Androgen Receptor Targeted Treatments of Prostate Cancer: 35 Years of Progress with Antiandrogens.

PURPOSE: Antiandrogens inhibit the androgen receptor and have an important role in the treatment of prostate cancer. This review provides a historical perspective on the development and clinical benefit of antiandrogens in the treatment of prostate cancer. MATERIALS AND METHODS: We searched PubMed® for clinical trials with the search terms antiandrogens and prostate cancer combined with drug names for antiandrogens. This article represents a collaboration of clinical investigators who have made critical scientific contributions leading to the approval of antiandrogens for treating patients with prostate cancer. RESULTS: Antiandrogens differ in chemical structure and exert varying efficacy and safety profiles. The unfavorable therapeutic index of steroidal antiandrogens led to replacement by safer nonsteroidal agents. Flutamide, nilutamide and bicalutamide, which were designed to target the androgen receptor, were developed primarily for use in combination with castration to provide combined androgen blockade. Modest clinical benefits were observed with the combination of first generation antiandrogens and castration vs castration alone. With increased knowledge of androgen receptor structure and its biological functions a new generation of antiandrogens without agonist activity was designed to provide more potent inhibition of the androgen receptor. Randomized clinical trials in patients with metastatic, castration resistant prostate cancer showed significant survival benefits, which led to the approval of enzalutamide in August 2012. Apalutamide was recently approved while darolutamide is not yet approved in the United States. These next generation antiandrogens are being actively tested in earlier disease states such as nonmetastatic prostate cancer. Evolving knowledge of resistance mechanisms to androgen receptor targeted treatments will stimulate research and drug discovery for additional compounds. Further testing in nonmetastatic castration resistant prostate cancer as well as castration sensitive disease states will hopefully augment our ability to treat a broader spectrum of patients with prostate cancer. CONCLUSIONS: Antiandrogens have already provided important benefits for prostate cancer treatment. Greater knowledge about the structural and functional biology of the androgen receptor in prostate cancer will facilitate further discovery and development of further improved antiandrogens with enhanced clinical activity in patients with advanced metastatic disease. Testing these new agents earlier in the course of prostate cancer may further improve the survival and quality of life of patients with current local and/or systemic treatment modalities.

Intermittent versus continuous androgen deprivation in prostate cancer.

BACKGROUND: Castration resistance occurs in most patients with metastatic hormone-sensitive prostate cancer who are receiving androgen-deprivation therapy. Replacing androgens before progression of the disease is hypothesized to prolong androgen dependence. METHODS: Men with newly diagnosed, metastatic, hormone-sensitive prostate cancer, a performance status of 0 to 2, and a prostate-specific antigen (PSA) level of 5 ng per milliliter or higher received a luteinizing hormone-releasing hormone analogue and an antiandrogen agent for 7 months. We then randomly assigned patients in whom the PSA level fell to 4 ng per milliliter or lower to continuous or intermittent androgen deprivation, with patients stratified according to prior or no prior hormonal therapy, performance status, and extent of disease (minimal or extensive). The coprimary objectives were to assess whether intermittent therapy was noninferior to continuous therapy with respect to survival, with a one-sided test with an upper boundary of the hazard ratio of 1.20, and whether quality of life differed between the groups 3 months after randomization. RESULTS: A total of 3040 patients were enrolled, of whom 1535 were included in the analysis: 765 randomly assigned to continuous androgen deprivation and 770 assigned to intermittent androgen deprivation. The median follow-up period was 9.8 years. Median survival was 5.8 years in the continuous-therapy group and 5.1 years in the intermittent-therapy group (hazard ratio for death with intermittent therapy, 1.10; 90% confidence interval, 0.99 to 1.23). Intermittent therapy was associated with better erectile function and mental health (P<0.001 and P=0.003, respectively) at month 3 but not thereafter. There were no significant differences between the groups in the number of treatment-related high-grade adverse events. CONCLUSIONS: Our findings were statistically inconclusive. In patients with metastatic hormone-sensitive prostate cancer, the confidence interval for survival exceeded the upper boundary for noninferiority, suggesting that we cannot rule out a 20% greater risk of death with intermittent therapy than with continuous therapy, but too few events occurred to rule out significant inferiority of intermittent therapy. Intermittent therapy resulted in small improvements in quality of life. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00002651.).

Intermittent androgen suppression for rising PSA level after radiotherapy.

BACKGROUND: Intermittent androgen deprivation for prostate-specific antigen (PSA) elevation after radiotherapy may improve quality of life and delay hormone resistance. We assessed overall survival with intermittent versus continuous androgen deprivation in a noninferiority randomized trial. METHODS: We enrolled patients with a PSA level greater than 3 ng per milliliter more than 1 year after primary or salvage radiotherapy for localized prostate cancer. Intermittent treatment was provided in 8-month cycles, with nontreatment periods determined according to the PSA level. The primary end point was overall survival. Secondary end points included quality of life, time to castration-resistant disease, and duration of nontreatment intervals. RESULTS: Of 1386 enrolled patients, 690 were randomly assigned to intermittent therapy and 696 to continuous therapy. Median follow-up was 6.9 years. There were no significant between-group differences in adverse events. In the intermittent-therapy group, full testosterone recovery occurred in 35% of patients, and testosterone recovery to the trial-entry threshold occurred in 79%. Intermittent therapy provided potential benefits with respect to physical function, fatigue, urinary problems, hot flashes, libido, and erectile function. There were 268 deaths in the intermittent-therapy group and 256 in the continuous-therapy group. Median overall survival was 8.8 years in the intermittent-therapy group versus 9.1 years in the continuous-therapy group (hazard ratio for death, 1.02; 95% confidence interval, 0.86 to 1.21). The estimated 7-year cumulative rates of disease-related death were 18% and 15% in the two groups, respectively (P=0.24). CONCLUSIONS: Intermittent androgen deprivation was noninferior to continuous therapy with respect to overall survival. Some quality-of-life factors improved with intermittent therapy. (Funded by the Canadian Cancer Society Research Institute and others; ClinicalTrials.gov number, NCT00003653.).

Sipuleucel-T immunotherapy for castration-resistant prostate cancer.

BACKGROUND: Sipuleucel-T, an autologous active cellular immunotherapy, has shown evidence of efficacy in reducing the risk of death among men with metastatic castration-resistant prostate cancer. METHODS: In this double-blind, placebo-controlled, multicenter phase 3 trial, we randomly assigned 512 patients in a 2:1 ratio to receive either sipuleucel-T (341 patients) or placebo (171 patients) administered intravenously every 2 weeks, for a total of three infusions. The primary end point was overall survival, analyzed by means of a stratified Cox regression model adjusted for baseline levels of serum prostate-specific antigen (PSA) and lactate dehydrogenase. RESULTS: In the sipuleucel-T group, there was a relative reduction of 22% in the risk of death as compared with the placebo group (hazard ratio, 0.78; 95% confidence interval [CI], 0.61 to 0.98; P=0.03). This reduction represented a 4.1-month improvement in median survival (25.8 months in the sipuleucel-T group vs. 21.7 months in the placebo group). The 36-month survival probability was 31.7% in the sipuleucel-T group versus 23.0% in the placebo group. The treatment effect was also observed with the use of an unadjusted Cox model and a log-rank test (hazard ratio, 0.77; 95% CI, 0.61 to 0.97; P=0.02) and after adjustment for use of docetaxel after the study therapy (hazard ratio, 0.78; 95% CI, 0.62 to 0.98; P=0.03). The time to objective disease progression was similar in the two study groups. Immune responses to the immunizing antigen were observed in patients who received sipuleucel-T. Adverse events that were more frequently reported in the sipuleucel-T group than in the placebo group included chills, fever, and headache. CONCLUSIONS: The use of sipuleucel-T prolonged overall survival among men with metastatic castration-resistant prostate cancer. No effect on the time to disease progression was observed. (Funded by Dendreon; ClinicalTrials.gov number, NCT00065442.)

Treatment options for localized prostate cancer.

In the United States, more than 90 percent of prostate cancers are detected by serum prostate-specific antigen testing. Most patients are found to have localized prostate cancer, and most of these patients undergo surgery or radiotherapy. However, many patients have low-risk cancer and can follow an active surveillance protocol instead of undergoing invasive treatments. Active surveillance is a new concept in which low-risk patients are closely followed and proceed to intervention only if their cancer progresses. Clinical guidelines can help in selecting between treatment or active surveillance based on the cancer's stage and grade, the patient's prostate-specific antigen level, and the comorbidity-adjusted life expectancy. Radical prostatectomy or external beam radiation therapy is recommended for higher-risk patients. These treatments are almost equivalent in effectiveness, but have different adverse effect profiles. Brachytherapy is an option for low- and moderate-risk patients. Evidence is insufficient to determine whether laparoscopic or robotic surgery or cryotherapy is superior to open radical prostatectomy.

A history of the Society of Urologic Oncology.

This narrative of the history of the Society of Urologic Oncology (SUO) presents the story of the founding and development of this organization and the creation and establishment of its initiatives and programs. It includes a description of how "Urologic Oncology: Seminars and Original Investigations" came to be designated as its "official journal", thus commemorating the anniversary of the Journal's twenty-five years of publication.

Quality of life after open or robotic prostatectomy, cryoablation or brachytherapy for localized prostate cancer.

PURPOSE: Health related quality of life concerns factor prominently in prostate cancer management. We describe health related quality of life impact and recovery profiles of 4 commonly used operative treatments for localized prostate cancer. MATERIALS AND METHODS: Beginning in February 2000 all patients treated with open radical prostatectomy, robot assisted laparoscopic prostatectomy, brachytherapy or cryotherapy were asked to complete the UCLA-PCI questionnaire before treatment, and at 3, 6, 12, 18, 24, 30 and 36 months after treatment. Outcomes were compared across treatment types with statistical analysis using univariate and multivariate models. RESULTS: A total of 785 patients treated between February 2000 and December 2008 were included in the analysis with a mean followup of 24 months. All health related quality of life domains were adversely affected by all treatments and recovery profiles varied significantly by treatment type. Overall urinary function and bother outcomes scored significantly higher after brachytherapy and cryotherapy compared to open radical prostatectomy and robotic assisted laparoscopic radical prostatectomy. Brachytherapy and cryotherapy had a 3-fold higher rate of return to baseline urinary function compared to open radical prostatectomy and robotic assisted laparoscopic radical prostatectomy. Sexual function and bother scores were highest after brachytherapy, with a 5-fold higher rate of return to baseline function compared to cryotherapy, open radical prostatectomy and robotic assisted laparoscopic radical prostatectomy. All 4 treatments were associated with relatively transient and less pronounced impact on bowel function and bother. CONCLUSIONS: In a study of sequential health related quality of life assessments brachytherapy and cryotherapy were associated with higher urinary function and bother scores compared to open radical prostatectomy and da Vinci prostatectomy. Brachytherapy was associated with higher sexual function and bother scores compared to open radical prostatectomy, robotic assisted laparoscopic radical prostatectomy and cryotherapy.

Open Label Phase II Study of Enzalutamide With Concurrent Administration of Radium 223 Dichloride in Patients With Castration-Resistant Prostate Cancer.

BACKGROUND: Numerous globally approved castration-resistant prostate cancer (CRPC) therapies are available. Enzalutamide and radium 223 (Ra 223) are approved for survival prolongation and ability to delay radiographic progression. Both have markedly different mechanisms of action as well as safety and tolerability profiles. We prospectively investigated their combined safety and tolerability. PATIENTS AND METHODS: EnzaRadiCate, a phase II investigator-initiated trial, enrolled subjects with metastatic CRPC from 4 United States uro-oncology research sites. Safety assessment included physical examination, Eastern Cooperative Oncology Group status, electrocardiogram results, laboratory values, opioid use, radiographic responses, and adverse events (AEs). Quality of life and pain were assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and the Brief Pain Inventory Short Form (BPI-SF) questionnaires. RESULTS: Thirty-nine subjects completed at least 2 cycles of Ra 223, and 34 (87%) completed all 6 cycles through and the EOT visit. Sixty-one treatment-related AEs were reported by 53.8% of subjects. The most frequent AEs were fatigue (25.6%), nausea (17.9%), and anemia (12.8%). Three subjects experienced non-treatment-related serious AEs. One subject was hospitalized for sepsis, and 2 deaths were attributed to disease progression. Fifteen (38.5%) subjects demonstrated radiographic progression, and 24 (61.5%) subjects had no radiographic progression. CONCLUSIONS: Safety and tolerability of combinatorial use of enzalutamide and Ra 223 were demonstrated. Subjects experienced improvements in quality of life and pain, without unexpected toxicities nor increases in falls, fractures, or deaths. Phase III combination trials of Ra 223 with novel oral hormonal agents are ongoing to further evaluate radiographic progression and overall survival benefit.

Survival of African-American and Caucasian men after sipuleucel-T immunotherapy: outcomes from the PROCEED registry.

PURPOSE: African Americans experience greater prostate cancer risk and mortality than do Caucasians. An analysis of pooled phase III data suggested differences in overall survival (OS) between African American and Caucasian men receiving sipuleucel-T. We explored this in PROCEED (NCT01306890), an FDA-requested registry in over 1900 patients with metastatic castration-resistant prostate cancer (mCRPC) treated with sipuleucel-T. PATIENTS AND METHODS: OS for patients who received ≥1 sipuleucel-T infusion was compared between African American and Caucasian men using an all patient set and a baseline prostate-specific antigen (PSA)-matched set (two Caucasians to every one African American with baseline PSAs within 10% of each other). Univariable and multivariable analyses were conducted. Survival data were examined using Kaplan-Meier and Cox proportional hazard methodologies. RESULTS: Median follow-up was 46.6 months. Overall survival differed between African American and Caucasian men with hazard ratios (HR) of 0.81 (95% confidence interval [CI]: 0.68-0.97, P = 0.03) in the all patient set and 0.70 (95% CI: 0.57-0.86, P < 0.001) in the PSA-matched set. Median OS was longer in African Americans than in Caucasian men for both analysis sets, e.g., 35.3 and 25.8 months, respectively, in the PSA-matched set. Similar results were observed in the all patient set. Differences were larger when treatment began at lower baseline PSA; curves were more similar among patients with higher baseline PSA. In patients with baseline PSA below the median, the HR was 0.52 (95% CI: 0.37-0.72, P < 0.001), with median OS of 54.3 versus 33.4 months. Known prognostic factors and African American race (multivariable analyses; HR: 0.60, 95% CI: 0.48-0.74, P < 0.001) were independently associated with OS. Use of post-sipuleucel-T anticancer interventions was balanced between races. CONCLUSION: In this exploratory analysis of a registry including nearly 12% African American men with mCRPC, OS was significantly different between African Americans and Caucasians, indicating further research is warranted.

Single center experience with third-generation cryosurgery for management of organ-confined prostate cancer: critical evaluation of short-term outcomes, complications, and patient quality of life.

BACKGROUND AND PURPOSE: Technical refinements such as improved ultrasonographic localization and the routine use of urethral warmers and small-gauge needle delivery systems have renewed interest in cryosurgical treatment as a minimally invasive option for selected patients with localized prostate cancer. Only three reports of quality of life (QoL) in prostate cryoablation exist, and none report on patients treated with third-generation cryoablative technology. We critically examine our initial series of consecutive patients at a single institution undergoing primary third-generation cryosurgical treatment of localized prostate cancer with respect to treatment outcome, morbidity profile, and QoL parameters. To our knowledge, this is the first QoL report on third-generation cryoablation of the prostate. PATIENTS AND METHODS: We retrospectively review the records of 89 consecutive patients with median followup of 11 months (1-32) who have undergone third-generation cryosurgical ablation of the prostate as primary treatment for localized prostate cancer with intention to cure. Patients were risk stratified according to preprocedural parameters of prostate-specific antigen (PSA), clinical stage, and Gleason score. PSA trends were recorded and treatment effectiveness was observed using different definitions of biochemical failure. Charts were reviewed for postprocedure complications. Quality of life was measured prospectively using the University of California, Los Angeles, Prostate Cancer Index as well as American Urological Association symptom scores. We compare a percent of baseline score (%BS) for various domains between our series of patients treated with primary cryoablation with a series of patients undergoing brachytherapy for localized prostate cancer. RESULTS: Treatment success was defined by achievement of a PSA nadir of < or =0.1 ng/mL and by biochemical disease-free survival (BDFS) assessed with both a PSA threshold of < or =0.4 ng/dL over time and the American Society for Therapeutic Radiology and Oncology (ASTRO) definition of three consecutive rises in PSA. According to risk stratification, 86%, 81.5%, and 78% of low-, intermediate-, and high-risk patients, respectively, achieved a PSA nadir of < or =0.1 ng/mL. Overall, at 12 months follow-up, 94% of patients achieved BDFS using ASTRO criteria while 70% achieved BDFS using a PSA threshold of < or =0.4 ng/mL. With risk stratification, 74%, 70%, and 60% of low-, intermediate-, and high-risk patients, respectively, achieved BDFS defined by PSA threshold of < or =0.4 ng/mL. Complications were rare. The response rate for Health Related Quality of Life (HRQoL) questionnaires was 71% for cryoablation patients and 51% for brachytherapy patients. At 12 months follow-up, patients undergoing cryoablation on average achieved urinary and bowel domain scores comparable to baseline, but sexual domains remained well below baseline. When compared with a brachytherapy series with better baseline sexual function (P = 0.04) and urinary function (P = 0.03), cryotherapy patients experienced more negative impact on sexual function steadily for up to 12 months (P = 0.02). Urinary function was similar between the groups until 18 months, at which time cryoablation patients fared better (P = 0.01); this was sustained up to 24 months (P = 0.04). CONCLUSIONS: Treatment success with cryosurgery varies with definition; however, our results are comparable to other series with regard to short-term cancer control. Complication rates in this series of third-generation cryosurgical patients are low. QoL characteristics of third-generation cryoablation are similar to those described in second-generation cryoablation series. Compared with brachytherapy, cryotherapy results in less irritative and obstructive voiding symptoms in the early post-treatment period and may improve urinary function up to 24 months after treatment. In a small group of older patients with baseline erectile dysfunction undergoing cryoablation, sexual function returns to 20% of its baseline value with up to 12 months follow-up.

Overexpression of alpha-defensin is associated with bladder cancer invasiveness.

Alpha-defensin (alpha-defensin) has been identified as a potential marker for bladder cancer in urine by surface enhanced laser desorption ionization studies, and confirmed using both immunoabsorption and immunodepletion studies. The objective of this study was to investigate the role of alpha-defensin in bladder cancer. Immunohistochemical analysis of tissue sections showed that alpha-defensin peptides are frequently expressed in bladder cancer cells. It is noteworthy that expression of alpha-defensins increased with tumor invasiveness. Surface enhanced laser desorption ionization analysis showed the presence of alpha-defensin in the T24 and A498 cancer cell lines. These cell lines show higher classically aggressive in vitro characteristics compared with the J82 cells that did not express alpha-defensin. Exogenously added alpha-defensin increased the proliferation and motility/invasiveness of these cell lines using respective assays. It is interesting that alpha-defensin peptides increased intracellular calcium ions (Ca2+). These data are consistent with a role for alpha-defensin in bladder cancer via modulation of cell motility and invasiveness using common intracellular signals, such as Ca2+. We propose that autocrine tumor expression of alpha-defensins may play an important role in facilitating the invasive phenotype of bladder cancer in patients.

Prospective longitudinal comparative study of early health-related quality-of-life outcomes in patients undergoing surgical treatment for localized prostate cancer: a short-term evaluation of five approaches from a single institution.

BACKGROUND AND PURPOSE: Quality of life (QoL) issues are a vital concern for the majority of patients seeking therapeutic intervention once they are found to have prostate cancer. A prospective longitudinal comparison using validated QoL instruments is a valuable technique to evaluate outcome differences. We evaluated the short-term QoL changes from baseline of five surgical approaches for localized prostate carcinoma delivered at a single institution. PATIENTS AND METHODS: A prospective longitudinal survey of 719 patients with newly diagnosed prostate cancer was initiated in 2001. The surgical procedures performed during this time period were open radical prostatectomy (ORP), laparoscopic radical prostatectomy (LRP), da Vinci robotic prostatectomy (dVP), (103)Pd brachytherapy ((103)Pd), and prostate cryoablation (PCryo). An Institutional Review Board-approved questionnaire comprised of validated QoL instruments (UCLA Prostate Cancer Index and American Urological Association Symptom Index [SI]) was mailed to enrolled patients prior to their selected surgery and again at 1, 3, 6, 9, 12, 18, 24, and 36 months after therapy. A percent of baseline score calculation including data from all five treatment cohorts for follow-up months 1, 3, and 6 was compared within groups. Group I consisted of patients undergoing ORP, LRP, or dVP. Group II consisted of patients undergoing (103)Pd or PCryo. RESULTS: Between January 2000 and April 2005, 498 patients (69%) were enrolled who completed the baseline questionnaire and at least one follow-up survey at 1, 3, or 6 months. The mean patient age at ORP, LRP, dVP, (103)Pd, and PCryo was 59, 61, 60, 67, and 72 years, respectively. Within Group I, early recovery of sexual function (at 3 months) appeared to occur sooner after dVP (35% return to baseline [RTB]) than ORP (24% RTB) and LRP (21% RTB) (P = 0.03). No other significant differences were noted, and trends toward improvement were seen in all groups. Within Group II, PCryo (18% RTB) had a more negative impact on sexual function at 3 months than did 103Pd (63% RTB) (P = 0.007), although a significant difference in baseline sexual function was also noted (P = 0.001). Early urinary function (at 1 month) was better after (103)Pd (82% RTB) than PCryo (72%) (P = 0.05), but this difference was lost at 6 months. In addition, the irritative and obstructive symptoms evaluated by the AUA SI were significantly worse (P = 0.003) at 3 months after (103)Pd than after PCryo. CONCLUSIONS: Different surgical approaches for the treatment of localized prostate cancer affect the shortterm QoL results in different ways. Urinary, sexual, and bowel function and bother are affected to a similar degree by ORP, LRP, and dVP. In an older population, the tissue destruction resulting from PCryo appears to relieve obstructive and irritative urinary symptoms but at the sacrifice of sexual function compared with (103)Pd.

Serum protein fingerprinting coupled with a pattern-matching algorithm distinguishes prostate cancer from benign prostate hyperplasia and healthy men.

The prostate-specific antigen test has been a major factor in increasing awareness and better patient management of prostate cancer (PCA), but its lack of specificity limits its use in diagnosis and makes for poor early detection of PCA. The objective of our studies is to identify better biomarkers for early detection of PCA using protein profiling technologies that can simultaneously resolve and analyze multiple proteins. Evaluating multiple proteins will be essential to establishing signature proteomic patterns that distinguish cancer from noncancer as well as identify all genetic subtypes of the cancer and their biological activity. In this study, we used a protein biochip surface enhanced laser desorption/ionization mass spectrometry approach coupled with an artificial intelligence learning algorithm to differentiate PCA from noncancer cohorts. Surface enhanced laser desorption/ionization mass spectrometry protein profiles of serum from 167 PCA patients, 77 patients with benign prostate hyperplasia, and 82 age-matched unaffected healthy men were used to train and develop a decision tree classification algorithm that used a nine-protein mass pattern that correctly classified 96% of the samples. A blinded test set, separated from the training set by a stratified random sampling before the analysis, was used to determine the sensitivity and specificity of the classification system. A sensitivity of 83%, a specificity of 97%, and a positive predictive value of 96% for the study population and 91% for the general population were obtained when comparing the PCA versus noncancer (benign prostate hyperplasia/healthy men) groups. This high-throughput proteomic classification system will provide a highly accurate and innovative approach for the early detection/diagnosis of PCA.

A Urologist's Personal View of Prostate Cancer.

A urologist's personal experience with multiple surgical, hormonal, and radio/immunotherapeutic options for the treatment of advanced prostate cancer and thoughts on the role of old and new therapies.