Androgen Deprivation Therapy Exposure Research Articles

Cognitive effects of long-term androgen deprivation therapy in older men with prostate cancer.

Androgen deprivation therapy (ADT) is a common treatment for prostate cancer (PCa), with increasing numbers of men on ADT for longer. Limited evidence suggests ADT impacts cognition. This study addressed gaps in the literature by focusing on older men with PCa and assessing ADT usage longer than 1year. This study of 133 men ≥65years of age with PCa included two groups: (1) men on ADT for 1-3years (ADT-exposed), and (2) a comparison group of men with PCa not on ADT (ADT-unexposed). Group comparisons on individual neuropsychological test scores are reported, as well as effect sizes (Cohen's d). Half (n=67) of the sample was ADT-exposed and half (n=66) were unexposed. The average age was 72years, most were White, and over 50% had at least secondary education. There were no statistically significant differences between groups by age, race, or education. Unadjusted analyses showed the ADT-exposed group, compared with the ADT-unexposed group, performed significantly lower in domains of verbal learning (d=0.45-0.52, p=0.01 to <0.01), verbal recall (d=0.33-0.54, p=0.06 to <0.01), and possible effects in visuospatial construction (d=0.33, p=0.08 to 0.06). When controlling for age and education, similar patterns emerged. The ADT exposed-group performed significantly lower in domains of verbal learning (d=0.45-0.52, p=0.06 to 0.03) and verbal recall (d=0.33-0.54, p=0.11 to 0.03), and possible effects in visuospatial construction d=0.33, p=0.18 to 0.13. This study suggests long-term ADT exposure impacts verbal learning, verbal recall, and possibly visuospatial abilities in older men (≥65) with PCa. The potential cognitive effects of ADT should be discussed with older patients considering long-term use of ADT.

Real-world analyses of mortality risk after androgen deprivation therapy initiation in Black vs. White patients with prostate cancer.

84 Background: 2 studies found significantly longer overall survival in Black vs. White patients with metastatic castration-resistant prostate cancer (PCa): a 2019 meta-analysis of 9 phase III trials and a 2020 registry study. Our real-world data study compared all-cause mortality risk for Black vs. White PCa patients. Compared to the prior studies, our study encompasses a broader scope and is not exclusive to men with castration-resistant PCa. Methods: Data were collected from the Decision Resources Group Real World Evidence repository, which links medical and prescription claims, and US Electronic Healthcare Records. The analysis set included PCa patients who received ≥1 androgen deprivation therapy (ADT) injection between 1991-2020. Cox regression was used to compare all-cause mortality rates between White and Black patients. Multivariable regression model accounted for the following variables: baseline metastasis, BMI, oncology vs. urology setting, antagonist vs. agonist, personal major adverse cardiovascular event (MACE) history, tobacco history, baseline PSA (&gt;4 vs. ≤4 ng/mL), race (White vs. Black), statin use, increasing age per year, ethnicity (non-Hispanic vs. Hispanic), increasing ADT exposure per year, diabetes, hypertension, and family MACE history. Results: 44,439 patients were included for the all-patient analyses. 34,762 patients were included in the Black vs White analyses: 5,817 and 28,945 were Black and White, respectively. Overall, mortality risk was 2.6% and 17% at 1 and 4 years after ADT initiation, respectively. Mortality risk after ADT initiation was 1.6% and 2.6% at 1 year and 11.7% and 18.1% at 4 years for Black and White patients, respectively. Both unadjusted (HR=1.66, 95% CI 1.53-1.80, p&lt;0.05) and adjusted (HR=1.24, 95% CI 1.01-1.52, p&lt;0.05) mortality risks were higher for White vs. Black patients. Conclusions: All-cause mortality incidence was higher in White vs. Black patients. Adding to the body of evidence, our research also reveals that Black race is associated with a protective effect on survival for all-cause mortality in men undergoing ADT. Potential hypotheses for higher mortality in White vs. Black patients include survival bias to MACE (i.e., Black patients may have died from PCa before having MACE), survival bias to be diagnosed with PCa (i.e., Black patients may have higher rate of CV death and kidney failure prior to PCa diagnosis), and protective effects of higher BMI in Black patients against cancer cachexia. The large size (~45,000 patients from a database with &gt;300 million patients), long follow-up (10 years for some patients), recent clinical experience (99% from 2010-2020), and diversity of the dataset give weight to the results being an accurate representation of current clinical experience. Future studies should confirm our findings that White PCa patients have higher mortality risk and investigate the above hypotheses.

Racial disparities in new-onset diabetes mellitus in prostate cancer patients on androgen deprivation therapy: a retrospective analysis of TriNetX data.

Prostate cancer (PCa) is the most common cancer in men in the US and androgen deprivation therapy (ADT) is the most frequently used systemic therapy for PCa. Data suggest that ADT is associated with an increased risk of new-onset diabetes mellitus (NODM) and cardiovascular complications. As the incidence and mortality of PCa are highest among the African American (AA) population, it is important to evaluate the difference in the incidence of NODM and ischemic heart disease (IHD) between AA men compared to Caucasian men. This is a retrospective cohort study utilizing the TriNetX database to assess NODM and IHD risk, risk difference, and risk ratio (RR) after recent ADT initiation in an AA cohort and a Caucasian cohort of patients with PCa. Propensity score matching (PSM) was performed by age, BMI, and confounding comorbidities. After matching, the cohort included 1159 AA patients and 843 Caucasian patients with NODM after ADT initiation. The IHD cohort included 1269 AA patients and 1248 Caucasian patients. The risk of incidence of NODM is higher among AA men at 11.6% risk compared to Caucasian men at 7.4%. The risk difference is 4.1% (95% CI = 3.4, 4.9) p = 0.000. The RR is 1.56 (95% CI = 1.43, 1.70). In contrast, risk difference and risk ratio of IHD was not significant between AA and Caucasian groups. ADT exposure increases the risk of NODM in men with PCa, especially among AA men compared with Caucasian men. Men receiving ADT should be monitored routinely for signs and symptoms of metabolic syndrome and diabetes. Targeted close monitoring of AA men on ADT would be critical to prevent and treat metabolic complications with potential of reducing disparities in PCa morbidity.

Androgen-deprivation therapy and risk of dementia in patients with prostate cancer: Clinical outcomes from real-world data.

5086 Background: Androgen deprivation therapy (ADT) is the cornerstone for the treatment advanced prostate cancer. However, there has been growing concerns regarding increased risk of dementia with ADT. Previous studies of dementia risk following ADT were controversial and inconclusive. Methods: Data was collected from an electronic health record database (TriNetX LLC., Cambridge, MA) which includes over 89 million patients from 56 healthcare systems in the United States. We identified males over the age 50 years who were diagnosed with any stage of prostate cancer between 2005 and 2022. Patients receiving ADT were 1:1 propensity score-matched with non-exposed controls for demographics and risk factors for dementia; diabetes mellitus, hypertension, hyperlipidemia, obesity, depression, cerebrovascular disease, tobacco use, alcohol dependence and benzodiazepine use. Patients with prior dementia, stroke, or TIA were excluded. Results: In a cohort of 627,025 men with prostate cancer, 73,933 patients (mean age of 70.8 years) received ADT and 57,005 patients (mean age of 70.4 years) did not. ADT exposure was associated with a diagnosis of dementia (Alzheimer’s disease, vascular dementia, or unspecified dementia); HR 1.6; 95% CI (1.49, 1.73). Subgroup analysis by dementia subtype is highlighted in (table). Compared to non-ADT group, exposure to ADT was associated with a statistically higher risk of dementia among whites (78.6% vs. 77.7%, P &lt;0.001), whereas there was no significant difference among African Americans. The risk of dementia with different ADT regimens is shown. Conclusions: This is the largest real-world study describing the association between ADT and the risk of dementia, including over 600 thousand prostate cancer patients. The risk of dementia was significantly higher in patients on ADT, with a 60% increased risk. The highest risk was witnessed with GnRH antagonists (degarelix), with a 92% increased risk. Interestingly, the increased risk of dementia in ADT groups was observed only among whites but not in African Americans. Possible causes of this discrepancy include socioeconomic disparities, bias that resulted in underdiagnosis, or biological differences. [Table: see text]

Replicating the timing of androgen deprivation therapy randomized trial (TROG 03.06 and VCOG PR 01-03 [TOAD]) for recurrent prostate cancer using real-world observational data.

e17090 Background: The landmark TOAD trial (Lancet Oncol 2016) demonstrated an overall survival benefit for immediate compared to delayed androgen deprivation therapy (ADT) for patients with recurrent prostate cancer or unsuitable for curative treatment. However, the extent to which TOAD trial results can be replicated in real-world population-based observational data is unknown. For these reasons, we used TOAD trial data and criteria to define a similar retrospective cohort of men with rising PSA after definitive treatment of localized prostate cancer to compare immediate versus delayed ADT for recurrent non-metastatic disease. Methods: We used two data sources to conduct this study: 1) TOAD trial data, and 2) national electronic health record, cancer registry, administrative, pharmacy, and laboratory data for men treated with radical prostatectomy or radiotherapy for localized prostate cancer and laboratory confirmed biochemical recurrence (BCR) between 2005- 2015 in the Veterans Health Administration. We defined BCR according to guidelines and used National Death Index data through 2019 for survival outcomes. We designated randomization to the ‘immediate’ and ‘delayed’ arms for men receiving ADT within (immediate) or after (delayed) 2 years of BCR in the observational data. We used Cox proportional hazards regression models adjusting for age, PSA at BCR, comorbidities, and Gleason score, stratified by prior ADT exposure, to compare survival outcomes for immediate versus delayed ADT. Results: We identified 9,866 men with BCR after radical prostatectomy, 3,431 after radiotherapy alone, and 2,703 after radiotherapy and adjuvant ADT. The mean age at randomization for the TOAD cohort was older (74.8 vs. 75.9 years, delayed vs. immediate) compared to our observational cohort (68.1 vs. 67.0 years, delayed vs. immediate). In unadjusted survival analyses, we found both overall and prostate cancer-specific survival were higher among patients with delayed ADT (log-rank p-value &lt; 0.001 for both). Our multivariable survival models among men with and without prior ADT exposure also demonstrated survival benefit associated with delayed ADT (prior ADT exposure, adjusted hazard ratio (aHR) 2.3, 95% confidence interval (CI) 1.7, 3.0, no prior ADT exposure 2.6, 95% CI 2.4, 2.8). Conclusions: The benefit of immediate ADT administration compared to delayed as reported within the TOAD study was not found in a comparable observational cohort of men with non-metastatic recurrent prostate cancer. Even after multivariable adjustment, we found clear association of delayed ADT administration with improved survival outcomes suggesting selection bias and unobserved confounding, or that delayed ADT may be warranted for selected patient populations necessitating further investigation. Source of Funding: NCI R01 CA242559.

Prostate cancer cells demonstrate unique metabolism and substrate adaptability acutely after androgen deprivation therapy.

Androgen deprivation therapy (ADT) has been the standard of care for advanced hormone-sensitive prostate cancer (PC), yet tumors invariably develop resistance resulting in castrate-resistant PC. The acute response of cancer cells to ADT includes apoptosis and cell death, but a large fraction remains arrested but viable. In this study, we focused on intensively characterizing the early metabolic changes that result after ADT to define potential metabolic targets for treatment. A combination of mass spectrometry, optical metabolic imaging which noninvasively measures drug responses in cells, oxygen consumption rate, and protein expression analysis was used to characterize and block metabolic pathways over several days in multiple PC cell lines with variable hormone response status including ADT sensitive lines LNCaP and VCaP, and resistant C4-2 and DU145. Mass spectrometry analysis of LNCaP pre- and postexposure to ADT revealed an abundance of glycolytic intermediates after ADT. In LNCaP and VCaP, a reduction in the optical redox ratio [NAD(P)H/FAD], extracellular acidification rate, and a downregulation of key regulatory enzymes for fatty acid and glutamine utilization was acutely observed after ADT. Screening several metabolic inhibitors revealed that blocking fatty acid oxidation and synthesis reversed this stress response in the optical redox ratio seen with ADT alone in LNCaP and VCaP. In contrast, both cell lines demonstrated increased sensitivity to the glycolytic inhibitor 2-Deoxy- d-glucose(2-DG) and maintained sensitivity to electron transport chain inhibitor Malonate after ADT exposure. ADT followed by 2-DG results in synergistic cell death, a result not seen with simultaneous administration. Hormone-sensitive PC cells displayed altered metabolic profiles early after ADT including an overall depression in energy metabolism, induction of a quiescent/senescent phenotype, and sensitivity to selected metabolic inhibitors. Glycolytic blocking agents (e.g., 2-DG) as a sequential treatment after ADT may be promising.

Extraction of Treatment Information From Electronic Health Records and Evaluation of Testosterone Recovery in Patients With Prostate Cancer.

Data quality and standardization remain a challenge when analyzing real-world clinical data. We built a clinical research database, using machine learning and natural learning processing, and investigated factors influencing testosterone recovery (T-recovery) in patients with localized prostate cancer (LPC) after initial androgen deprivation therapy (ADT). Medication and treatment-associated dates missing in structured tables were extracted from patient notes using ConceptMapper, an automated data extraction tool, standardized and curated in Sema4 clinical research database. ADT usage duration was evaluated, and T-recovery in patients with LPC was analyzed by the Kaplan-Meier method and multivariable Cox proportional hazards models. We assessed the prognostic value of post-ADT T-recovery with prostate-specific antigen progression-free survival and failure-free survival. In total, 4,125 of 30,832 (13.4%) patients with prostate cancer had medication exclusively from notes with high precision and recall, F1 score ≥ 0.95. Association of dates with medication usage had a F1 score of 0.76. ADT duration estimation had higher accuracy combining information from notes to tables from electronic medical record (70% v 45%). Baseline testosterone was the strongest predictor of T-recovery in these patients. Patients with a baseline testosterone ≥ 300 ng/dL recovered in 9.79 versus 38 months for patients with baseline testosterone < 300 ng/dL (P < .0001). Shorter prostate-specific antigen progression-free interval was observed for patients with T-recovery (≥ 300 ng/dL) at 6 months after ADT cessation compared with patients without T-recovery (< 300 ng/dL; 13.7 v 25.1 months; P = .055). We augmented structured electronic medical record data with data extracted from notes and improved the accuracy of medication information for patients. ADT exposure and T-recovery in patients with LPC produced results consistent with the literature and clinical experience and illustrates the power of applying machine learning methods to enhance the quality of real-world evidence in answering clinically relevant questions.

A phase I study of ADXS-504, a cancer type specific immunotherapy, for patients with biochemically recurrent prostate cancer.

TPS5115 Background: Roughly 20%-30% of prostate cancer patients experience biochemical recurrence (BCR), rising prostate-specific antigen (PSA) levels, after definitive therapy with radical prostatectomy (RP) or radiation therapy (RT). The optimal therapy and timing of treatment for BCR is unknown, however, for patients who are not eligible for salvage radiation, androgen deprivation therapy (ADT) is the standard first-line treatment. ADT is an effective therapy but has many acute and long-term toxicities. Novel strategies to reduce ADT exposure and prolong disease control are needed. ADXS-504 is a live attenuated Listeria monocytogenes (Lm)-based immunotherapy consisting of a truncated nonhemolytic fragment of listeriolysin O (tLLO) fused to a total of 24 tumor associated antigens (TAA). ADXS-504 was designed so that nearly 20% of patients with BCR cancer will express at least one of the targeted hotspot mutation peptide antigens and that &gt;90% will express at least one of the TAAs targeted by the sequence-optimized TAA peptide antigens. By combining these shared, commonly expressed antigen targets into a single Lm-based immunotherapy, ADXS-504 provides the potential for a potent, disease-specific approach to treating patients with prostate cancer. In addition to the generation of antigen-specific T cell responses, treatment with Lm-based immunotherapies has been shown to reprogram the tumor microenvironment (TME), by reducing the frequencies and function of immunosuppressive regulatory T cells and myeloid-derived suppressor cells within the TME. A pre-clinical murine model showed that a proto-type Lm-construct could reduce the number of metastases after removal of the primary tumor by eliminating residual tumor cells. We hypothesize that ADXS-504 is safe and promotes anti-tumor immune responses that may delay or prevent the use of ADT in castration sensitive prostate cancer. Methods: This is an open-label dose-escalation phase I trial of ADXS-504 in patients with BCR of prostate cancer previously treated with RP or RT. The study will enroll up to 18 subjects with BCR with a PSA ≥ 0.3 and a PSADT ≥ 4 months without evidence of metastatic disease on traditional CT imaging and bone scans. ADXS-504 will be given by IV every 4 weeks level for 6 study treatments, followed by maintenance therapy given every 12 weeks for 4 doses for overall total of 10 doses of study treatment. DLTs will be evaluated over the first 28 days of treatment. PSA response, PSADT, and adverse events will be summarized. The Kaplan- Meier method will be used to estimate time to PSA progression and rPFS. Immunologic activity will be evaluated by ELISpot analysis, flow cytometry, and multiplex assays and blood samples will be collected for gene sequencing analysis. The study is currently open to enrollment. Clinical trial information: NCT05077098.

Association between Androgen Deprivation Therapy and the Risk of Inflammatory Rheumatic Diseases in Men with Prostate Cancer: Nationwide Cohort Study in Lithuania.

Background: The aim of this study was to assess the association between androgen deprivation therapy (ADT) and the risk of inflammatory rheumatic diseases in men with prostate cancer. Methods: Patients with prostate cancer between 2012 and 2016 were identified from the Lithuanian Cancer Registry and the National Health Insurance Fund database, on the basis of rheumatic diseases diagnoses and information on prescriptions for androgen deprivation therapy. Cox proportional hazard models were used to estimate hazard ratios (HR) to compare the risks of rheumatic diseases caused by androgen deprivation therapy exposure in groups of prostate cancer patients. Results: A total of 12,505 prostate cancer patients were included in this study, out of whom 3070 were ADT users and 9390 were ADT non-users. We observed a higher risk of rheumatic diseases in the cohort of prostate cancer patients treated with ADT compared with ADT non-users (HR 1.55, 95% confidence interval (CI) 1.01–2.28). Detailed risk by cumulative use of ADT was performed for rheumatoid arthritis, and a statistically significant higher risk was found in the group with longest cumulative ADT exposure (>105 weeks) (HR 3.18, 95% CI 1.39–7.29). Conclusions: Our study suggests that ADT usage could be associated with increased risk of rheumatoid arthritis, adding to the many known side effects of ADT.

Better Understanding the Timing Of Androgen Deprivation Trial Outcomes: Impacts of Prior Androgen Deprivation Therapy.

BackgroundThe Timing Of Androgen Deprivation (TOAD) trial found an overall survival benefit for immediate vs delayed androgen deprivation therapy (ADT) for prostate-specific antigen (PSA)–relapsed or noncurable prostate cancer. However, broad eligibility criteria allowed entry of a heterogeneous participant group, including those with prior ADT exposure, raising concerns about subsequent androgen sensitivity. For these reasons, we completed previously specified subgroup analyses to assess if prior ADT was associated with ADT timing efficacy after PSA relapse.MethodsWe examined TOAD trial patient-level data for participants with PSA relapse after local therapy. We performed Kaplan-Meier analyses for overall survival stratified by prior ADT and randomized treatment arm (immediate or delayed ADT). We compared group characteristics using Mann-Whitney U and Fisher exact tests. All hypothesis tests were 2-sided.ResultsWe identified 261 patients with PSA relapse, 125 of whom received prior ADT. Patients with prior ADT had higher PSA at presentation (12.1 vs 9.0 ng/mL; P < .001), more cT3 disease (38.4% vs 25.0%; P = .007), and more likely received radiotherapy as local treatment (80.0% vs 47.8%; P < .001) but were otherwise similar to patients without prior ADT exposure. Within this prior ADT group, those who received immediate ADT (n = 56) had improved overall survival compared with those who received delayed ADT (n = 69; P = .02). This benefit was not observed in the group with no prior ADT (P = .98).ConclusionsThe survival benefit demonstrated in the TOAD trial may be driven by patients who received ADT prior to trial entry. We provide possible explanations for this finding with implications for treatment of PSA-relapsed prostate cancer and future study planning.

Androgen deprivation therapy, comorbidity, cancer stage and mortality from COVID-19 in men with prostate cancer

Background Androgens facilitate entrance of the severe acute respiratory syndrome coronavirus 2 into respiratory epithelial cells, and male sex is associated with a higher risk of death from corona virus disease (COVID-19). Androgen deprivation therapy (ADT) could possibly improve COVID-19 outcomes. Methods In a case–control study nested in the Prostate Cancer data Base Sweden (PCBaSe) RAPID 2019, we evaluated the association between ADT and COVID-19 as registered cause of death in men with prostate cancer. Each case was matched to 50 controls by region. We used conditional logistic regression to adjust for confounders and also evaluated potential impact of residual confounding. Results We identified 474 men who died from COVID-19 in March–December 2020. In crude analyses, ADT exposure was associated with an increased risk of COVID-19 death (odds ratio [OR] 5.05, 95% CI: 4.18–6.10); however, the OR was substantially attenuated after adjustment for age, comorbidity, prostate cancer characteristics at diagnosis, recent healthcare use, and indicators of advanced cancer (adjusted OR 1.25, 95% CI: 0.95–1.65). If adjustment has accounted for at least 85% of confounding, then the true effect could be no more than a 5% reduction of the odds for COVID-19 death. Conclusions The increased mortality from COVID-19 in men with prostate cancer treated with ADT was mainly related to high age, comorbidity, and more advanced prostate cancer. There was no evidence to support the hypothesis that ADT is associated with improved COVID-19 outcomes.

Androgen Deprivation Therapy and the Risk of Dementia after Treatment for Prostate Cancer.

The association between androgen deprivation therapy (ADT) and dementia in men with prostate cancer remains inconclusive. We assessed the association between cumulative ADT exposure and the onset of dementia in a nationwide longitudinal registry of men with prostate cancer. A retrospective analysis of men aged ≥50 years from the CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) registry was performed. The primary outcome was onset of dementia after primary treatment. ADT exposure was expressed as a time-varying independent variable of total ADT exposure. The probability of receiving ADT was estimated using a propensity score. Cox proportional hazards regression was performed to determine the association between ADT exposure and dementia with competing risk of death, adjusted for propensity score and clinical covariates among men receiving various treatments. Of 13,570 men 317 (2.3%) were diagnosed with dementia after a median of 7.0 years (IQR 3.0-12.0) of followup. Cumulative ADT use was significantly associated with dementia (HR 2.02; 95% CI 1.40-2.91; p <0.01) after adjustment. In a subset of 8,506 men, where propensity score matched by whether or not they received ADT, there was also an association between ADT use and dementia (HR 1.59; 95% CI 1.03-2.44; p=0.04). There was no association between primary treatment type and onset of dementia in the 8,489 men in the cohort who did not receive ADT. Cumulative ADT exposure was associated with dementia. This increased risk should be accompanied by a careful discussion of the needs and benefits of ADT in those being considered for treatment.

MP24-06 CUMULATIVE ANDROGEN DEPRIVATION THERAPY EXPOSURE FOR PROSTATE CANCER IS ASSOCIATED WITH AN INCREASED RISK OF DEMENTIA

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) II (MP24)1 Sep 2021MP24-06 CUMULATIVE ANDROGEN DEPRIVATION THERAPY EXPOSURE FOR PROSTATE CANCER IS ASSOCIATED WITH AN INCREASED RISK OF DEMENTIA Peter E. Lonergan, Samuel L. Washington, Shoujun Zhao, Janet E. Cowan, Jeanette M. Broering, Matthew R. Cooperberg, and Peter R. Carroll Peter E. LonerganPeter E. Lonergan More articles by this author , Samuel L. WashingtonSamuel L. Washington More articles by this author , Shoujun ZhaoShoujun Zhao More articles by this author , Janet E. CowanJanet E. Cowan More articles by this author , Jeanette M. BroeringJeanette M. Broering More articles by this author , Matthew R. CooperbergMatthew R. Cooperberg More articles by this author , and Peter R. CarrollPeter R. Carroll More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002015.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The association between androgen deprivation therapy (ADT) and dementia in men with prostate cancer remains controversial and the strength of this association remains unclear. This study assessed the association between cumulative ADT exposure and the onset of dementia after treatment in a nationwide registry of men with prostate cancer. METHODS: A retrospective analysis of men aged ≥ 50 years from the UCSF Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry from 43 primarily community-based US urology practices was performed. The primary outcome was onset of dementia after prostate cancer treatment including radical prostatectomy, external beam radiation therapy (EBRT), brachytherapy with or without EBRT, or active surveillance/watchful waiting. ADT exposure was expressed as a time-varying independent variable of total ADT exposure throughout follow up. The probability of receiving ADT was estimated using a propensity score to reduce selection bias by equating groups based on baseline characteristics. Cox proportional hazards regression was performed to determine the association between ADT exposure and dementia with competing risk of death, adjusted for propensity score and clinical covariates among men receiving various treatments. RESULTS: Of 13,570 participants, 317 (2.0%) were diagnosed with dementia with a median follow up of 7.0 years (interquartile range [IQR] 3.0-12.0). Cumulative ADT use was significantly associated with dementia (HR 2.02; 95% CI, 1.40-2.91; p=0.0002) after adjustment. In a subset of 8,506 men, propensity score matched by whether or not they received ADT, the association between ADT use and dementia (HR 1.59; 95% CI, 1.03-2.45; p=0.04) remained significant. Primary treatment type was not associated with onset of dementia in the 8,489 men in the cohort who did not receive ADT. CONCLUSIONS: Cumulative ADT exposure was associated with the onset of dementia. This increased risk should be accompanied by a careful and complete discussion of the needs and benefits of ADT in those being considered for such treatment. Source of Funding: UCSF Goldberg-Benioff Program in Cancer Translational Biology © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e413-e414 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Peter E. Lonergan More articles by this author Samuel L. Washington More articles by this author Shoujun Zhao More articles by this author Janet E. Cowan More articles by this author Jeanette M. Broering More articles by this author Matthew R. Cooperberg More articles by this author Peter R. Carroll More articles by this author Expand All Advertisement Loading ...

Myocardial perfusion PET imaging to evaluate coronary microvascular dysfunction in men with prostate cancer receiving androgen deprivation therapy.

211 Background: Strategies to inform cardiovascular (CV) risk are needed for prostate cancer patients initiating androgen deprivation therapy (ADT). Reduced myocardial blood flow reserve (MBFR) and coronary microvascular dysfunction (CMD) represent functional counterparts of traditional CV risk factors, including hyperlipidemia, insulin-resistance, and the metabolic syndrome. Myocardial perfusion PET stress imaging quantifies MBFR and detects CMD. However, the potential utility of these measures to indicate adverse CV changes in prostate cancer patients receiving ADT is poorly understood. Methods: In this prospective study (NCT03535987), eligible prostate cancer patients were planned for at least 6 months of ADT and curative-intent radiation therapy. All patients had a Framingham 10-year general CV risk score of at least 10% and no prior ADT exposure. Myocardial perfusion PET stress imaging was performed within 3 weeks of ADT initiation and again following 6 months of ADT exposure. MBFR was calculated as the ratio of MBF during stress / MBF during rest, and CMD was defined per established criteria as reduced MBFR (ratio &lt; 2.0) in patients without coronary artery disease. Study outcomes included the change in MBFR following 6 months of ADT exposure and the incidence of reduced MBFR and CMD. McNemar’s test and Wilcoxon signed rank test were used for comparison of paired data. Results: Fifteen patients completed baseline myocardial perfusion PET imaging, of whom 13 completed follow-up imaging at 6 months. At baseline, the median (IQR) Framingham CV risk score was 30.4% (19.6, 35.5). One patient (7.7%) had reduced MBFR at baseline, and 5 additional patients (46.2%) developed newly reduced MBFR (ratio &lt; 2.0) within 6 months of ADT initiation (p = 0.025). While no patients had CMD at baseline, 3 patients (30%) developed incident CMD (p = 0.083). MBFR declined in 69% of patients [median decline -0.32 (IQR -0.51, -0.22)] over 6 months ADT exposure. Conclusions: Myocardial perfusion PET imaging demonstrated a high incidence of reduced MBFR and CMD within 6 months of ADT initiation. These findings support further investigation of myocardial PET imaging, a widely-available clinical tool, as a potential research and clinical strategy to inform CV risk assessment in prostate cancer patients receiving ADT. Clinical trial information: NCT03535987.

Reduced Cardiorespiratory Fitness and Increased Cardiovascular Mortality After Prolonged Androgen Deprivation Therapy for Prostate Cancer

BackgroundProlonged androgen deprivation therapy (ADT) is favored over short-term use in patients with localized high-risk prostate cancer (PC). ObjectivesThis study sought to compare cardiorespiratory fitness (CRF) and cardiovascular (CV) mortality among patients with PC with and without ADT exposure and to explore how duration of ADT exposure influences CRF and CV mortality. MethodsRetrospective cohort study of patients referred for exercise treadmill testing (ETT) after a PC diagnosis. PC risk classification was based on Gleason score (GS): high risk if GS ≥8; intermediate risk if GS = 7; and low risk if GS <7. CRF was categorized by metabolic equivalents (METs): METs >8 defined as good CRF and METs ≤8 as reduced CRF. ADT exposure was categorized as short term (≤6 months) versus prolonged (>6 months). ResultsA total of 616 patients underwent an ETT a median of 4.8 years (interquartile range: 2.0, 7.9 years) after PC diagnosis. Of those, 150 patients (24.3%) received ADT prior to the ETT; 99 with short-term and 51 with prolonged exposure. 504 patients (81.8%) had ≥2 CV risk factors. Prolonged ADT was associated with reduced CRF (odds ratio [OR]: 2.71; 95% confidence interval [CI]: 1.31 to 5.61; p = 0.007) and increased CV mortality (hazard ratio [HR]: 3.87; 95% CI: 1.16 to 12.96; p = 0.028) in adjusted analyses. Although the association between short-term ADT exposure and reduced CRF was of borderline significance (OR: 1.71; 95% CI: 1.00 to 2.94; p = 0.052), there was no association with CV mortality (HR: 1.60; 95% CI: 0.51 to 5.01; p = 0.420) in adjusted Cox regression models. ConclusionsAmong patients with PC and high baseline CV risk, prolonged ADT exposure was associated with reduced CRF and increased CV mortality.

Use of bisphosphonates and other bone supportive agents in the management of prostate cancer-A UK perspective.

To explore the practice and views of uro-oncologists in the UK regarding their use of bone supportive agents in patients with prostate cancer. An expert-devised online questionnaire was completed by members of the British Uro-oncology Group (BUG). Of 160 uro-oncologists invited, 81 completed the questionnaire. Approximately 70% of respondents never use a bone supportive agent in patients with metastatic hormone-naïve prostate cancer on androgen deprivation therapy (ADT). However, use was more frequent in men with metastatic castration-resistant prostate cancer, from first-line treatment onwards. The majority of uro-oncologists do not use a bone supportive agent to prevent skeletal-related events in men with non-metastatic disease unless the individual patient is at an increased risk of osteoporosis. In men with more advanced disease, respondents would use an oral or intravenous (IV) bisphosphonate in 41% and 61% of patients, respectively. Zoledronic acid is the first-choice bone supportive treatment in 77% of cases, with the lack of clinical data cited as a barrier to use for other IV bisphosphonates. Local guidelines also have a significant influence on the use of bone supportive agents, especially with respect to denosumab. Bone mineral density measurement is conducted in approximately 40% of men with ADT exposure of 2 years or longer, or those with metastatic prostate cancer. Uro-oncologists in the UK generally do not use bone supportive agents for men with metastatic hormone-naïve prostate cancer or those with non-metastatic disease. However, increasing the duration of ADT and the presence of castration-resistant metastatic prostate cancer increases use.

The Risk of Cardiovascular Disease in Prostate Cancer Patients Receiving Androgen Deprivation Therapies.

Androgen deprivation therapy (ADT), with a proven role in prostate cancer management, has been associated with various cardiovascular diseases. However, few studies have investigated these associations by type of ADT, particularly for newer ADTs such as the gonadotropin-releasing hormone (GnRH) antagonist degarelix. We investigated the risk of cardiovascular disease by type of ADT in a real-world setting. We identified men newly diagnosed with prostate cancer, from 2009 to 2015, from the Scottish Cancer Registry and ADTs from the nationwide Prescribing Information System. Cardiovascular events were based upon hospitalization (from hospital records) or death from cardiovascular disease (from death records). We used Cox regression to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for cardiovascular events with time-varying ADT exposure, comparing ADT users with untreated patients, after adjusting for potential confounders, including prior cardiovascular disease. The cohort contained 20,216 prostate cancer patients, followed for 73,570 person-years, during which there were 3,853 cardiovascular events. ADT was associated with a 30% increase in cardiovascular events (adjusted HR = 1.3; 95% CI = 1.2, 1.4). This reflected increases in cardiovascular events associated with GnRH agonists (adjusted HR = 1.3; 95% CI = 1.2, 1.4), degarelix (adjusted HR = 1.5; 95% CI = 1.2, 1.9), but not bicalutamide monotherapy (adjusted HR = 1.0; 95% CI = 0.82, 1.3). There were increased risks of cardiovascular disease with the use of GnRH agonists and degarelix, but not with bicalutamide monotherapy. This is the first study to observe increased cardiovascular risks with degarelix, but the cause of this association is unclear and merits further investigation.

PD13-08 ANALYZING THE ASSOCIATION BETWEEN EXPOSURE TO ANDROGEN DEPRIVATION THERAPY AND THE ONSET OF ALZHEIMER'S DISEASE AND DEMENTIA IN MEN WITH PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Epidemiology & Natural History I (PD13)1 Apr 2020PD13-08 ANALYZING THE ASSOCIATION BETWEEN EXPOSURE TO ANDROGEN DEPRIVATION THERAPY AND THE ONSET OF ALZHEIMER'S DISEASE AND DEMENTIA IN MEN WITH PROSTATE CANCER Peter E Lonergan*, Samuel L Washington, Shoujun Zhao, Janet E Cowan, Jeanette M Broering, and Peter R Carroll Peter E Lonergan*Peter E Lonergan* More articles by this author , Samuel L WashingtonSamuel L Washington More articles by this author , Shoujun ZhaoShoujun Zhao More articles by this author , Janet E CowanJanet E Cowan More articles by this author , Jeanette M BroeringJeanette M Broering More articles by this author , and Peter R CarrollPeter R Carroll More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000847.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Recent studies have suggested an association between androgen deprivation therapy (ADT) and an increased risk of Alzheimer’s disease and/or dementia (ADD) in men with prostate cancer; however this effect is not conclusive. We sought to examine the association between exposure to ADT and the onset of ADD in a nationwide registry of men diagnosed with prostate cancer, primarily in community-based urological practices. METHODS: A retrospective review of prospectively collected data from the national CaPSURE cohort study between 1995 and 2017 was performed. Men diagnosed with prostate cancer aged ≥ 65 years and without a pre-existing diagnosis of ADD were included. ADT was defined as LHRH agonist or antagonist. Onset of dementia was identified using ICD9/10 codes at office visits/hospitalizations, medication use, or change in study status due to dementia symptoms reported by proxy. A multivariable competing risk regression analysis, with all-cause mortality as the competing risk, was performed to determine if there was an association between ADT exposure and the onset of ADD. Preliminary models tested for interactions between age, CAPRA risk and ADT exposure. The final model was adjusted for ADT exposure, age, sociodemographics, comorbidities, clinical CAPRA score and year of treatment. RESULTS: From 15,310 men enrolled, 7,957 met the study criteria. 4,916 men (62%) received no ADT, 1,434 men (18%) received ADT following local treatment and 1,607 (20%) had primary ADT. The median follow up was 7.0 years (IQR 4.0-11.0). ADD occurred in 264 men at a median (IQR) of 8.0 years (4.0-12.0). Life table estimates of onset were 2% at 7 years and 6% at 14 years after treatment. Estimates of all-cause death were 7% at 7 years and 37% at 14 years. On multivariable competing risk model (see figure), onset of ADD was not independently associated with ADT, while age and clinical CAPRA at diagnosis were significantly associated with risk of onset. The interaction terms representing ADT exposure with age and with CAPRA also were not significant. CONCLUSIONS: In our cohort ADT was not associated with the onset of ADD when accounting for all-cause mortality as a competing risk. Age and disease characteristics were more closely associated with risk of onset. Source of Funding: None © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e269-e269 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Peter E Lonergan* More articles by this author Samuel L Washington More articles by this author Shoujun Zhao More articles by this author Janet E Cowan More articles by this author Jeanette M Broering More articles by this author Peter R Carroll More articles by this author Expand All Advertisement PDF downloadLoading ...

Clinical fracture associated with androgen deprivation therapy: A retrospective study of early phase clinical trial cohorts.

234 Background: Androgen deprivation therapy (ADT) is the mainstay treatment in both locally advanced and metastatic prostate cancer. Unfortunately, ADT is associated with rapid loss of bone mineral density (a surrogate for fracture risk) within the first 12 months of initial therapy. Methods: A retrospective review of early phase NCI clinical trials from 2006 to 2013 was conducted to assess the risk of fracture for prostate cancer patients treated with ADT. Results: Seven clinical trials of prostate cancer patients who received ADT between 2006 and 2013 were identified. A total of 464 patients were enrolled in the trials. Patient median age was 64 years, the majority were white (90%), and had good performance status. The median baseline prostate specific antigen level was 29.3 ng/ml and the majority of patients had a Gleason score pattern of &gt;7 (71%). Disease was characterized as involving bone only in 43% of patients and multiple sites (bone, node and/or visceral) in 35%. Of 381 patients for which data were available, 36% received prior hormonal therapy, 37% underwent surgical castration, and 16% received radiation therapy. The most common grade 1-2 adverse events reported in the 7 trials were fatigue (36%), followed by hot flashes (27%), anemia (17%) and hyperglycemia (15%). The most common grade &gt;3 adverse events reported were hypertension and hyperglycemia (3% each). Of the total 464 patients, 7 (0.4%) reported having a fracture (5 were baseline and 2 developed while on treatment). Conclusions: Our study reconfirms the association between clinical fracture and ADT exposure; however, the incidence of fracture rate was less than 1%, which was lower than the published population-based cohorts. The difference could be attributed to short-term ADT exposure, and short-duration of follow up. Clinicians should educate patients about risk of fracture with ADT and offer bone health agent earlier in patients at high risk for fracture and also with underlying co-morbidities such as diabetes, poor performance status, chronic steroid use, or undergo radiation therapy.

The changing landscape in the management of newly diagnosed castration sensitive metastatic prostate cancer

Metastatic prostate cancer is a heterogeneous disease entity. Men without prior androgen deprivation therapy exposure are termed metastatic castration sensitive prostate cancer (mCSPC). The goal of this article is to update the reader on the rapidly changing landscape of treatment for men with mCSPC. Along with the options available to the clinician for treatment of men with mCSPC, the care of these patients has evolved into a multi-disciplinary field with expanding roles for medical, urologic, and radiation oncologists.