Castrate Levels Research Articles

Extreme bipolar androgen therapy with darolutamide and testosterone cypionate in patients with metastatic castration-resistant prostate cancer: ExBAT (LACOG 0620) trial.

TPS276 Background: Prostate cancer has an intrinsic dependence on androgens and androgen receptor (AR) regulation. Suppression of gonadal androgen synthesis known as androgen deprivation therapy (ADT), either by orchiectomy or by pharmacological modulation, represents the treatment backbone of metastatic disease. Unfortunately, almost invariably, patients develop resistance to ADT, progressing to a state called castration-resistant prostate cancer (CRPC), defined as disease progression at serum testosterone levels in the castrate range. Bipolar Androgen Therapy (BAT), consisting of exogenous supraphysiological doses of testosterone followed by castrate levels, has shown clinical activity in multiple early phase clinical trials, in addition to improvement of quality of life (QoL) in CRPC patients. Alternated administration of BAT and novel AR-targeted therapies, a strategy entitled by our group as Extreme Bipolar Androgen Therapy (ExBAT), has never been tested in patients with CRPC. The objective of our study is to assess the ExBAT approach in metastatic CRPC. Methods: ExBAT (NCT04558866) is a phase 2, single-arm, multicenter trial assessing patients with mCRPC who progressed to abiraterone by PCWG3 criteria. Prior docetaxel for metastatic hormone-sensitive disease is allowed if ≥ 12 months elapsed from last dose of docetaxel. Included patients receive testosterone cypionate 400 mg IM on day 1 followed by darolutamide 1,200 mg/day orally for 4 weeks (starting on day 29 through day 56) on 63-day cycles. The primary endpoint is radiographic progression-free survival (rPFS) at 12 months. Secondary endpoints include PSA decline rates, overall survival, toxicity, quality of life, and predictive biomarkers of response/survival. Tumor assessments are performed every 9 weeks, for the first 2 cycles and every 18 weeks thereafter up to 12 months. Patients with disease progression with clinical benefit are allowed to continue treatment. Patients without disease progression after 12 months are allowed to receive study treatment on Extension Phase. The sample size of 47 patients (considering 5% drop-out) was calculated based on the primary endpoint using a two-sided 5% significance level Chi-square Test for One Proportion and achieves 80% power to detect the difference between a 50% rPFS at 12 months comparing with 30% in the historic control group. NCT04558866. From June2021 to September2022, 31 of planned 47 patients have been enrolled in 8 Brazilian centers. Results are not available at the time of submission. Clinical trial information: NCT04558866 .

Implementing 18F-DCFPyL PET in clinical practice: Prescribing patterns and utilization at a large academic center.

42 Background: 18F-DCFPyL imaging was recently approved for initial staging in patients (pts) with prostate cancer and suspected metastasis and for those with biochemical recurrence (BCR). 18F-DCFPyL recently became available at our NCI-Designated Comprehensive Cancer Center comprising 6 teaching hospitals and 2 outpatient facilities. As real-world data on 18F-DCFPyL usage in the US are lacking, our objective was to describe prescription patterns and utilization for 18F-DCFPyL. Methods: We identified 18F-DCFPyL scans performed at our center from 1/1/2022-5/10/2022 and abstracted corresponding clinical data through electronic medical record (EMR) review. Demographic, laboratory, pathological and clinical data and provider-level usage were characterized by review of the EMR and, if necessary and feasible, provider interview. Results: There were 164 18F-DCFPyL scans performed across the study period for 164 unique pts (median age 70 years, 73.8% White, 20.1% Black). Ordering providers belonged to Medical Oncology (54.3%), Radiation Oncology (42.7%), Urology (2.4%), and Nuclear Medicine (1%). The majority of scans were ordered for isolated PSA rise (n=93, 56.7%) and initial staging (n=26, 15.9%), in concordance with FDA-approved indications. Nevertheless, many scans were ordered for alternate indications. Restaging of pts with known refractory or metastatic disease (11.0%), PSA persistence after definitive therapy (8.5%), and PSA rises below the threshold of BCR (4.9%) were common alternate rationales for imaging. A minority of scans had a secondary indication such as RT field planning, distinguishing between two primary cancers, PSA persistence in high-risk disease, possible radioisotope therapy, and, most frequently, clarification of lesions seen on conventional imaging (n = 7). 22 pts were on androgen-deprivation (ADT, n=17) or anti-androgens (AR, n=11) when receiving PSMA imaging, with 5 pts on both; the median testosterone at time of imaging was <20 ng/dL. Indeterminate lesions, defined as tracer avid with uncertain malignant status, were most often found in lymph nodes (n = 22) and focal rib lesions (n = 17), of which 12 were solitary, 3 were multifocal and 2 were superimposed on fractures. Conclusions: Shortly after adoption at a large cancer center, 18F-DCFPyL has been prescribed in various clinical settings outside of FDA approvals. Around 1/8 were performed with pts on ADT/AR, with testosterone at castrate levels. Findings of uncertain malignant etiology included solitary (7%) and multifocal (2%) rib lesions. These data reveal substantial variability in usage and areas of uncertainty in the interpretation of 18F-DCFPyL imaging in real-world clinical settings, underlining the need for further studies on its potential usefulness in expanded indications.

The difference in serum testosterone recovery between Gn-RH Antagonist and LH-RH agonist among patients with prostate cancer treated with radiation therapy.

382 Background: Only limited data exist related to the serum testosterone (TST) recovery after discontinuation of Gn-RH antagonist (Degarelix acetate). In the present study, we investigated the difference in serum testosterone (TST) recovery between LH-RH agonist and Gn-RH antagonist among prostate cancer (Pca) patients received radiation therapy in combination with androgen deprivation therapy (ADT). Methods: We analyzed the association between TST levels after the end of endocrine therapy and clinical factors in 130 patients who underwent ADT for prostate cancer at Chiba University hospital between May 2003 and May 2020. The proportional hazards model and Kaplan-Meier methods were used for the statistical analysis. Results: The median patient age and PSA were 72 years, and 16.8ng/mL, respectively. The median initial TST and nadir TST were 457 ng/dL, and 20ng/dL, respectively. The median duration of ADT was 857 days. As factors affect the speed of recovery to the castration level (TST 50 ng/dL), univariate analysis showed that Gn-RH antagonist presented the significantly shorter TST recovery compared to those of LH-RH agonist (HR 1.9, p=0.0078), together with the duration of hormone therapy (857 days) and Nadir TST level (20 ng/dL), GS8 and PSA (16.8ng/mL). Multivariate analysis showed that Nadir TST level was an independent predictor (HR 2.0, p=0.0093). As factors affect the speed of recovery to the physiological level (TST 200 ng/dL), univariate analysis showed that Gn-RH antagonist presented the significantly shorter TST recovery compared to those of LH-RH agonist (HR 2.1, p=0.0064). Multivariate analysis showed that duration was the only independent predictor (HR0.34, p=0.0029). Kaplan-Meier curve demonstrated shorter time for the TST recovery in Gn-RH antagonist compared to the LH-RH agonist for the castration level (p=0.0064) and the physiological level (p=0.0052). Conclusions: TST recoveries were significantly shorter in Pca patients treated with Gn-RH antagonist than LH-RH agonist. Nadir TST value, duration, and a type of LH-RH drug may comprehensively suggest us the dynamics of TST recovery after ADT. [Table: see text]

A multi-center, prospective, observational study of patients with prostate cancer being treated with relugolix: OPTYX.

TPS398 Background: Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) receptor agonists or antagonists are the foundation of advanced prostate cancer (aPC) treatment. Relugolix is an oral non-peptide GnRH receptor antagonist approved in the US for the treatment of aPC. In the phase 3 HERO trial, relugolix maintained suppression of testosterone to castration levels in 96.7% of men from Day 29 to 48 weeks, with superiority to leuprolide acetate. Relugolix was well tolerated and associated with a 54% lower risk of major adverse cardiovascular events relative to leuprolide acetate (Shore N, NEJM 2020;382;23). The goal of this current study (OPTYX) is to generate real-world evidence about the safety and effectiveness of relugolix in patients with prostate cancer during routine clinical care. Methods: This prospective observational cohort study (registry) is enrolling patients who have planned initiation with relugolix within 1 month prior to the time of study enrollment. The study is designed to prospectively understand the actual experience of patients with prostate cancer treated with relugolix through data collection on patients selected for treatment, treatment patterns, adherence, patient reported quality of life (QoL) and safety data. Additionally, a better understanding of the trajectory of patients with prostate cancer following cessation of relugolix therapy will be gained by observing the clinical course of the disease, health outcomes, and health-related quality-of-life (HRQoL) in these patients. Inclusion criteria include patients > 18 years old with prostate cancer and planned total treatment with relugolix of at least 4 months. Estimated enrollment is 1000 patients, and patients will be followed for up to 5 years. In addition to assessing routine clinical care and disease progression, patient reported outcomes will be assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) for HRQoL and Simplified Medication Adherence Questionnaire (SMAQ) for adherence at 3 and 6 months then every 6 months. Clinical trial information: NCT05467176 .

Mechanisms of Prostate Cancer Cells Survival and Their Therapeutic Targeting.

Prostate cancer (PCa) is today the second most common cancer in the world, with almost 400,000 deaths annually. Multiple factors are involved in the etiology of PCa, such as older age, genetic mutations, ethnicity, diet, or inflammation. Modern treatment of PCa involves radical surgical treatment or radiation therapy in the stages when the tumor is limited to the prostate. When metastases develop, the standard procedure is androgen deprivation therapy, which aims to reduce the level of circulating testosterone, which is achieved by surgical or medical castration. However, when the level of testosterone decreases to the castration level, the tumor cells adapt to the new conditions through different mechanisms, which enable their unhindered growth and survival, despite the therapy. New knowledge about the biology of the so-called of castration-resistant PCa and the way it adapts to therapy will enable the development of new drugs, whose goal is to prolong the survival of patients with this stage of the disease, which will be discussed in this review.

Testosterone castration levels in patients with prostate cancer: Is there a difference between GnRH agonist and GnRH antagonist? Primary results of an open-label randomized control study.

To compare testosterone castration levels between patients treated with the gonadotropin-releasing hormone (GnRH) antagonist, degarelix, and GnRH agonist. Patients with prostate cancer (PCa) of a single outpatient clinic were randomized (2:1) to receive degarelix (group A) or GnRH agonist (group B). The study evaluated testosterone and prostate-specific antigen (PSA) levels, patients' age, Gleason score and the presence of metastases (nodal or bone). Testosterone and PSA levels were measured at 1st, 6th, 12th, and 18th months. Mann-Whitney test and Spearman correlation were used to investigate independent variable while standard multiple regression was performed to explore statistically significant correlations. Kruskal-Wallis test was used to compare testosterone levels at follow-up. The study included 168 patients, 107 in group A and 61 in group B. Testosterone levels at 1st month were significantly lower in patients under GnRH antagonist than those receiving GnRH agonist (group A: 22 ng/dL vs. group B: 29 ng/dL, p=0.011). However, PSA values did not differ significantly between groups (group A: 0.130 ng/mL vs. group B: 0.067 ng/mL, p=0.261). In multivariate analysis, treatment with degarelix was an independent factor of lower testosterone levels at 1st month (p=0.013). Comparison of testosterone levels at 6, 12, and 18 months did not reveal any significant difference within each group. In patients with PCa who are candidates for androgen deprivation therapy, the administration of GnRH antagonist seems to achieve significantly lower testosterone levels compared to treatment with GnRH agonist at 1st month of treatment.

Hypothalamic molecular correlates of photoperiod-induced spring migration in intact and castrated male redheaded buntings

This study investigated the molecular changes associated with neural plasticity in photoperiodic induction of spring migration in intact and castrated redheaded bunting, Emberiza bruniceps. We measured the hypothalamic mRNA expression of genes in birds that were photostimulated into winter non-migratory and spring (vernal) migratory phenotypes under short and long photoperiods, respectively. These included genes associated with the appetitive phase of reproduction (spring migration drive, th and ddc genes encoding for tyrosine hydroxylase and dopamine decarboxylase enzymes, respectively), sleep/awake state (pmch gene encoding for pro-melanin concentrating hormone; hcrt and hcrtr2 encoding for the hypocretin/orexin and its receptor, respectively) and neurogenesis (dcx and neuN coding for doublecortin and neuronal nuclear proteins, respectively). Higher th mRNA levels suggested an upregulated dopamine synthesis in the hypothalamus of spring migrants. Similarly, elevated hcrt and hcrtr2 mRNA levels suggested an increased wakefulness, and those of dcx and neuN genes suggested an enhanced neurogenesis during the spring migration state. Further, compared to intact birds, the lower th and pmch, and higher hcrtr2 and neuN mRNA levels in castrates suggested a role of testicular steroids in modulation of the appetitive phase of reproduction, sleep and awake states, and neurogenesis during spring migration period. These results provide insights into molecular changes linked with important hypothalamic molecular pathways and steroidal influence in the photoperiodic induction of spring migration in obligate migratory songbirds.

Adherence With Oral Anticancer Therapies: Clinical Trial versus Real-World Experiences with a Focus on Prostate Cancer.

In this review, we address adherence rates in clinical settings, barriers to compliance with dosing schedules, and potential strategies to overcome challenges in maintaining high levels of adherence. Four studies reporting real-world adherence to prostate cancer medications, 52 studies describing barriers to adherence, and 16 studies on methods to minimize poor adherence were reviewed. Mean nonadherence rates of 25 to 51% have been identified in prostate cancer patients prescribed oral therapies, with higher rates in older patients. An extensive review of prostate cancer patients receiving gonadotropin hormone-releasing hormone agonist injections found an overall nonadherence rate of over 27%. Patients may encounter barriers to complying with dosing instructions related to the medication (eg, complex dosing schedules, the total burden of medication management, fasting or dietary requirements, high medication costs, adverse effects, and drug-drug interactions). Barriers may also be related to patient-specific factors (eg, suboptimal education regarding the importance of adherence, physical limitations and cognitive decline associated with advancing age, living alone without a care partner, high symptom burden, needle phobia, and comorbid mental disorders). Interventions to improve dosing adherence may include automated reminders, treatment diaries, educational materials, and the involvement of patients, family members, care partners, and healthcare teams. Many oral anticancer medications improve survival in men with prostate cancer and therefore it is vital to establish good adherence by understanding the pitfalls that patients may encounter. In situations where both oral and injectable drugs are interchangeable, injections of long-acting drugs lead to fewer opportunities for dosing nonadherence than oral therapies. In contrast, oral medicines do not require scheduling for injections and travel for injection appointments. Therefore, maximizing adherence to all treatment regimens will reduce the chance of efficacy failures and likely lead to improved clinical outcomes.

Increased AR expression in castration-resistant prostate cancer rapidly induces AR signaling reprogramming with the collaboration of EZH2.

Elevated androgen receptor (AR) expression is a hallmark of castration-resistant prostate cancer (CRPC) and contributes to the restoration of AR signaling under the conditions of androgen deprivation. However, whether overexpressed AR alone with the stimulation of castrate levels of androgens can be sufficient to induce the reprogramming of AR signaling for the adaptation of prostate cancer (PCa) cells remains unclear. In this study, we used a PCa model with inducible overexpression of AR to examine the acute effects of AR overexpression on its cistrome and transcriptome. Our results show that overexpression of AR alone in conjunction with lower androgen levels can rapidly redistribute AR chromatin binding and activates a distinct transcription program that is enriched for DNA damage repair pathways. Moreover, using a recently developed bioinformatic tool, we predicted the involvement of EZH2 in this AR reprogramming and subsequently identified a subset of AR/EZH2 co-targeting genes, which are overexpressed in CRPC and associated with worse patient outcomes. Mechanistically, we found that AR-EZH2 interaction is impaired by the pre-castration level of androgens but can be recovered by the post-castration level of androgens. Overall, our study provides new molecular insights into AR signaling reprogramming with the engagement of specific epigenetic factors.

Population PK and Semimechanistic PK/PD Modeling and Simulation of Relugolix Effects on Testosterone Suppression in Men with Prostate Cancer.

Relugolix, the first orally active, nonpeptide gonadotropin-releasing hormone receptor antagonist, is approved in the United States and the European Union for the treatment of adult patients with advanced prostate cancer. The recommended dosing regimen is a 360-mg loading dose followed by a 120-mg daily dose. Relugolix and testosterone concentration data and clinical information from two phase I studies, two phase II studies, and the phase III safety and efficacy study (HERO) were used to develop a population pharmacokinetic (PopPK) model and a semimechanistic population pharmacokinetic/pharmacodynamic (PopPK/PD) model that characterized relugolix exposure and its relationship to testosterone concentrations. Age, body weight, and Black/African American race had at most minimal effects on relugolix exposure or testosterone concentrations with no clinical relevance. Simulations using the PopPK/PD model confirmed the recommended dosing regimen of relugolix, with the median simulated testosterone concentrations predicted to achieve castration levels (< 50 ng/dL) and profound castration levels (< 20 ng/dL) by day 2 and day 9, respectively, and demonstrated that 97.3% and 85.5% of the patients remained at castration levels (< 50 ng/dL) upon temporary interruption of treatment for 7 days and 14 days, respectively. Collectively, simulations based on the PopPK and PopPK/PD models were consistent with actual data from clinical studies, reflecting the high predictiveness of the models and supporting the reliability of model-based simulations. These models can be used to provide guidance regarding dosing recommendations under various circumstances (e.g., temporary interruption of treatment, if needed) for relugolix.

Flare on [18F]PSMA-1007 PET/CT after short-term androgen deprivation therapy and its correlation to FDG uptake: possible marker of tumor aggressiveness in treatment-naïve metastatic prostate cancer patients

PurposeShort-term androgen deprivation therapy (ADT) is known to increase heterogeneously prostate-specific membrane antigen (PSMA) expression. This phenomenon might indicate the potential of cancer lesions to respond to ADT. In this prospective study, we evaluated the flare on [18F]PSMA-1007 PET/CT after ADT in metastatic prostate cancer (PCa). Given that aggressive PCa tends to display FDG uptake, we particularly investigated whether the changes in PSMA uptake might correlate with glucose metabolism.MethodsTwenty-five men with newly diagnosed treatment-naïve metastatic PCa were enrolled in this prospective registered clinical trial. All the patients underwent [18F]PSMA-1007 PET/CT immediately before and 3–4 weeks after ADT initiation (degarelix). Before ADT, [18F]FDG PET/CT was also performed. Standardized uptake values (SUV)max of primary and metastatic lesions were calculated in all PET scans. Serum PSA and testosterone blood samples were collected before the two PSMA PET scans. The changes in PSMA uptake after ADT were represented as ΔSUVmax.ResultsAll the patients reached castration levels of testosterone at the time of the second [18F]PSMA-1007 PET/CT. Overall, 57 prostate, 314 lymph nodes (LN), and 406 bone lesions were analyzed. After ADT, 104 (26%) bone, 33 (11%) LN, and 6 (11%) prostate lesions showed an increase (≥ 20%) in PSMA uptake, with a median ΔSUVmax of + 50%, + 60%, and + 45%, respectively. Among the lesions detected at the baseline [18F]PSMA-1007 PET/CT, 63% bone and 46% LN were FDG-positive. In these metastases, a negative correlation was observed between the PSMA ΔSUVmax and FDG SUVmax (p < 0.0001). Moreover, a negative correlation between the ΔSUVmax and the decrease in serum PSA after ADT was noted (p < 0.0001).ConclusionsA heterogeneous increase in PSMA uptake after ADT was detected, most evidently in bone metastases. We observed a negative correlation between the PSMA flare and the intensity of glucose uptake as well as the decrease of serum PSA, suggesting that lesions presenting with such flare might potentially be less aggressive.Trial registrationNCT03876912, registered 15 March 2019.

Real-world treatment patterns among veterans with nonmetastatic castration-resistant prostate cancer (nmCRPC).

e17042 Background: Prostate cancer (PC) is the most common cancer diagnosed among U.S. Veterans. Non-metastatic castration-resistant prostate cancer (nmCRPC) occurs in patients who, despite having received androgen deprivation therapy, experience a rising prostate-specific antigen (PSA) and castrate testosterone levels, with no evidence of metastatic disease on radiographic imaging. Given the recent approval of novel antiandrogens, the treatment landscape for nmCRPC has rapidly evolved. Although there have been numerous clinical trials examining the safety and efficacy of these treatments, few studies have identified real-world treatment patterns among nmCRPC patients. Methods: We conducted a retrospective observational study using patient information obtained from the Veterans Affairs (VA) Clinical Cancer Registry and the VA Corporate Data Warehouse (CDW) to identify patients who were diagnosed with PC at the VA, and later developed nmCRPC, defined as having: (1) evidence of rising PSA, i.e., 2 consecutive increases in PSA concentration over a baseline value; (2) evidence of ongoing androgen deprivation consisting of a serum testosterone level of ≤50 ng/dL (≤2.0 nmol/L); and (3) no evidence of metastatic disease on radiology reports. Treatments were extracted from CDW pharmacy dispensation records and were indexed at nmCRPC diagnosis. Results: A total of 12,549 patients were diagnosed with nmCRPC and treated in the VA from 2006 to 2020; of these, 7,239 (58%) were white, 3,386 (27%) were black, 784 (6%) were Hispanic, and 1,140 (9%) other. Median age at PC diagnosis was 69 years, with most patients residing in the South 4,817 (38%). Of the 7,659 (61%) patients receiving first-line (1L) nmCRPC therapy, 5,508 (72%) received bicalutamide, 621 (8%) ketoconazole, 563 (7%) abiraterone, 492 (6%) enzalutamide, and 242 (3%) flutamide. Although bicalutamide remained the most frequently used 1L nmCRPC therapy regardless of year, the adoption of abiraterone and enzalutamide beginning in 2012 resulted in a decline of 1L bicalutamide from 80% of patients in 2006 to 43% in 2020. Ketoconazole was the second most common 1L nmCRPC therapy and the most common second-line (2L) and third line (3L) nmCRPC therapy. Of patients receiving 1L therapy, 2,244 (31%) received 2L therapy, and of these, 708 (32%) received 3L therapy. Conclusions: To our knowledge, this is the largest real-world cohort of nmCRPC patients treated in a nationwide equal-access health care system. Despite the recent approval of several nmCRPC treatments (apalutamide, darolutamide, enzalutamide) which have demonstrated improved metastasis-free survival and treatment-related quality of life, our real-world findings suggest that older, first-generation antiandrogens remain the predominant 1L treatment for nmCRPC patients.

Plain language summary of the HERO study comparing relugolix with leuprolide for men with advanced prostate cancer.

This is a summary of a research study (known as a clinical trial) called HERO. The HERO study compared how well relugolix and leuprolide worked in lowering blood testosterone to sustained castration levels in men with advanced prostate cancer. Sustained castration is a blood testosterone level below 50 ng/dl from Day 29 through 48 weeks of treatment. Researchers looked at 930 adult men with advanced prostate cancer: 622 of these men took relugolix (by mouth once daily) and 308 received leuprolide (injected every 3 months). The HERO study showed that more men taking relugolix (97%) achieved sustained castration through 48 weeks than men receiving leuprolide (89%). This decrease in testosterone also happened more quickly in men taking relugolix. In 184 men who were followed up for 90 days after completing treatment, blood levels of testosterone returned to normal in more men who took relugolix than men who received leuprolide. Side effects were similar among men taking relugolix or receiving leuprolide, and most were identified as mild or moderate in terms of how bad they were. In men with advanced prostate cancer and compared with those receiving leuprolide, more men taking relugolix had lower levels of blood testosterone. ClinicalTrials.gov NCT number: NCT03085095.

Testosterone (T) recovery profiles after short-term androgen deprivation therapy (ADT)

ABSTRACT Introduction ADT plays a major role in several scenarios for men with prostate cancer. T recovery after ADT cessation may be incomplete with 10% of men estimated to suffer persistent castrate levels after long-term ADT. Objective The objective of this study was to evaluate T recovery after short courses of ADT. Methods Study population included men treated with ≤6 months of ADT in association with radiation therapy (RT). Early morning T levels were collected at baseline and periodically after ADT cessation. T recovery after ADT cessation was analyzed in 2 ways: improvement to non-castrate level (T ≥50 ng/dL), and recovery to normal (T ≥ 300 ng/dL). Recovery rates and median survival time were estimated using Kaplan-Meier statistics and predictors analyzed using Cox proportional hazard ratios. Results 88 men with a mean age of 68 ± 8 years at time of ADT were analyzed. Median duration of ADT was 3.1 months; 56% had an ADT duration between 1-3 months and 44% between 4-6 months. Mean pre-ADT T level was 390 ± 158 ng/dL. After cessation of ADT, median time to non- castrate levels was 9.3 (IQR = 6.3 – 18.5) months and 15.8 (IQR = 8.3 - 33.8) ‘months for recovery to T ≥300 ng/dL. Higher baseline T levels (T &amp;gt; 400 ng/dL) was associated with a faster recovery to normal T level (HR = 1.80, 95% CI = 1.09 – 2.95), but not to non-castrate level. Neither age &amp;gt; 65 years, prevalent diabetes, nor ADT duration of 4-6 months vs ≤ 3 months were significantly associated with a slower T recovery. Conclusions Most of our patients remained with low T levels one year after the cessation of ADT. Higher baseline T was associated with faster T recovery to normal (T ≥ 300 ng/dL). Disclosure Work supported by industry: no.

MP48-03 PREVALENCE AND NATURAL HISTORY OF NON-METASTATIC CASTRATE RESISTANT PROSTATE CANCER: A POPULATION-BASED ANALYSIS

You have accessJournal of UrologyCME1 May 2022MP48-03 PREVALENCE AND NATURAL HISTORY OF NON-METASTATIC CASTRATE RESISTANT PROSTATE CANCER: A POPULATION-BASED ANALYSIS Amanda Hird, Erind Dvorani, Refik Saskin, Sender Herschorn, Ronald Kodama, Girish Kulkarni, and Robert Nam Amanda HirdAmanda Hird More articles by this author , Erind DvoraniErind Dvorani More articles by this author , Refik SaskinRefik Saskin More articles by this author , Sender HerschornSender Herschorn More articles by this author , Ronald KodamaRonald Kodama More articles by this author , Girish KulkarniGirish Kulkarni More articles by this author , and Robert NamRobert Nam More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002619.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The natural history of non-metastatic castrate resistant prostate cancer (nmCRPC) prior to the introduction of novel anti-androgen agents in a real-world setting is largely unknown. Our primary aim was to determine the prevalence and natural history of nmCRPC. METHODS: This was a retrospective population-based cohort study of men with nmCRPC in Ontario, Canada. Patients with a diagnosis of prostate cancer, castrate level of testosterone (<1.7 nmol/L) and a PSA >2.0 nmol/L with a subsequent rise >25% from the nadir, and without diagnostic or treatment codes for metastasis were included. Annual prevalence of nmCRPC was calculated. Crude time from nmCRPC to metastasis and death are presented as medians with interquartile range (IQR). Predictors of time from nmCRPC to prostate cancer death were compared using univariable and multivariable Fine and Gray subdistributional hazard models to account for the competing risk of non-prostate cancer death. RESULTS: From January 2007 until March 2018, we identified 2045 patients with nmCRPC. Median age was 79 years (IQR: 72-84). A total of 984 patients (48.1%) received upfront hormonal therapy while 584 (25.8%) received initial radiotherapy (RT) and 478 (23.4%) previously underwent radical prostatectomy. Median time from primary treatment to nmCRPC was 6 years (IQR: 3-10). PSA at the time of meeting nmCRPC criteria was a median of 3.0 ng/L. Patients were followed for a median 31.1 months (IQR: 19.8-47.9). The overall annual prevalence of nmCRPC ranged from 1,519-1,913 patients, representing 7-12% of men with prostate cancer prescribed androgen deprivation therapy each year. Crude median time from nmCRPC to all-cause death was 37.6 months (IQR: 22.1-55.4). Median time from nmCRPC to metastasis and metastasis to all-cause death was 20.0 and 8.3 months, respectively. On regression analysis, older patients, patients who had a higher PSA at the time of meeting nmCRPC criteria, and patients with grade group 4-5 disease had a shorter time from nmCRPC to prostate cancer death. CONCLUSIONS: This is the largest analysis of the prevalence and natural history of nmCRPC. The current study can be used as a historical cohort to compare how novel imaging modalities and advancements in systemic therapy for patients with nmCRPC impact prevalence estimates and disease trajectory over time. Source of Funding: This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health (MOH) and Ministry of Long-Term Care (MLTC) (grant number not applicable). This study also received funding from the Ajmera Family Chair in Urologic Oncology awarded to RKN (grant number not applicable). We thank IQVIA Solutions Canada Inc. for use of their Drug Information File © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e821 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Amanda Hird More articles by this author Erind Dvorani More articles by this author Refik Saskin More articles by this author Sender Herschorn More articles by this author Ronald Kodama More articles by this author Girish Kulkarni More articles by this author Robert Nam More articles by this author Expand All Advertisement PDF DownloadLoading ...

MP48-05 CHANGES IN PITUITARY–GONADAL HORMONES AFTER ENZALUTAMIDE OR ABIRATERONE PLUS PREDNISONE IN MEN WITH CASTRATION-RESISTANT PROSTATE CANCER (HEAT): RESULTS FROM A RANDOMISED CLINICAL TRIAL

You have accessJournal of UrologyCME1 May 2022MP48-05 CHANGES IN PITUITARY–GONADAL HORMONES AFTER ENZALUTAMIDE OR ABIRATERONE PLUS PREDNISONE IN MEN WITH CASTRATION-RESISTANT PROSTATE CANCER (HEAT): RESULTS FROM A RANDOMISED CLINICAL TRIAL Klara Ternov, Jens Sønksen, Mikkel Fode, Henriette Lindberg, Caroline Kistorp, Rasmus Bisbjerg, Jens Faber, Ganesh Palapattu, and Peter Busch Østergren Klara TernovKlara Ternov More articles by this author , Jens SønksenJens Sønksen More articles by this author , Mikkel FodeMikkel Fode More articles by this author , Henriette LindbergHenriette Lindberg More articles by this author , Caroline KistorpCaroline Kistorp More articles by this author , Rasmus BisbjergRasmus Bisbjerg More articles by this author , Jens FaberJens Faber More articles by this author , Ganesh PalapattuGanesh Palapattu More articles by this author , and Peter Busch ØstergrenPeter Busch Østergren More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002619.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Enzalutamide (ENZ) and abiraterone acetate plus prednisone (AAP) are both androgen receptor targeting treatments for metastatic castration-resistant prostate cancer (mCRPC). AAP inhibits the androgen production, whereas ENZ blocks the androgen receptor signalling. Herein, we compare treatment changes between ENZ and AAP in hormones of the pituitary–gonadal axis. METHODS: First-line ENZ (160 mg/day) and AAP (1000 mg abiraterone acetate and 10 mg prednisone/day) for mCRPC were compared in this randomised (1:1) phase IV trial. Eligible patients had progressive metastatic prostate cancer castrate levels of testosterone (<1.7 nmol/L). Fasting serum hormones, including testosterone, free-testosterone, sexual hormone binding globulin (SHGB), follicle-stimulating hormone (FSH) and luteinizing hormone (LH), were measured by the gold standard assay liquid chromatography – tandem mass spectrometry before 11 am at baseline and at 12-week post-intervention. The treatment difference in changed hormones was compared with logarithmic mixed models analysis, and the within-subject change for each treatment group was analysed with logarithmic paired samples t-test. RESULTS: From June 2017 to September 2019, 170 participants were randomized to receive ENZ (n=84 analysed) or AAP (n=85 analysed). A 19.9% higher increase in FSH was found for ENZ than AAP. A larger decline in testosterone and SHGB was found for AAP than ENZ. More patients had lower than detectable levels of free-testosterone in the AAP group (83/85) than the ENZ group (6/84) (chi-square test p <0.001). CONCLUSIONS: In men with castrate-levels of testosterone, ENZ and AAP both inhibit the androgen stimulation of prostate cancer, but by different mechanism of action resulting in different pituitary–gonadal hormonal profiles. Source of Funding: Herlev and Gentofte University Hospital © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e821 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Klara Ternov More articles by this author Jens Sønksen More articles by this author Mikkel Fode More articles by this author Henriette Lindberg More articles by this author Caroline Kistorp More articles by this author Rasmus Bisbjerg More articles by this author Jens Faber More articles by this author Ganesh Palapattu More articles by this author Peter Busch Østergren More articles by this author Expand All Advertisement PDF DownloadLoading ...

Association between GnRH analogue use and atopic diseases in patients with prostate cancer: A population-based retrospective cohort study.

PurposeGonadotropin-releasing hormone (GnRH) analogues reduce testosterone levels to castration levels in patients with prostate cancer. However, the role of testosterone in atopic diseases has remained undefined. We aimed to investigate this role.Materials and methodsThis retrospective cohort study was conducted using the National Health Insurance Research Database (NHIRD). Patients with prostate cancer were categorized into two groups according to whether they received GnRH analogue treatment (study group I) or not (study group II), and men without prostate cancer and with no GnRH analogue use were defined to comprise the comparison group after their ages and index years were matched with group II. Cox proportional hazard models were used to assess the hazard ratio (HR) of atopic diseases.ResultsGroup I, group II, and the comparison group comprised 663, 2,172, and 8,688 individuals, respectively. Group I had a significantly lower risk of atopic diseases (adjusted HR: 0.66, 95% CI, 0.49–0.89, p < 0.01) than did group II. A reduced risk of atopic diseases was found when GnRH analogues were prescribed for 2 months (adjusted HR 0.53, 95% CI, 0.29–0.97, p = 0.04) and 2–14 months (adjusted HR 0.66, 95% CI, 0.49–0.89, p = 0.007). No significant difference in the risk of atopic diseases between group II and the comparison group was observed.ConclusionsA decreased risk of atopic diseases was observed in patients with prostate cancer treated with GnRH analogues. Further studies are warranted to verify the association between testosterone levels and atopic diseases.

Targeting the androgen receptor signaling pathway in advanced prostate cancer.

This article summarizes current androgen receptor (AR)-directed therapies that have received regulatory approval for the treatment of advanced prostate adenocarcinoma (herein referred to as prostate cancer, PC). PC is an androgen-dependent malignancy in which ligands including testosterone and dihydrotestosterone bind to AR, initiating androgen-AR complex translocation to the nucleus followed by AR-mediated transcription of target genes. Androgen deprivation therapy (ADT), including gonadotropin hormone-releasing hormone (GnRH) agonists with or without AR antagonists (antiandrogens), GnRH antagonists, or bilateral orchiectomy, forms the backbone of treatment for patients with metastatic castration-naive PC and/or castration-resistant PC (CRPC). ADT is also an option for high-risk, early-stage PC after prostatectomy and/or radiation. While ADT is often very effective as initial therapy, resistance ultimately develops despite suppression of gonadal and/or adrenal androgens, leading to CRPC, which is characterized by mechanisms such as reactivation of the AR signaling pathway, AR gene overexpression, and mutations in the ligand-binding domain of AR that lead to disease progression, resulting in increased symptom burden and ultimately death. However, disease in patients with CRPC is still dependent on androgen signaling, and these patients continue on ADT to maintain a castrate level of serum testosterone. Novel hormonal therapies including agents that target AR directly (eg, AR antagonists) are often added to ADT in this setting. Targeting the AR signaling pathway led to the development of second-generation AR antagonists, examples of which include enzalutamide, apalutamide, and darolutamide. These agents do not exhibit partial agonism, possess a higher affinity for AR, and are postulated to improve survival outcomes relative to their first-generation counterparts for patients with CRPC. Lastly, the emergence of ADT, including second-generation AR antagonists, has led to the development of supportive care for treatment-related adverse effects. Major advances have been made in targeting the AR signaling pathway in patients with advanced PC. Further studies are warranted to identify the optimal sequencing of therapies to maximize treatment benefit. Mitigation of treatment-related adverse effects presents new opportunities to advance clinical pharmacy practice.

Testosterone (T) Recovery Profiles After Short-Term Androgen Deprivation Therapy (ADT)

ABSTRACT Introduction ADT plays a major role in several scenarios for men with prostate cancer. T recovery after ADT cessation may be incomplete with 10% of men estimated to suffer persistent castrate levels after long-term ADT. Objective The objective of this study was to evaluate T recovery after short courses of ADT. Methods Study population included men treated with ≤6 months of ADT in association with radiation therapy (RT). Early morning T levels were collected at baseline and periodically after ADT cessation. T recovery after ADT cessation was analyzed in 2 ways: improvement to non-castrate level (T ≥50 ng/dL), and recovery to normal (T ≥ 300 ng/dL). Recovery rates and median survival time were estimated using Kaplan-Meier statistics and predictors analyzed using Cox proportional hazard ratios. Results 88 men with a mean age of 68 ± 8 years at time of ADT were analyzed. Median duration of ADT was 3.1 months; 56% had an ADT duration between 1-3 months and 44% between 4-6 months. Mean pre-ADT T level was 390 ± 158 ng/dL. After cessation of ADT, median time to non- castrate levels was 9.3 (IQR = 6.3 – 18.5) months and 15.8 (IQR = 8.3 - 33.8) ‘months for recovery to T ≥300 ng/dL. Higher baseline T levels (T &amp;gt; 400 ng/dL) was associated with a faster recovery to normal T level (HR = 1.80, 95% CI = 1.09 – 2.95), but not to non-castrate level. Neither age &amp;gt; 65 years, prevalent diabetes, nor ADT duration of 4-6 months vs ≤ 3 months were significantly associated with a slower T recovery. Conclusions Most of our patients remained with low T levels one year after the cessation of ADT. Higher baseline T was associated with faster T recovery to normal (T ≥ 300 ng/dL). Disclosure No

Randomized controlled trial of GnRH antagonist monotherapy versus GnRH agonist plus bicalutamide (CAB) for patients with metastatic hormone-sensitive prostate cancer (mHSPC) (KYUCOG-1401).

99 Background: To investigate a clinical response of GnRH antagonist monotherapy against CAB therapy for mHSPC. Methods: Histopathological confirmed mHSPC patients were randomly assigned to GnRH antagonist monotherapy group (Group A) and CAB group (Group B). A deferred CAB therapy by adding bicalutamide to GnRH antagonist was performed in Group A after PSA progression. The primary endpoint was PSA progression free survival (PSA-PFS). The secondary endpoints were time to CAB treatment failure (CAB-TTF), radiographic progression free survival (rPFS), overall survival (OS), change of PSA, effect on hormone dynamics, change of bone metabolic markers, effect on lipid metabolism, adverse events (AE). This trial was registered with UMIN-CTR (UMIN000014243). Results: A total of 200 patients (101 patients in Group A and 99 in Group B) were registered from June 2014 to June 2017. The PSA-PFS was significantly better in Group B (HR (95% CI) =1.40 (1.01-1.95), p=0.041) as shown in the table. Time to CAB treatment failure (TTF) tended to be better in Group A, but there was no statistically significant difference in CAB-TTF between two groups (Table). rPFS and OS were also not statistically significant difference (Table). Time to PSA nadir was significantly shorter in Group B (HR (95% CI) = 0.72 (0.54 - 0.97), p = 0.028). The proportion of patients whose serum testosterone did not reach or maintain the castration level was more frequent in Group A (significant difference at 60 weeks, p = 0.046). There was no significant difference in the effect of bone metabolic markers and lipid metabolism between two groups. In terms of AE, injection-site-reaction was more frequent in Group A. Conclusions: LH-RH agonist CAB therapy (Group B) prolonged PSA-PFS compared to LH-RH antagonist monotherapy (Group A), probably due to the higher frequency of insufficient achievement of castration level in Group A. However, a deferred CAB therapy by adding bicalutamide to GnRH antagonist resulted in no difference in CAB-TTF, rPFS and OS. Clinical trial information: UMIN000014243.[Table: see text]