NCCN Guidelines® Insights: Prostate Cancer, Version 3.2024.

The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel's discussions for the 2024 update to the guidelines with regard to initial risk stratification, initial management of very-low-risk disease, and the treatment of nonmetastatic recurrence.

Accelerator-Based Production of Scandium Radioisotopes for Applications in Prostate Cancer: Toward Building a Pipeline for Rapid Development of Novel Theranostics.

In the field of nuclear medicine, the ß+ -emitting 43Sc and ß- -emitting 47Sc are promising candidates in cancer diagnosis and targeted radionuclide therapy (TRT) due to their favorable decay schema and shared pharmacokinetics as a true theranostic pair. Additionally, scandium is a group-3 transition metal (like 177Lu) and exhibits affinity for DOTA-based chelators, which have been studied in depth, making the barrier to implementation lower for 43/47Sc than for other proposed true theranostics. Before 43/47Sc can see widespread pre-clinical evaluation, however, an accessible production methodology must be established and each isotope's radiolabeling and animal imaging capabilities studied with a widely utilized tracer. As such, a simple means of converting an 18 MeV biomedical cyclotron to support solid targets and produce 43Sc via the 42Ca(d,n)43Sc reaction has been devised, exhibiting reasonable yields. The NatTi(γ,p)47Sc reaction is also investigated along with the successful implementation of chemical separation and purification methods for 43/47Sc. The conjugation of 43/47Sc with PSMA-617 at specific activities of up to 8.94 MBq/nmol and the subsequent imaging of LNCaP-ENZaR tumor xenografts in mouse models with both 43/47Sc-PSMA-617 are also presented.

The impact of enzalutamide on quality of life in men with metastatic hormone-sensitive prostate cancer based on prior therapy, risk, and symptom subgroups.

BACKGROUND: Enzalutamide plus androgen deprivation therapy (ADT) improved radiographic progression-free survival versus ADT alone in patients with metastatic hormone-sensitive prostate cancer (mHSPC) in ARCHES (NCT02677896). While health-related quality of life (HRQoL) was generally maintained in the intent-to-treat population, we further analyzed patient-reported outcomes (PROs) in defined subgroups. METHODS: ARCHES was a randomized, double-blind, placebo-controlled, phase 3 study. Patients with mHSPC received enzalutamide (160 mg/day) plus ADT (n = 574) or placebo plus ADT (n = 576). Questionnaires, including the Functional Assessment of Cancer Therapy-Prostate, Brief Pain Inventory-Short Form, and EuroQol 5-Dimension, 5-Level (EQ-5D-5L), were completed at baseline, Week 13, and every 12 weeks until disease progression. PRO endpoints were time to first confirmed clinically meaningful deterioration (TTFCD) in HRQoL or pain. Subgroups included prognostic risk, pain/HRQoL, prior docetaxel, and local therapy (radical prostatectomy [RP] and/or radiotherapy [RT]). RESULTS: There were several between-treatment differences in TTFCD for pain and functioning/HRQoL PROs. Enzalutamide plus ADT delayed TTFCD for worst pain in the prior RT group (not reached vs. 14.06 months; hazard ratio [HR]: 0.56 [95% confidence interval: 0.34-0.94]) and pain interference in low-baseline-HRQoL group (19.32 vs. 11.20 months; HR: 0.64 [0.44-0.94]) versus placebo plus ADT. In prior/no prior RP, prior RT, prior local therapy, no prior docetaxel, mild baseline pain, and low-risk subgroups, TTFCD was delayed for the EQ-5D-5L visual analog scale. CONCLUSION: Enzalutamide plus ADT provides clinical benefits in defined patient subgroups versus ADT alone, while maintaining lack of pain and high HRQoL, with delayed deterioration in several HRQoL measures.

Comparison of out-of-pocket costs and adherence between the two arms of the prospective, randomized abiraterone food effect trial.

PURPOSE: Abiraterone acetate, prescribed for metastatic prostate cancer, has enhanced absorption with food. This effect was exploited in a randomized trial which showed noninferiority of PSA decline for 250 mg abiraterone with a low-fat meal (LOW) compared to 1,000 mg abiraterone fasting (STD). Drug was obtained via patient insurance. Patient out-of-pocket costs and adherence were surveyed. METHODS: Trial participants were randomized to STD or LOW, and surveys of adherence and out-of-pocket costs were administered at baseline and just before coming off study (follow-up). RESULTS: Out-of-pocket costs were available from 20 of 36 STD and 21 of 36 LOW patients. Median out-of-pocket costs for a month of drug were $0 (LOW) and $5 (STD); mean costs were $43.61 (LOW) and $393.83 (STD). The two groups did not differ significantly (p = 0.421). Maximum out-of-pocket cost was $1,000 (LOW) and $4,000 (STD). Monthly out-of-pocket costs > $500 were found in 1 LOW and 5 STD patients. For adherence, only 11 STD and 19 LOW patients had questionnaires completed at both baseline and follow-up. STD adherence was 98.18% at baseline and 91.69% at follow-up, differing significantly (p = 0.0078). LOW adherence was 96.52% at baseline and 97.86% at follow-up, not differing significantly (p = 0.3511). Adherence did not correlate with demographics. At follow-up, increasing adherence correlated significantly with decreasing dose (p = 0.013; rho = - 0.458). CONCLUSIONS: Out-of-pocket costs did not differ significantly in this limited analysis. Adherence was significantly different in STD as the trial progressed, which was not found in LOW. TRIAL REGISTRATION: ClinicalTrials.gov NCT01543776; registered March 5, 2012.

Prevalence of potential interactions of medications, including herbs and supplements, before, during, and after chemotherapy in patients with breast and prostate cancer.

BACKGROUND: The use of herbs and supplements (HS) is common among patients with cancer, yet limited information exists about potential medication interactions (PMIs) with HS use around chemotherapy. METHODS: Patients with breast or prostate cancer who had recently finished chemotherapy at 2 academic medical centers were surveyed by telephone. Interviewers inquired about all medications, including HS, before, during, and after chemotherapy. Micromedex, Lexicomp, and Natural Medicines Comprehensive Database interaction software programs were used to determine PMIs. RESULTS: A total of 67 subjects (age range, 39-77 years) were evaluated in this study. Participants were primarily White patients (73%) with breast cancer (87%). The median number of medications was 11 (range, 2-28) during the entire study and was highest during chemotherapy (7; range, 2-22). Approximately four-fifths (84%) used HS. A total of 1747 PMIs were identified, and they represented 635 unique PMIs across all 3 timeframes, with most occurring during chemotherapy. Prescription-related PMIs (70%) were the most common type, and they were followed by HS-related (56%) and anticancer treatment-related PMIs (22%). Approximately half of the PMIs (54%) were categorized as moderate interactions, and more than one-third (38%) were categorized as major interactions. Patient use of HS increased from 51% during chemotherapy to 66% after chemotherapy, and this correlated with an increased prevalence of HS PMIs (46% to 60%). HS users were more likely to be at risk for a major PMI than non-HS users (92% vs 70%; P = .038). CONCLUSIONS: The use of HS remains prevalent among patients with cancer and may place them at risk for PMIs both during chemotherapy and after the completion of treatment. LAY SUMMARY: This study evaluates the risk of potential medication interactions for patients with breast or prostate cancer undergoing chemotherapy. The results show that patients often use herbs and supplements during treatment. Prescription medications are most often associated with medication interactions, which are followed by herb and supplement-related interactions. More than one-third of potential medication interactions are considered major. Patients should be educated about the risk of herb and supplement-related medication interactions during treatment.

A prospective clinical and transcriptomic feasibility study of oral-only hormonal therapy with radiation for unfavorable prostate cancer in men 70 years of age and older or with comorbidity.

BACKGROUND: Androgen deprivation therapy (ADT) improves outcomes in unfavorable-risk prostate cancer (PCa) treated with radiation therapy (RT). It was hypothesized that replacing luteinizing hormone-releasing hormone (LHRH) agonists with a 5-α-reductase inhibitor (5-ARI) would improve hormonal health-related quality of life (HRQOL) without differentially suppressing androgen-responsive (AR) gene expression. METHODS: Patients with localized unfavorable-risk PCa, aged ≥70 years or Charlson Comorbidity Index score ≥2 were treated with oral ADT (oADT), consisting of 4 months of bicalutamide, a 5-ARI, and RT at 78 Gy. The primary end point was Expanded Prostate Cancer Index Composite HRQOL at 6 months ≤30%, and improvement compared with a synchronous standard of care (SOC) cohort receiving 4 months of bicalutamide and long-term LHRH agonist with RT. RNA sequencing was performed from matched pre-/post-ADT prostate tumor biopsies in a subset of men. Differential gene and pathway expressional changes were examined using gene set enrichment. RESULTS: Between 2011 and 2018, 40 and 30 men were enrolled in the oADT and SOC cohorts, respectively. Median follow-up was 40 months. Those with ≤30% decline in hormonal HRQOL at 6 months was 97% (oADT) and 93% (SOC). The average 6-month hormonal decline was 1% (oADT) versus 12% (SOC; P = .04). The 4-year freedom from biochemical failure was 88% (oADT) versus 81% (SOC; P = .48). RNA sequencing (n = 9) showed similar numbers of downregulated and upregulated genes between the treatment groups (fold-change = 2; false-discovery rate-adjusted P ≤ .05). Both treatments comparably decreased the expression of 20 genes in canonical androgen receptor signaling. CONCLUSIONS: For men with PCa undergoing RT, oral versus standard ADT may improve 6-month QOL and appears to have a similar impact on androgen-responsive gene expression.

Efficacy of Enzalutamide plus Androgen Deprivation Therapy in Metastatic Hormone-Sensitive Prostate Cancer by Pattern of Metastatic Spread: ARCHES Post Hoc Analyses.

PURPOSE: Enzalutamide plus androgen deprivation therapy has previously been shown to improve clinical outcomes in men with metastatic hormone-sensitive prostate cancer (ARCHES; NCT02677896). Here, we assessed if and how the pattern of metastatic spread impacts efficacy of enzalutamide plus androgen deprivation therapy in men enrolled in ARCHES. MATERIALS AND METHODS: Men with metastatic hormone-sensitive prostate cancer were randomized 1:1 to enzalutamide (160 mg/day) plus androgen deprivation therapy or placebo plus androgen deprivation therapy, stratified by disease volume and prior docetaxel treatment. The primary end point was radiographic progression-free survival. Secondary end points included time to prostate specific antigen progression, initiation of new antineoplastic therapy, first symptomatic skeletal event and castration resistance. Post hoc analyses were performed by pattern of metastatic spread based on study entry imaging. RESULTS: Of the overall population with metastases identified at enrollment (1,146), the largest patient subgroups were those with bone metastases only (513) and those with bone plus lymph node metastases (351); there were fewer men with lymph node metastases only (154) and men with visceral±bone or lymph node metastases (128). Enzalutamide plus androgen deprivation therapy reduced the risk of radiographic progression vs placebo plus androgen deprivation therapy in men with bone metastases only (HR 0.33) and bone plus lymph node metastases (HR 0.31). Similar improvements in secondary end points were also observed in these subgroups. CONCLUSIONS: These findings indicate that treatment with enzalutamide plus androgen deprivation therapy provides improvements in men with bone and/or lymph node metastases but may be less effective in men with visceral patterns of spread.

Slow-, Tight-Binding Inhibition of CYP17A1 by Abiraterone Redefines Its Kinetic Selectivity and Dosing Regimen.

Substantial evidence underscores the clinical efficacy of inhibiting CYP17A1-mediated androgen biosynthesis by abiraterone for treatment of prostate oncology. Previous structural analysis and in vitro assays revealed inconsistencies surrounding the nature and potency of CYP17A1 inhibition by abiraterone. Here, we establish that abiraterone is a slow-, tight-binding inhibitor of CYP17A1, with initial weak binding preceding the subsequent slow isomerization to a high-affinity CYP17A1-abiraterone complex. The in vitro inhibition constant of the final high-affinity CYP17A1-abiraterone complex ( ( K i * = 0.39 nM )yielded a binding free energy of -12.8 kcal/mol that was quantitatively consistent with the in silico prediction of -14.5 kcal/mol. Prolonged suppression of dehydroepiandrosterone (DHEA) concentrations observed in VCaP cells after abiraterone washout corroborated its protracted CYP17A1 engagement. Molecular dynamics simulations illuminated potential structural determinants underlying the rapid reversible binding characterizing the two-step induced-fit model. Given the extended residence time (42 hours) of abiraterone within the CYP17A1 active site, in silico simulations demonstrated sustained target engagement even when most abiraterone has been eliminated systemically. Subsequent pharmacokinetic-pharmacodynamic (PK-PD) modeling linking time-dependent CYP17A1 occupancy to in vitro steroidogenic dynamics predicted comparable suppression of downstream DHEA-sulfate at both 1000- and 500-mg doses of abiraterone acetate. This enabled mechanistic rationalization of a clinically reported PK-PD disconnect, in which equipotent reduction of downstream plasma DHEA-sulfate levels was achieved despite a lower systemic exposure of abiraterone. Our novel findings provide the impetus for re-evaluating the current dosing paradigm of abiraterone with the aim of preserving PD efficacy while mitigating its dose-dependent adverse effects and financial burden. SIGNIFICANCE STATEMENT: With the advent of novel molecularly targeted anticancer modalities, it is becoming increasingly evident that optimal dose selection must necessarily be predicated on mechanistic characterization of the relationships between target exposure, drug-target interactions, and pharmacodynamic endpoints. Nevertheless, efficacy has always been perceived as being exclusively synonymous with affinity-based measurements of drug-target binding. This work demonstrates how elucidating the slow-, tight-binding inhibition of CYP17A1 by abiraterone via in vitro and in silico analyses was pivotal in establishing the role of kinetic selectivity in mediating time-dependent CYP17A1 engagement and eventually downstream efficacy outcomes.

Phase 1b trial of docetaxel, prednisone, and pazopanib in men with metastatic castration-resistant prostate cancer.

BACKGROUND: Docetaxel prednisone is a standard of care for men with metastatic castration-resistant prostate cancer (mCRPC), and plasma vascular endothelial growth factor (VEGF) levels are a poor prognostic factor in this population; therefore, we evaluated the combination of docetaxel prednisone with pazopanib, an oral VEGF receptor inhibitor, for safety and preliminary efficacy. METHODS: This is a two-site phase 1b Department of Defense Prostate Cancer Clinical Trials Consortium trial of docetaxel, prednisone, and pazopanib once daily and ongoing androgen deprivation therapy and prophylactic pegfilgrastim in men with mCRPC. The primary endpoint was safety and the determination of a maximum tolerated dose (MTD) through a dose-escalation and expansion design; secondary endpoints included progression-free and overall survival (OS), prostate specific antigen (PSA) declines, radiographic responses, and pharmacokinetic and plasma angiokine biomarker analyses. RESULTS: Twenty-five men were treated over six dose levels. Pegfilgrastim was added to the regimen after myelosuppression limited dose escalation. With pegfilgrastim, our target MTD of docetaxel 75 mg/m2 q3 weeks; prednisone 10 mg daily; and pazopanib 800 mg daily was reached. Eleven additional patients were accrued at this dose level for a total of 36 patients. Dose-limiting toxicities included neutropenia, syncope, and hypertension. Three deaths attributed to study treatment occurred. The objective response rate was 31%; median PFS was 14.1 months (95% confidence interval [CI]: 7.1 and 22.2); and OS was 18.6 months (95% CI: 11.8 and 22.2). CONCLUSIONS: The combination of docetaxel, prednisone, and pazopanib (with pegfilgrastim) was tolerable at full doses and demonstrated promising efficacy in a relatively poor risk patients with mCRPC. Further development of predictive biomarkers may enrich for patients who receive clinical benefit from this regimen.

A Phase Ib Study of Axitinib in Combination with Crizotinib in Patients with Metastatic Renal Cell Cancer or Other Advanced Solid Tumors.

LESSONS LEARNED: The combination of axitinib and crizotinib has a manageable safety and tolerability profile, consistent with the profiles of the individual agents when administered as monotherapy.The antitumor activity reported here for the combination axitinib/crizotinib does not support further study of this combination treatment in metastatic renal cell carcinoma given the current treatment landscape. BACKGROUND: Vascular endothelial growth factor (VEGF) inhibitors have been successfully used to treat metastatic renal cell carcinoma (mRCC); however, resistance eventually develops in most cases. Tyrosine protein kinase Met (MET) expression increases following VEGF inhibition, and inhibition of both has shown additive effects in controlling tumor growth and metastasis. We therefore conducted a study of axitinib plus crizotinib in advanced solid tumors and mRCC. METHODS: This phase Ib study included a dose-escalation phase (starting doses: axitinib 3 mg plus crizotinib 200 mg) to estimate maximum tolerated dose (MTD) in patients with solid tumors and a dose-expansion phase to examine preliminary efficacy in treatment-naïve patients with mRCC. Safety, pharmacokinetics, and biomarkers were also assessed. RESULTS: No patients in the dose-escalation phase (n = 22) experienced dose-limiting toxicity; MTD was estimated to be axitinib 5 mg plus crizotinib 250 mg. The most common grade ≥3 adverse events were hypertension (18.2%) and fatigue (9.1%). In the dose-expansion phase, overall response rate was 30% (95% confidence interval [CI], 11.9-54.3), and progression-free survival was 5.6 months (95% CI, 3.5-not reached). CONCLUSION: The combination of axitinib plus crizotinib, at estimated MTD, had a manageable safety profile and showed evidence of modest antitumor activity in mRCC.

Phase II randomized, double-blind, placebo-controlled study of tivantinib in men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC).

Background Tivantinib is a non-ATP competitive inhibitor of c-MET receptor tyrosine kinase that may have additional cytotoxic mechanisms including tubulin inhibition. Prostate cancer demonstrates higher c-MET expression as the disease progresses to more advanced stages and to a castration resistant state. Methods 80 patients (pts) with asymptomatic or minimally symptomatic mCRPC were assigned (2:1) to either tivantinib 360 mg PO BID or placebo (P). The primary endpoint was progression free survival (PFS). Results Of the 80 pts. enrolled, 78 (52 tivantinib, 26 P) received treatment and were evaluable. Median follow up is 8.9 months (range: 2.3 to 19.6 months). Patients treated with tivantinib had significantly better PFS vs. those treated with placebo (medians: 5.5 mo vs 3.7 mo, respectively; HR = 0.55, 95% CI: 0.33 to 0.90; p = 0.02). Grade 3 febrile neutropenia was seen in 1 patient on tivantinib while grade 3 and 4 neutropenia was recorded in 1 patient each on tivantinib and placebo. Grade 3 sinus bradycardia was recorded in two men on the tivantinib arm. Conclusions Tivantinib has mild toxicity and improved PFS in men with asymptomatic or minimally symptomatic mCRPC.

Phase Ib Trial of Cabazitaxel and Tasquinimod in Men With Heavily Pretreated Metastatic Castration Resistant Prostate Cancer (mCRPC): The CATCH Trial.

BACKGROUND: Tasquinimod is an immunomodulating and anti-antiangiogenic oral agent with anti-prostate cancer activity in preclinical studies and in clinical trials of men with metastatic castration resistant prostate cancer (mCRPC), including single agent activity and in combination with taxanes. We sought to identify the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of tasquinimod in combination with cabazitaxel and prednisone in men with chemorefractory mCRPC. METHODS: Men with mCRPC who had failed prior docetaxel chemotherapy received cabazitaxel 25 mg/m2 every 3 weeks with oral tasquinimod at 1 of 3 escalating dose levels (0.25, 0.5, and 1.0 mg once daily) with prednisone and PEG-filgastrim support, using a 3 + 3 dose escalation design. Treatment continued until progressive disease or unacceptable toxicity. RESULTS: We enrolled 25 men with chemorefractory mCRPC. The RP2D was 0.5 mg tasquinimod based on excess DLTs (two of three men) observed at dose level 3 (1.0 mg) including grade 3 sensory neuropathy and grade 3 atrial fibrillation. Dose level 2 was expanded to 14 men, where 3 DLTs were observed: grade 3 fatigue, grade 4 febrile neutropenia, and grade 3 liver function abnormalities. The proportion of men with a ≥30% PSA decline was 63% and the median composite progression-free survival (PFS) was 8.5 months (95% CI 4.2-16.4 months) based on 12 PFS events. The median number of cycles of cabazitaxel was 6 (range 1-13), with six men receiving >10 cycles. Best overall RECIST responses (CR + PR) were observed in three men (12%), with stable disease in 12 (48%). No pharmacokinetic interactions were observed. CONCLUSIONS: We determined the RP2D of tasquinimod combined with cabazitaxel to be 0.5 mg daily following a 3 week lead-in of tasquinimod 0.25 mg with growth factor support. No unexpected toxicities occurred. Prostate 77: 385-395, 2017. © 2016 Wiley Periodicals, Inc.

Saracatinib as a metastasis inhibitor in metastatic castration-resistant prostate cancer: A University of Chicago Phase 2 Consortium and DOD/PCF Prostate Cancer Clinical Trials Consortium Study.

BACKGROUND: Fyn is a kinase that is upregulated in a subset of metastatic castration-resistant prostate cancer. Saracatinib potently inhibits Fyn activation. We have noted a relationship between Fyn expression and directional motility, a cellular process related to metastasis. As such we hypothesized that treatment with saracatinib would increase the time required to develop new metastatic lesions. METHODS: Patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel were eligible for enrollment. This study was executed as a randomized discontinuation trial. During a lead-in phase of two 28-Day cycles, all patients received saracatinib. Afterward, patients with radiographically stable disease were randomized to either saracatinib or placebo. Patients continued treatment until evidence of new metastasis. RESULTS: Thirty-one patients were treated. Only 26% of patients had stable disease after 8 weeks and thus proceeded to randomization. This required early termination of the study for futility. The 70% of patients who progressed after the lead-in phase exhibited expansion of existing lesions or decompensation due to clinical progression without new metastatic lesions. Fatigue was reported in more than 25% of patients (all grades) with only two patients experiencing grade 3 toxicity. Other grade 3 adverse events included dehydration, thrombocytopenia, and weakness. CONCLUSIONS: This study was unable to determine if saracatinib had potential as metastasis inhibitor. Metastasis inhibition by saracatinib may still be viable in an earlier time in the disease history.

The pluripotency factor Nanog is directly upregulated by the androgen receptor in prostate cancer cells.

BACKGROUND: The Androgen Receptor (AR) is a nuclear hormone receptor that functions as a critical oncogene in all stages of prostate cancer progression, including progression to castration-resistance following androgen-deprivation therapy. Thus, identifying and targeting critical AR-regulated genes is one potential method to block castration-resistant cancer proliferation. Of particular importance are transcription factors that regulate stem cell pluripotency; many of these genes are emerging as critical oncogenes in numerous tumor cell types. Of these, Nanog has been previously shown to increase the self-renewal and stem-like properties of prostate cancer cells. Thus, we hypothesized that Nanog is a candidate AR target gene that may impart castration-resistance. METHODS: We modulated AR signaling in LNCaP prostate cancer cells and assayed for Nanog expression. Direct AR binding to the NANOG promoter was tested using AR Chromatin Immunoprecipation (ChIP) and analyses of publically available AR ChIP-sequencing data-sets. Nanog over-expressing cells were analyzed for cell growth and cytotoxicity in response to the AR antagonist enzalutamide and the microtubule stabilizing agent docetaxel. RESULTS: AR signaling upregulates Nanog mRNA and protein. AR binds directly to the NANOG promoter, and was not identified within 75 kb of the NANOGP8 pseudogene, suggesting the NANOG gene locus was preferentially activated. Nanog overexpression in LNCaP cells increases overall growth, but does not increase resistance to enzalutamide or docetaxel. CONCLUSIONS: Nanog is a novel oncogenic AR target gene in prostate cancer cells, and stable expression of Nanog increases proliferation and growth of prostate cancer cells, but not resistance to enzalutamide or docetaxel.

National trends in prostate cancer screening among older American men with limited 9-year life expectancies: evidence of an increased need for shared decision making.

BACKGROUND: Prostate-specific antigen (PSA) screening for prostate cancer remains controversial. Most groups recommend informed decision making for men with 10 years of remaining life expectancy. The primary objective of this observational cohort study was to investigate the association between predicted 9-year mortality and prostate cancer screening among American men aged ≥65 years in 2005 and 2010. The second objective was to analyze the proportions of men who discussed screening with their physicians. METHODS: Data were extracted from the 2005 and 2010 National Health Interview Surveys. Men aged ≥65 years without prostate cancer were divided into predicted 9-year mortality quartiles. The proportions of men confirming a screening PSA within the prior year were determined. Logistic regression was used to compare screening rates. RESULTS: Screening rates for men aged ≥65 years were 48% in 2005 and 48% in 2010 (P = .9). Men ages 65 to 74 years who had <27% predicted 9-year mortality were most commonly screened, with 56% screened in 2010, compared with 34% of men aged ≥75 years with >75% predicted 9-year mortality. Approximately 55% of screened men aged ≥75 years who had ≥53% predicted 9-year mortality recalled discussing the advantages of screening, whereas 25% recalled discussing the disadvantages. CONCLUSIONS: Prostate cancer screening with PSA did not differ significantly between 2005 and 2010 for men aged ≥65 years based on predicted 9-year mortality. Approximately 33% of older men with a high likelihood of 9-year mortality were screened despite minimal clinical benefit. Twice as many men recalled discussing the potential advantages of screening compared with the disadvantages. Cancer 2014;120:1491-1498. © 2014 American Cancer Society.

Quantitative characterization of androgen receptor protein expression and cellular localization in circulating tumor cells from patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Many current therapies for metastatic castration-resistant prostate cancer (mCRPC) are aimed at AR signaling; however, resistance to these therapies is inevitable. To personalize CRPC therapy in an individual with clinical progression despite maximal AR signaling blockade, it is important to characterize the status of AR activity within their cancer. Biopsies of bone metastases are invasive and frequently fail to yield sufficient tissue for further study. Evaluation of circulating tumor cells (CTCs) offers an alternative, minimally invasive mechanism to characterize and study late-stage disease. The goal of this study was to evaluate the utility of CTC interrogation with respect to the AR as a potential novel therapeutic biomarker in patients with mCRPC. METHODS: Fifteen mL of whole blood was collected from patients with progressive, metastatic mCRPC, the mononuclear cell portion was isolated, and fluorescence-activated cell sorting (FACS) was used to isolate and evaluate CTCs. A novel protocol was optimized to use ImageStreamX to quantitatively analyze AR expression and subcellular localization within CTCs. Co-expression of AR and the proliferation marker Ki67 was also determined using ImageStreamX. RESULTS: We found inter-patient and intra-patient heterogeneity in expression and localization of AR. Increased AR expression and nuclear localization are associated with elevated co-expression of Ki-67, consistent with the continued role for AR in castration-resistant disease. Despite intra-patient heterogeneity, CTCs from patients with prior exposure to abiraterone had increased AR expression compared to CTCs from patients who were abiraterone-naïve. CONCLUSIONS: As our toolbox for targeting AR function expands, our ability to evaluate AR expression and function within tumor samples from patients with late-stage disease will likely be a critical component of the personalized management of advanced prostate cancer. AR expression and nuclear localization varies within patients and between patients; however it remains associated with markers of proliferation. This supports a molecularly diverse AR-centric pathobiology imparting castration-resistance.

Hormonal Therapy and Radiation Therapy in Prostate Cancer: 5-Year Outcomes From a Trial Evaluating Combined Androgen Blockade With 5-Alpha Reductase Inhibitors as an Alternative to Gonadotropin Releasing Hormone Agonists.

BACKGROUND: We previously reported that for men undergoing combined androgen deprivation therapy (ADT) and radiation therapy (RT) for prostate cancer, substitution of LHRH-agonists with 5-α- reductase inhibitors (5-ARIs) led to improved preservation of 6-month hormonal quality of life (hQOL). With longer term follow-up, we evaluated disease control. METHODS: In this non-randomized trial, men with unfavorable intermediate or high-risk prostate cancer, aged ≥70 years or with Charlson Comorbidity Index ≥2, were treated with RT (78-79.2 Gy in 39-44 fractions) and either oral ADT (oADT; 5-ARI with antiandrogen) or standard of care ADT (SOC; leuprolide with antiandrogen) for up to 28 months. The primary endpoint was EPIC hQOL; secondary endpoints included biochemical control and survival as well as changes in cholesterol and hemoglobin levels. RESULTS: Between 2011 and 2018, 70 men were enrolled (40 in oADT; 30 in SOC). Median follow-up was 65 months [IQR 36-94]. Five-year freedom from biochemical failure for oADT and SOC was 89% versus 86%, disease free survival was 62% versus 69%, cancer-specific survival was 100% versus 96%, and overall survival was 70% versus 81% (all P>.1). Testosterone (2 mo through 3 yr) and hemoglobin levels (2 mo through 2 yr) were higher, and cholesterol levels (1 yr) were lower in the oADT groups (all P < .05). CONCLUSIONS: In this non-randomized study, men treated with combined RT and oADT had better preservation of hQOL and comparable 5-year disease outcomes to men treated with SOC. Eugonadal testosterone with this approach may yield measurable benefits in cholesterol and hemoglobin levels.

A Phase I Trial of Enzalutamide Plus Selective Glucocorticoid Receptor Modulator Relacorilant in Patients with Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: The majority of patients with metastatic prostate cancer who receive androgen-deprivation therapy and androgen receptor (AR) signaling inhibitors (ARSI) progress. Activation of the glucocorticoid receptor (GR) is associated with ARSI resistance. This single-arm phase I trial assessed safety and pharmacokinetic (PK) feasibility of a combined AR antagonist (enzalutamide) and selective GR modulator (relacorilant) in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: This was a phase I trial (NCT03674814) of relacorilant and enzalutamide in patients with refractory mCRPC enrolled using a 6+3 design. The enzalutamide dose was kept constant at 120 mg/d with escalating doses of relacorilant based on safety and PK measures in cohorts of ≥6 patients. The primary objective was safety and establishment of pharmacologically active doses. Secondary objectives were related to antitumor activity. RESULTS: Thirty-five patients with mCRPC were enrolled. Twenty-three were accrued across three dose cohorts in the dose-escalation phase, and 12 enrolled at the recommended phase II dose. The combination was generally well tolerated, safe, and achieved desirable enzalutamide PK. RP2D of 120 + 150 mg/d, respectively, was established. Median time on study was 2.2 months with four patients remaining on study for longer than 11 months. Four of 12 evaluable patients had a prostate-specific antigen (PSA) partial response. CONCLUSIONS: This is the first prospective trial combining an AR antagonist and a nonsteroidal selective GR modulator. The combination was safe and well tolerated with PSA response and prolonged disease control observed in a limited subset of patients. Further prospective trials are justified to evaluate efficacy and identify predictive biomarkers of response.