) 20.3 (1.1) 22.2 (1.6)
 Change at wk 12 (LOCF) −11.6 (1.3) −8.6 (1.9) .20 −11.8 (1.5) −5.9 (2.3) .039
 Change at wk 12 (OC) −11.6 (1.3) −7.4 (1.8) 0.065 −11.7 (1.3) −6.0 (2.2) .036
Secondary endpoints
Prostate volume, mL
 Baseline 53.5 (5.5) 50.3 (4.5)
 Change at wk 12 (LOCF) −21.8 (2.7) −14.0 (3.9) .10
Qmax, mL/sec
 Baseline 9.3 (0.8) 8.3 (0.8)
 Change at wk 12 (OC) 3.3 (1.2) 1.3 (1.6) .32
  • Abbreviations: AA, antiandrogen; IPSS, International Prostate Symptom Score; LOCF, last observation carried forward; LUTS, lower urinary tract symptoms; OC, observed cases; PP, per protocol; Qmax, urinary flow rates; SEM, standard error of the mean.
  • a Actual number of observations may vary.
  • Reprinted with permission from Anderson J, Al-Ali G, Wirth M, et al. Degarelix versus goserelin (+ antiandrogen flare protection) in the relief of lower urinary tract symptoms secondary to prostate cancer: results from a Phase IIIb study (NCT00831233). Urol Int. 2013;90:321-328.63

Another trial assessed these drug options at week 12.64 Decreases in the IPSS score were greater in patients treated with degarelix compared with those treated with goserelin (change from baseline in patients with a baseline IPSS > 13 was −6.7 ± 1.8 vs −4.0 ± 1.0; P = .02). The number of patients with a change in the IPSS score of ≥ 3 over baseline was also significantly higher with degarelix (61.0% vs 44.3%; P = .02). Results of a more recent study have provided additional support for this observation.65 However, the clinical value and overall impact on QoL remains to be determined.

Outstanding Questions Regarding the Role of ADT in Patients With Early Prostate Cancer

There are several unresolved questions concerning ADT use in patients with early PCa:
  1. Can antiandrogens be omitted when patients are managed with a GnRH antagonist?
  2. Is there a therapeutic benefit to the suppression of FSH in addition to testosterone?
  3. What is the optimal duration of long-term ADT for patients with unfavorable intermediate-risk and high-risk disease when used with RT?
  4. Should NHT be added in men undergoing adjuvant or salvage RT after RP?

Conclusions

In men with unfavorable, intermediate-risk to high-risk, clinically localized or locally advanced PCa, ADT is used routinely in combination with definitive RT as neoadjuvant or adjuvant therapy, and appears to provide survival benefits in selected patients. A new class of ADT, GnRH antagonists, offers an alternative approach to hormonal therapy in patients with PCa. Currently, the most extensively investigated and widely available GnRH antagonist is degarelix. This agent displays similar efficacy to agonists, but with a more rapid reduction in testosterone and PSA with no testosterone flare and some evidence to suggest that there may be better PSA control. Results of ongoing studies with degarelix in patients with early-stage disease will likely clarify its potential future role in this setting.

FUNDING SUPPORT

No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES

Dr. Roach has received honoraria, lecture fees, and expenses from the following: Takeda; ESI Educational Symposium; e-HIMS Global Congress on Prostate Cancer; Varian Medical Systems; Prostate Cancer Research Institute; Society of Urooncology, Turkey; University of California at Davis; AstraZeneca; Nihon Medi-Physics; and Astellas Pharma. He has acted as an as-yet unpaid consultant for Quest Laboratories. He has received honoraria from Bayer and travel expenses from Morehouse College. Dr. Roach has also acted as a consultant for, member of the Advisory Board of, and provided editorial support for Ferring Pharma (which provided editing assistance for the current article) and has acted as a consultant and member of the advisory board for Millennium and Arista. He has acted as a legal consultant for the Mayo Clinic and as a member of the National Cancer Institute National Cancer Advisory Board. He has also been an author for and received royalties from Up-to-Date, Springer, and Elsevier.