Celestia S. Higano, MD, FACP, medical oncologist with expertise in genitourinary oncology, member, Clinical Research Division, Fred Hutchinson Cancer Research Center, professor, Department of Medicine and Urology, University of Washington, Seattle Cancer Care Alliance, discusses the state of immunotherapy in prostate cancer.

In 2010, sipuleucel-T (Provenge) became the first immuno-oncology drug to receive regulatory approval in prostate cancer. Although single-agent immunotherapy has shown modest activity in this space, combinations could help harness immune response.

Many small, phase 1/2 trials are ongoing with immunotherapy, says Higano. At the University of Washington, investigators are administering a vaccine followed by a PD-1 inhibitor. Many clinical trials are evaluating PD-1 inhibitors in combination with other agents, as well as with or without PARP inhibitors, concludes Higano.

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Celestia S. Higano, MD, FACP, discusses the state of immunotherapy in prostate cancer.

Dr. Higano on the State of Immunotherapy in Prostate Cancer

Neal Shore, MD, FACS, is the medical director for the Carolina Urologic Research Center

	To determine if 7 months of intermittent degarelix treatment is noninferior to continuous androgen deprivation in maintaining suppression of prostate-specific antigen (PSA) at 14 months.	

	Patients with rising PSA after prior definitive therapy were randomized to intermittent (degarelix) or continuous (degarelix or leuprolide) treatment arms. All patients initially received 7 months of androgen deprivation. After 7 months, men randomized to intermittent therapy were scheduled to enter a 7-month off-treatment period; degarelix was restarted if PSA levels were >2 ng/mL. Predefined criteria for noninferiority of the primary endpoint, proportion of patients with PSA ≤4 ng/mL, was the lower limit of the 95% CI difference between the intermittent and continuous treatment arms being greater than -12.5% at month 14. PSA, testosterone, and quality-of-life measures were assessed in all patients at multiple time points.

	A total of 409 patients were randomized to intermittent (degarelix, n = 177) or continuous (degarelix, n = 50; leuprolide, n = 182) treatment. At month 14, the lower confidence interval limit for intermittent versus continuous treatment was -0.19%; therefore, noninferiority was established. No patients in the intermittent arm had PSA >4 ng/mL at month 14, although 35 patients restarted degarelix before month 14. PSA was >4 ng/mL in 3 (1.6%) patients receiving continuous treatment. In the intermittent arm, 116 (85%) men had testosterone >0.5 ng/mL at a median of 112 days off therapy (95% CI, 112-140). Intermittent treatment was associated with improved sexual drive assessed by the sexual function inventory at month 14 (

 = 0.027). The most frequently reported adverse event in all arms was hot flashes. Injection site reactions were more frequent in patients receiving degarelix.

	Intermittent degarelix administered as described is noninferior to continuous androgen deprivation in maintaining PSA suppression at month 14. These data indicate that degarelix is a suitable treatment option in men being considered for intermittent androgen ablation.

Androgen deprivation therapy (ADT) is the mainstay of treatment for men with metastatic prostate cancer (PCa) and has been shown to improve survival in combination with radiation therapy in men with high-risk localized disease.

It is also commonly used to treat men with biochemical relapse, especially when classified as high risk. Unlike bilateral orchiectomy, medical castration is reversible and may be used on an intermittent basis. ADT is associated with characteristic side effects including hot flashes; decreased libido, bone mineral density, body mass, muscle mass, and strength; increased body fat, weight; insulin resistance; cardiovascular toxicity; and emotional and cognitive changes.

 The potential physical benefits of an intermittent regimen with one or more off-treatment periods are considered to be due to complete or partial testosterone recovery allowing moderation of side effects and improvement of quality of life (QoL).

Two phase III noninferiority trials of luteinizing hormone-releasing hormone (LHRH) agonists have compared intermittent androgen deprivation (IAD) with continuous androgen deprivation (CAD).

 The National Cancer Institute of Canada trial, PR-7 (NCT00003653), enrolled patients with biochemical failure after primary or salvage radiotherapy for localized disease.7 IAD was noninferior to CAD for overall survival (8.8 vs 9.1 years, respectively; HR = 1.02), and scores for hot flashes, desire for sexual activity, and urinary symptoms were significantly improved. Also, men in the CAD arm of PR-7 who achieved nadir testosterone levels <20 ng/mL had an increased time to hormone resistance, demonstrating the importance of achieving low testosterone levels while on treatment.

The second trial, SWOG 9346 (NCT00002651), compared IAD with CAD for patients diagnosed with metastatic disease (median follow-up, 9.8 years).

 Median survival was 5.8 years and 5.1 years in the CAD and IAD arms, respectively (HR, 1.10). Although survival noninferiority for IAD was inconclusive, IAD was associated with better erectile function and mental health 3 months after discontinuing ADT in the IAD arm compared withthe CAD arm.

Degarelix is a gonadotropin-releasing hormone (GnRH) antagonist providing rapid and sustained testosterone suppression, yet, it has a short half-life of approximately 4 weeks.

 Unlike LHRH agonists, GnRH antagonists immediately suppress the secretion of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone without initially overstimulating the GnRH receptor. Thus, there is no transient increase in testosterone, no need for flare protection with an antiandrogen, and a more rapid castration,10 which may be favorable characteristics for IAD therapy.

A recent noncomparative study of European men with histologically confirmed prostate cancer requiring ADT demonstrated that IAD with degarelix was well tolerated, and increases in testosterone were associated with improved erectile function prior to prostate-specific antigen (PSA) reaching the predefined level at which treatment was reinitiated (>4 ng/ mL).

 The current trial aimed to determine if intermittent use of a GnRH antagonist, degarelix, is non-inferior to continuous use of an LHRH agonist in maintaining a pre-specified level of PSA suppression at month 14 (≤4 ng/mL) while evaluating testosterone levels and potential impact on QoL. Non-inferiority in regards of PSA levels was established if the lower limit of the 95% CI difference between the intermittent and continuous treatment arms was greater than -12.5%, a predefined difference considered not clinically relevant. Addressing this endpoint will provide preliminary data as to whether an antagonist such as degarelix is equivalent to LHRH agonists when used as intermittent therapy and assess tolerability compared with continuous ADT.

Study Design: This open-label, controlled, parallel-arm, multicenter trial (NCT00928434) randomized patients 7:2:7 to intermittent (degarelix; n = 177) or continuous (degarelix; n = 50; leuprolide; n = 182) treatment, respectively. Randomization lists were prepared centrally (Department of Global Biometrics, Ferring Pharmaceuticals A/S) using a validated computer program. The trial was conducted in accordance with the Declaration of Helsinki, with applicable FDA regulations and the International Conference on Harmonization Guidelines for Good Clinical Practice. Appropriate Institutional Review Boards for each site approved the study protocol and amendments, and all patientsprovided written, informed consent.

Men ≥18 years with histologically confirmed prostate adenocarcinoma and a negative bone scan with rising serum PSA levels after prior definitive therapy for whom hormone therapy was indicated were eligible. The minimum criteria were screening serum testosterone ≥1.5 ng/mL, Eastern Cooperative Oncology Group score ≤2, and a rise in PSA of ≥0.2 ng/mL following radical prostatectomy or 3 separate PSA levels higher than nadir PSA after other primary therapy. Exclusion criteria included hormone therapy within 6 months or bicalutamide within 2 months of randomization. Patients receiving neoadjuvant hormone therapy for more than 4 months or adjuvant hormone therapy for more than 6 months were excluded.

The initiation phase comprised 7 months of degarelix 1-month depot formulation (starting dose 240 mg; 6 monthly 80-mg maintenance doses) or leuprolide (1-month injection [7.5 mg] and two 3-month [22.5 mg] injections). Patients with PSA ≤2 ng/mL at month 7 entered a second 7-month phase. Intermittent arm patients entered an off-treatment period. If PSA increased to >2 ng/mL, degarelix was reintroduced (240 mg followed by 80 mg monthly) until PSA was ≤2 ng/mL or the investigator determined the patient needed another treatment. Patients in the continuous treatment arms were maintained on monthly degarelix or leuprolide every three months. Blood samples for testosterone and PSA were obtained monthly and analyzed at a certified central laboratory. Serum testosterone levels were determined using a validated liquid chromatography system with tandem mass spectrometry assay. PSA was analyzed using a validated immunoassay.

The safety analysis set comprised all men who received at least one dose of ADT and included laboratory values (biochemistry, hematology, and urine analysis) and clinical variables (including patient-reported injection-site tolerability, adverse events (AEs), electrocardiograms, and physical examination). AEs were graded according to National Cancer Institute Common Terminology Criteria for AEs (Version 4.02).

The primary endpoint was the proportion of patients with serum PSA ≤4.0 ng/mL at month 14 for intermittent degarelix treatment vs continuous therapy (degarelix and leuprolide arms combined). Noninferiority was established if the lower limit of the 95% CI difference between the intermittent and continuous treatments was greater than -12.5%. Secondary endpoints included time to PSA >2 ng/mL in the intermittent arm during off-treatment time vs continuous therapy, time to testosterone >0.5 ng/mL and ≥1.5 ng/mL in the intermittent arm, proportion of intermittent-arm patients requiring additional degarelix dosing, development of castration resistance (2 consecutive rises in PSA ≥2 weeks apart and 50% greater than nadir despite castrate levels of testosterone),13,14 and disease progression (rising PSA despite castrate testosterone levels, additional PCa therapy, or death from any cause). Efficacy endpoints were assessed at month 14 in all patients eligible for the second phase (with at least one primary endpoint efficacy measurement between months 7 — 14).

Additional secondary endpoints relating to QoL and sexual function were assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P) and the sexual function inventory (SFI), respectively. FACT-P was completed at every visit during the study and assesses physical, social/family, emotional, and functional well-being, as well as prostate-related symptoms. The SFI was completed at baseline, visit 4, and prior to stopping treatment. During the off-treatment phase, the SFI was completed every 2 months and at the end-of-trial visit. It is a widely used, multidimensional, self-report instrument specifically designed to evaluate sexual function and satisfaction of men on treatment or with conditions that may affect sexual function.

Primary endpoint response rates between intermittent and continuous therapy were compared using Fisher’s exact test and the confidence interval determined using a normal approximation to the binomial distribution. Assuming a common response rate of 80% of patients with PSA <4 ng/mL at month 14 and adjusting for patients potentially discontinued after 7 months, 175 patients in both the intermittent degarelix and continuous leuprolide arms and 50 in the continuous degarelix arm would give 80% power to detect a non-inferiority limit of -12.5%. Secondary endpoints comprising time-to-event variables were assessed by the Kaplan-Meier method and log-rank test. QoL and SFI outcomes were assessed by cross-sectional analyses of covariance (ANCOVA) using baseline values as a covariate. Exploratory sub-analyses for the intermittent arm included time to testosterone >0.5 ng/mL according to age, baseline PSA, disease stage, and PSA at month 7. Efficacy analysis were carried out for the subjects eligible for the second phase of the study with at least one efficacy measurement in this phase.

In total, 409 patients were randomized to intermittent (degarelix, n = 177) or continuous treatment (degarelix, n = 50; leuprolide, n = 182). Baseline characteristics are shown in Table 1. Of 403 patients who initiated treatment, 25 (6%) patients had PSA >2.0 ng/mL at month 7 and were ineligible to enter the second phase of the study 

 An additional 50 patients discontinued before the seventh month, 328 patients entered the second phase, and 301 (74%) patients completed the trial 

. Overall, 37 patients discontinued due to AEs; the other main reasons for patients not completing the trial are shown in Figure 1. Response Analysis: The response rate was similar between the intermittent arm (100%; 95% CI, 97.3—100.0) and the combined continuous arms (98.4%, 95% CI; 95.5–99.7; 

. The lower CI limit for the comparison of intermittent vs combined continuous arms was —0.19%; and therefore the threshold for noninferiority was met. Time to PSA >4.0 ng/mL was similar between the intermittent arm and the combined continuous arms (

 = 0.4758). Time to PSA >4.0 ng/mL was not different between the intermittent arm and either continuous degarelix or leuprolide 

. At month 14, no patients in the intermittent arm and 3 (1.6%) in the combined continuous arms had PSA >4 ng/mL (1 [2.4%] and 2 [1.3%] patients in the continuous degarelix and leuprolide arms, respectively; Figure 2a). In the intermittent arm, 35 (26%) patients restarted degarelix before month 14 for PSA >2 ng/mL.

During months 7 to 14, 38 (28%) patients in the intermittent arm had PSA >2 ng/mL compared with 3 (6%) and 8 (5%) patients in the continuous degarelix and leuprolide arms, respectively (P <0.001). Castration resistance occurred in 3 (2%) patients in the intermittent arm prior to month 7, 1 (2%) patient in the continuous degarelix arm between month 7 and 14, and no patients in the continuous leuprolide arm.

Testosterone suppression was similar across study arms after treatment initiation. Median testosterone levels at month 3 were 0.07 ng/mL (range 0.02—0.31 ng/mL), 0.06 ng/mL (range 0.02–0.22 ng/mL), and 0.08 ng/mL (range 0.02–0.38 ng/mL) in the intermittent and continuous degarelix and leuprolide arms, respectively. Testosterone values were significantly higher in the intermittent arm during months 9 to 14 when patients were off therapy (

 <0.05 at each monthly measurement) (Figure 3a). At month 14, median testosterone was 1.65 ng/mL (range 0.015—16.2) in the intermittent arm, 0.075 ng/mL (range 0.015 – 0.94) in the continuous degarelix arm, and 0.07 ng/mL (range 0.015 – 0.25) in the continuous leuprolide arm.

Testosterone levels >0.5 ng/mL occurred in 116 (85%) intermittent-arm patients after a median of 112 days (95% CI, 112—140) from the cessation of degarelix (28 days after the last dose). The probability of testosterone >0.5 ng/mL was higher for patients aged differences in time to testosterone >0.5 ng/mL in the intermittent arm by disease stage, baseline PSA level, and PSA level at month 7 (P = 0.077, 0.506, and 0.384, respectively). Increase in testosterone to normal levels (>1.5 ng/mL) occurred in 94 (69%) intermittentarm patients (median 168 days, 95% CI 140–168 days) and 0 (0%) and 1 (<1%) in the continuous degarelix and leuprolide arms, respectively. After 14 months, the median testosterone levels in men in the intermittent arm who had reached normal levels was 2.67 ng/mL (range 0.015 – 16.2). Quality of Life: Sexual drive as measured in the SFI was improved at month 14 in patients in the intermittent arm versus those on continuous degarelix or leuprolide therapy (

 In the intermittent arm, men with normal SFI scores at baseline were more likely to have significant increases in total SFI score (P = 0.034), sexual drive (

 = 0.010) while off treatment than than those on continuous degarelix and leuprolide arms with normal SFI scores at baseline.

Treatment emergent AEs were reported for 159 (91%) intermittent patients and 47 (94%) and 158 (89%) of patients in the continuous degarelix and continuous leuprolide arms, respectively (Table 2). The most frequently reported AE was hot flashes in 87 (50%), 26 (52%), and 110 (62%) of patients in the intermittent degarelix, continuous degarelix, and continuous leuprolide arms, respectively. Injection site reactions were reported by 58% and 66% of intermittent and continuous degarelix patients, respectively, and by 12% of patients in the continuous leuprolide arm. Injection site reactions were mild to moderate (grade 1—2) except 1 patient with grade 4 injection site erythema, induration, and pain (continuous degarelix arm). The type and frequency of AEs during the first 7 months and months 7 to 14 of the study were similar. Grade 3 AEs were reported for 26 (15%), 6 (12%), and 18 (10%) patients in the intermittent degarelix, continuous degarelix, and continuous leuprolide arms, respectively (Table 2). There were 4 deaths (2 patients each in the intermittent degarelix and continuous leuprolide arms), none of which were considered related to study treatment or prostate cancer. Overall, 37 patients discontinued therapy due to treatment-related AEs (grades 1–3); 14 (8%), 5 (10%), and 18 (10%) patients from the intermittent degarelix, continuous degarelix, and continuous leuprolide arms, respectively 

The frequency, type, and grade of AEsleading to discontinuation was similar across treatment arms.

These data suggest that intermittent use of degarelix as defined in this trial is non-inferior to continuous treatment with either degarelix or leuprolide with regard to maintenance of PSA ≤4 ng/ mL at month 14. In the continuous treatment arms, rising PSA during months 7 to 14 may signal early castration resistant prostate cancer (CRPC). In contrast, rising PSA in the intermittent arm while off treatment was associated with increasing testosterone levels. As all patients in the intermittent arm who resumed ADT had a fall in PSA, there was no indication of early CRPC in this arm. This did not occur in any patients confirming that, despite a rise in PSA, these patients were not yet castration resistant. The treatment cycle length and PSA parameters (start intermittent phase if PSA ≤4 ng/mL and restart ADT when PSA >2 ng/ mL) of this study are broadly similar to those used in other randomized trials of IAD versus CAD. Induction therapy is typically 6 to 8 months and the off-treatment period is initiated if PSA reaches <0.5 to <10 ng/mL (or a predefined percentage reduction from baseline).

 Reintroduction of ADT in previous trials was triggered by PSA reaching either 10 or 20 ng/mL (or exceeding baseline)7,8 or >4 ng/mL in the previous single-arm trial of degarelix in the intermittent treatment setting.

Following discontinuation, the short half-life of degarelix11 appears to allow a rapid testosterone increase to above castrate levels. After 7 months off degarelix, testosterone levels reached normal (1.5 ng/mL or 5.21 nmol/L) in 69% of patients, with a median level of 2.67 ng/mL. The data reported here are similar to those from a recent uncontrolled, open-label European-based study of degarelix.

 In the first off-treatment period, the median time to testosterone >0.5 ng/mL was 112 days and time to PSA >4 ng/mL, 392 days.

Direct comparison with other trials is challenging due to differences in patient characteristics, treatments, and reporting parameters. However, the PR-7 study reported that, after 8 months of ADT with an LHRH analog, testosterone returned to baseline (>1.45 ng/mL or 5 nmol/L) in 79% of patients within 24 months of stopping ADT.

It could be speculated that an intermittent regimen with degarelix may allow a more rapid increase in testosterone that, in turn, may translate into more rapid improvement of side effects related to testosterone suppression. A comparison trial would be necessary to confirm this possibility.

In the current study, increased mean testosterone levels with intermittent therapy were associated with statistically higher sexual drive at month 14 compared with patients on continuous ADT. Patients with normal sexual function before initiating ADT had greater SFI improvements once testosterone levels increased, and there is a possibility these patients may benefit most from the potential sexual function improvements associated with IAD therapy. No other robust improvements in QoL for patients stopping treatment were found, which may partly bedue to weaknesses of the QoL instruments for such assessments. Benefits in QoL with IAD for individual patients may depend on treatment cycle, testosterone status, and age.

Administration of degarelix or leuprolide for up to 14 months was well tolerated. There was a higher rate of injection site reactions associated with the subcutaneous administration of degarelix compared with intramuscular injection of leuprolide. Injection site reactions were generally mild in nature and mostly reported following the first dose, consistent with results of previous studies.

 The distinct different mechanism of LHRH agonists versus GnRH antagonists may be of relevance for the safety profile. Recently, LHRH agonist therapy has been associated with an increased risk of cardiovascular events in men with a history of cardiovascular disease

and of acute kidney injury in men with newly diagnosed nonmetastatic prostate cancer.

Interestingly, the same mechanism has been hypothesized to explain both these effects: GnRH receptor-mediated activation of T lymphocytes and cytokine secretion promoting subsequent inflammation and atherosclerotic plaque rupture.

 Alternatively, GnRH antagonists or orchiectomy would not activate these inflammatory pathways, possibly explaining differences in the AEs associated with these different methods of androgen deprivation.

Limitations of this study include the proportion of patients with an unclassifiable disease stage (due to limited imaging work-up at baseline) and following patients for only 14 months. As subjects in the intermittent group were treated if their PSA exceeded 2.0 ng/mL while off treatment, it is not possible to conclude whether men in the intermittent arm would have experienced PSA >4.0 ng/mL during the study term if left untreated. Also, 14 months may be insufficient time to assess the development of castration resistant disease (2 PSA measurements of >4 ng/mL while receiving ADT) in the intermittent arm due to the inherent delay caused by the off-treatment period.

ADT is associated with a number of AEs, some of which may be alleviated by intermittent treatment. In this trial, intermittent degarelix treatment was noninferior to CAD in terms of PSA control at 14 months, indicating degarelix is a viable therapeutic option in the intermittent setting. The potential clinical relevance of the difference in mechanism of action between a GnRH antagonist and LHRH agonists in this setting, for example, in patients at risk of cardiovascular disease, requires longer-term randomized controlled trials.

E. David Crawford, MD, is from University of Colorado, Denver, Aurora, CO. Neal Shore, MD, FACS, is from Carolina Urologic Research Center, Myrtle Beach, SC. Celestia S. Higano, MD, FACP, is from University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA. Anders Neijber, MD, PhD, MBA, is from Ferring Pharmaceuticals, Copenhagen, Denmark. Vladimir Yankov, MD, is from Ferring Pharmaceuticals, Parsippany-Troy Hills, NJ. Acknowledgements: E. David Crawford, MD, and Neal Shore, MD, FACS, were co-principle investigators of the trial. Anders Neijber, MD, PhD, MBA, and Vladimir Yankov, MD were responsible for data analysis. All authors were responsible for interpretation of data, drafting the paper and critical revisions. Disclosure: The trial reported in this analysis was sponsored by Ferring Pharmaceuticals. Medical writing support (funded by Ferring) was provided by Matthew deSchoolmeester, PhD, of Bioscript Medical. Professor Crawford has received honoraria from Ferring Pharmaceuticals and other companies for participating in scientific meetings and advisory boards. Dr. Shore has received honoraria from Ferring Pharmaceuticals and other companies for participating in scientific meetings and advisory boards. Dr. Higano has received honoraria from Ferring Pharmaceuticals for participating in an advisory board. Drs. Neijber and Yankov are Ferring employees.

 E. David Crawford, MD, Urologic Oncology, School of Medicine, University of Colorado Denver, P.O. Box 6510, Mail Stop F710, 1665 Aurora Ct., Aurora, CO 80045. Phone: 720-848-0195; fax: 728-848-0203; email: david.crawford@ucdenver.edu

			Pilepich MV, Winter K, Lawton CA, et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31. 

			Jones CU, Hunt D, McGowan DG, et al. Radiotherapy and short-term androgen deprivation for localized prostate cancer. 

			Bolla M, Van Tienhoven G, Warde P, et al. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. 

			Higano CS. Side effects of androgen deprivation therapy: monitoring and minimizing toxicity. Uro

			Cary KC, Singla N, Cowan JE, Carroll PR, Cooperberg MR. Impact of androgen deprivation therapy on mental and emotional well-being in men with prostate cancer: analysis from the CaPSURE registry. 

			Buchan NC, Goldenberg SL. Intermittent androgen suppression for prostate cancer. 

			Crook JM, O’Callaghan CJ, Duncan G, et al. Intermittent androgen suppression for rising PSA level after radiotherapy. 

			Hussain M, Tangen CM, Berry DL, et al. Intermittent versus continuous androgen deprivation in prostate cancer. 

			Klotz L, O’Callaghan C, Ding K, et al. Nadir testosterone within first year of androgen-deprivation therapy (ADT) predicts for time to castration-resistant progression: a secondary analysis of the PR-7 trial of intermittent versus continuous ADT. 

			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. 

			Balchen T, Agerso H, Olesen T, Jensen J, Senderovitz T. Pharmacokinetics, pharmacodynamics, and safety of a novel fast-acting gonadotropin-releasing hormone receptor blocker, degarelix, in healthy men. Poster presented at 8th International Symposium on GnRH Analogues in Cancer and Human Reproduction.

			Boccon-Gibod L, Albers P, Morote J, et al. Degarelix as an intermittent androgen deprivation therapy for one or more treatment cycles in patients with prostate cancer. 

			D’Amico AV, Moul JW, Carroll PR, Sun L, Lubeck D, Chen MH. Surrogate end point for prostate cancer-specific mortality after radical prostatectomy or radiation therapy. 

			Patel A, Dorey F, Franklin J, deKernion JB. Recurrence patterns after radical retropubic prostatectomy: clinical usefulness of prostate specific antigen doubling times and log slope prostate specific antigen. 

			Klotz L, Toren P. Androgen deprivation therapy in advanced prostate cancer: is intermittent therapy the new standard of care? 

			Levine GN, D’Amico AV, Berger P, et al. Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. 

			Gandaglia G, Sun M, Briganti A, Karakiewicz PI. Reply to E. David Crawford and Bo-Eric Persson’s Letter to the Editor re: Giorgio Gandaglia, Maxine Sun, Jim C. Hu, et al. Gonadotropin-releasing Hormone Agonists and Acute Kidney Injury in Patients with Prostate Cancer. Eur Urol. In press. http://dx.doi. org/10.1016/j.eururo.2014.01.026. 

			Albertsen PC, Klotz L, Tombal B, Grady J, Olesen TK, Nilsson J. Cardiovascular morbidity associated with gonadotropin releasing hormone agonists and an antagonist. 

			Crawford ED, Persson BE. Re: Giorgio Gandaglia, Maxine Sun, Jim C. Hu, et al. Gonadotropin-releasing Hormone Agonists and Acute Kidney Injury in Patients with Prostate Cancer. 

 In press. http://dx.doi.org/10.1016/j.eururo.2014.01.026.

Articles

Intermittent degarelix administered as described is noninferior to continuous androgen deprivation in maintaining PSA suppression, which indicates that degarelix is a suitable treatment option in men being considered for intermittent androgen ablation.

Celestia S. Higano, MD, FACP

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Dr. Higano on the State of Immunotherapy in Prostate Cancer

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