LHRH Antagonist Research Articles

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 ...

Functions of Lysosomes in Mammalian Female Reproductive System

The lysosome is the most acidic membrane-bound intracellular organelle. Lysosomal acidity is primarily maintained by vacuolar H+-ATPase (V-ATPase) and counter ion channels. There are >60 hydrolytic enzymes in the lysosome for its fundamental digestive role. Lysosomes also play important roles in endocytosis, exocytosis, autophagy, and cell death. Studies that have implicated roles of lysosomes in the female reproductive system are reviewed here. In the ovary, lysosomes are implicated in the preparation of free cholesterol for steroidogenesis and degradation of regulators of steroidogenesis, regulation of follicular atresia, follicle rupture during ovulation, luteal cell survival, and luteal regression. In the oviduct, lysosomes are involved in endocytosis of both serum and oviductal luminal components. In the uterus during the menstrual/estrous cycle, lysosomes are associated with endometrial secretion, apoptosis, and menstruation. In the uterus during early pregnancy, lysosomes are involved in the temporal and directional changes of endocytosis, uterine epithelial acidification upon embryo implantation initiation, and embryo-maternal mutual communications via extracellular vesicles. In the placenta, lysosomes are implicated in nutrient transport and placental separation from the uterus for parturition. In the mammary gland, lysosomes are important for mammary gland development and involution. These findings suggest/demonstrate functions of lysosomes in multiple processes of female reproduction, from ovulation to ovarian steroidogenesis for pregnancy maintenance, and from essential in utero nurturing of developing embryos/fetuses via embryo/fetal-maternal communications, to optional postpartum nurturing of newborns via lactation. Future studies using genetically or modified animal models and pharmacological approaches will provide novel insights into the functions and mechanisms of lysosomes in the mammalian female reproductive system.

Oligopelvis-GETUG P07: A multicenter phase II trial of combined salvage radiotherapy and hormone therapy in oligorecurrent pelvic node relapses of prostate cancer.

93 Background: Oligorecurrent pelvic nodal relapse of prostatic cancer is a challenge for regional salvage treatments. We conducted OLIGOPELVIS – GETUG P07, a phase II trial of combined salvage radiotherapy and hormone therapy in oligorecurrent pelvic node relapses of prostate cancer (NCT02274779). Methods: OLIGOPELVIS–GETUG P07 was a prospective multi-center phase II trial investigating high-dose salvage pelvic irradiation with an additional dose to the fluorocholine-based positron-emission-tomography (FCH- PET)-positive pelvic lymph nodes (PLN), combined with six-month androgen blockade (LH-RH agonist or antagonist injections). The prescribed dose was 54 Gy in 1.8 Gy fractions with up to 66 Gy in 2.2 Gy fractions to the pathological PLN. Toxicity (CTCAE v4) and complete response rates (PSA < 0.20 ng/ml) were analyzed. The main objective was to assess biochemical-clinical failure defined by a cluster of events including PSA progression (≥25 % and ≥ 2 ng/ml above the nadir) or clinical evidence of local or metastatic progression or post- treatment initiation of hormonal therapy or prostate cancer-related death. We hypothesized that salvage treatment would achieve a 2-year relapse-free survival of 70 %. Results: Seventy-four patients were recruited in fifteen French radiation oncology departments between August 2014 and July 2016. Seven were excluded before treatment because of violation of the inclusion criteria. The intention-to-treat analysis therefore included sixty-seven patients. Half of them had received prior prostatic/prostate bed irradiation. Median age was 67.7. Grade 2+ two-year urinary and intestinal toxicity were 10% and 2% respectively. At 2 and 3 years, 73.1 and 45.9% of patients achieved a persisting complete response respectively. After a median follow-up of 34 months, the 2-year progression-free survival rate was 77.6%. Median progression-free survival was 40.1 months. Conclusions: Combined pelvic salvage radiotherapy and hormone therapy allowed for prolonged tumor control in oligorecurrent pelvic node relapses of prostate cancer with limited toxicity. Clinical trial information: NCT02274779.

Upfront Docetaxel with LH-RH Antagonist for Metastatic Hormone Sensitive Prostate Cancer Considering Epithelial to Mesenchymal Transition

Objective: Upfront docetaxel use for hormone naïve advanced prostate cancer is reported that it successfully delayed the progression to hormone refractory stage, though the adequate methodology to obtain the maximum effect is unclear. We investigated these issues from our experiences of upfront docetaxel use with LH-RH antagonist for metastatic hormone sensitive prostate cancer, aiming at the prevention of epithelial-mesenchymal transition (EMT) for apoptosis tolerance. Patients and Methods: Of 31 stage IV new prostate cancer patients treated with upfront docetaxel and LH-RH antagonist (Degarelix), 25 patients who could be followed more than 12 months (mean 36.2 months) were analyzed. Docetaxel was used two to three courses basically 75 mg/m2 dose initializing two weeks after the induction of first Degarelix. Results: The clinical course was divided clearly to two groups according to prostate specific antigen (PSA) values. Of 25 patients, 12 patient’s PSA did not decrease below 0.1 ng/ml within 6 months (group A) and gradually rose afterwards. PSA in another 13 patients (group B) decreased below 0.1 within 6 months and kept below 0.1 during the follow up period. Although statistically not significant, the initial group A’s PSA was higher than group B’s (average 1308 and 353 ng/ml), however, number of metastasis, Gleason sum, and bone metastatic extent of disease showed no difference between them. Among group B patients, 7 cases had only upfront docetaxel and hormonal therapy, and some of these patients showed only atrophic gland and fibrotic tissue at second prostate biopsy (specimens after more than two years of therapy), suggesting complete response. Conclusion: Our study suggested that PSA value at 6 months may predict the outcome of whole therapy. Patients showing PSA less than 0.1 ng/ml at 6 months and requiring no therapy other than docetaxel and hormone may be induced to complete response. Upfront docetaxel with LH-RH antagonist may prevent EMT for obtaining apoptosis tolerance, in case the patient does not have the castration-resistant clone at the beginning of the therapy (group B).

Is there still a role for bilateral orchidectomy in androgen-deprivation therapy for metastatic prostate cancer?

ABSTRACTObjective: To compare bilateral orchidectomy, as the classical ‘gold standard’ androgen-deprivation therapy (ADT), and ADT using a luteinising hormone-releasing hormone (LHRH) antagonist (degarelix) for the treatment of metastatic prostate cancer regarding their short-term biochemical efficacy, testosterone castrate level, tolerability, and effect on health-related quality of life (HRQoL).Patients and methods: A total of 60 patients with newly diagnosed metastatic prostate cancer were managed by either bilateral orchidectomy or degarelix injection as ADT. Both groups were compared according to their prostate-specific antigen (PSA) nadir and testosterone level at the 6-month follow-up. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) after 12 months.Results: Bilateral orchidectomy and degarelix showed comparable results for PSA reduction, but there was a statistically significantly lower castrate level of testosterone in the bilateral orchidectomy group. Using the EROTC QLQC-30, bilateral orchidectomy was associated with better HRQoL, better global health status, and better functional status.Conclusion: Bilateral orchidectomy resulted in lower castrate levels of testosterone, which may be associated with better disease control, together with better HRQoL and general health status compared to LHRH antagonist (degarelix). These results indicate that we should consider revisiting bilateral orchidectomy as a valuable and effective treatment option for ADT.Abbreviations: ADT: androgen-deprivation therapy; EORTC (QLQ-C30): European Organisation for Research and Treatment of Cancer (Quality of Life Questionnaire-Core 30); HRQoL: health-related quality of life

900TiP - A phase II randomized, open-label study comparing salvage radiotherapy in combination with 6 months of androgen-deprivation therapy with LHRH agonist or antagonist versus anti-androgen therapy with apalutamide in patients with biochemical progression after radical prostatectomy

BackgroundSalvage radiotherapy (SRT) is a potentially curative option for patients with rising PSA (biochemical recurrence) after radical prostatectomy. Recently, success rates of SRT were significantly improved through the use of concomitant anti-androgen (AAT) or androgen-deprivation (ADT) therapy. In RTOG 96-01, 2 years of bicalutamide 150mg resulted in a 5% OS benefit at 12-years. In GETUG-AFU 16, 5-year progression-free survival was significantly improved when SRT was combined with 6 months of an LHRH agonist. Based on GETUG-AFU 16, most European urologists and (radiation) oncologists now combine SRT with at least 6 months of ADT. However, ADT comes with several serious side-effects, both physical (cardiovascular, metabolic, musculoskeletal) and psychological (sexual, emotional and cognitive). Considering RTOG 96-01, and in view of new AAT options, it appears worthwhile to look for alternatives. In that respect, apalutamide (ERLEADA®), a next-generation anti-androgen, is an interesting candidate. Trial designThis is a phase II randomized, open-label study comparing SRT in combination with 6 months of LHRH (ant)agonist (arm A) versus 6 cycles of apalutamide 240mg daily (each cycle is 28 +/- 2 days) (arm B) in hormone-naïve patients with biochemical recurrence (PSA > 0.1 µg/L at least 8 weeks after radical prostatectomy). Patients with severe erectile dysfunction are excluded. All subjects will receive SRT as standard of care and will be randomly assigned in a 1:1 ratio to arm A or B. Primary objective is to compare sexual function, based on the EPIC-26 sexual domain score, at 9 months (i.e. 3 months after the end of hormonal treatment). Secondary endpoints include general quality of life (EPIC-26, EORTC QLQ C30 and PR25, FACT-P), acute as well as late toxicity (CTCAE version 5.0), and PSA (complete) response rates (i.e. decline from baseline in PSA level of 80% (90%) or greater). The trial was approved by the local ethics committee on April 2nd 2019 and started recruiting immediately thereafter. Clinical trial identificationNCT03899077; 2018-004365-13. Legal entity responsible for the studyGZA Hospitals. FundingJanssen. DisclosureAll authors have declared no conflicts of interest.

Angiotensin blockade attenuates diabetic nephropathy in hypogonadal adult male rats.

This study examined the effect of the aromatase inhibitor letrozole (0.5 mg/kg) alone or in combination with the angiotensin-receptor blocker valsartan (30 mg/kg) against streptozocin-induced diabetic nephropathy (DN) in hypogonadal (HG) rats for 12 weeks. First, we tested the HG effect on hormone levels, inflammatory cytokines, and oxidative stress in nondiabetic (ND) and diabetic (D) rats. HG was induced with the luteinizing hormone-releasing hormone antagonist cetrorelix (0.71 mg/kg). Diabetes enhanced hormonal hypogonadism and increased inflammation and oxidative stress. Next, experiments examined the effect of early letrozole and valsartan intervention on DN in HG rats. HG-ND and HG-D rats were treated with letrozole alone or in combination with valsartan. HG-D rats developed proteinuria and had increased blood urea nitrogen and creatinine, and histopathological evidence of renal injury, including glomerular hypertrophy and mesangial expansion. Valsartan alone or in combination with letrozole reduced proteinuria, improved renal functions, and reduced diabetes-induced renal angiotensin II. Both agents ameliorated nuclear factor kappa light chain enhancer of activated B cells, interleukin 1β, interleukin 6, and tumor necrosis factor alpha levels. The combination decreased superoxide dismutase, malondialdehyde, and glutathione peroxidase levels, and prevented glomerular hypertrophy. In HG-D rats, valsartan reduced renal collagen IV and transforming growth factor-beta 1, especially when the testosterone level was corrected by letrozole. Thus, normalizing testosterone and inhibiting renal angiotensin II have a renoprotective effect against DN in HG male rats.

A randomized phase Ib/II study of nivolumab with or without BMS-986253 in combination with a short course of ADT in men with castration-sensitive prostate cancer (MAGIC-8).

TPS329 Background: Androgen deprivation therapy (ADT) is highly effective in castration-sensitive prostate cancer (CSPC) but is associated with significant side effects. Novel strategies to reduce ADT exposure and prolong disease control are needed. ADT initially induces a complex immune infiltrate within prostate tumors, suggesting that immunologic intervention may be more effective at the time of castration. Emerging data suggests that the cytokine interleukin-8 (IL-8) recruits immunosuppressive polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the tumor microenvironment (TME) of many malignancies, including prostate cancer and serum IL-8 levels correlate with lack of response to anti-PD-1 therapy. We hypothesize that immunotherapy with nivolumab (a PD-1 inhibitor) with or without BMS-986253 (an IL-8 inhibitor) combined with degarelix (an LHRH antagonist) will be safe and promote an anti-tumor immune response that can prolong time to disease relapse in CSPC. Methods: This is a randomized, multicenter, two-arm, phase 1b/2 trial of patients with biochemically-recurrent or low volume metastatic CSPC and a rapidly rising PSA (≤12 months). 60 patients will receive immunotherapy with nivolumab or nivolumab plus BMS-986253 for 24 weeks. 16 weeks of ADT with degarelix will be added after 8 weeks of immunotherapy alone. The primary endpoints are safety and PSA relapse rate 10 months after the initiation of therapy. Secondary endpoints include relapse-free survival (RFS), time to testosterone recovery, rate of metastatic progression and change in PSA with immunotherapy alone. Correlative studies will quantify the systemic immune response through cytokine analysis and peripheral T cell profiling using serum and whole blood specimens collected from all enrolled patients. Pre- and on-treatment biopsies will also be obtained from the subgroup of patients with metastatic disease to further define changes in the TME using RNA-sequencing and quantitative multiplex immunofluorescence. The study is open with 1 patient currently enrolled at the time of submission. Clinical trial information: NCT03689699.

The significance of palliative surgery in castration-resistant prostate cancer

If prostate cancer recurs after primary treatment, deprivation therapy with LHRH analogues or antagonists is the treatment of choice in men with metastatic prostate cancer. However, this treatment only achieves palliative results. Median time to progression ranges between 11 and 78 months. After the introduction of Docetaxel as a first-line treatment in castration-resistant prostate cancer (CRPCA) and cabazitaxel as a second-line chemotherapy, several new drugs containing abiraterone, enzalutamide, radium 223 and sipuleucel-T have become available, which can lead to complete or partial remissions in metastasis, but do not have an effect on the prostate itself as has been shown recently. As a result of local progression of CRPCA, local complications of the urinary tract such as subvesical obstruction, recurrent gross haematuria with or without clotting, upper urinary tract dilatation, rectourethral or rectovesical fistulae and rectal obstruction will occur in about one third of all patients. Several surgical treatment options are available to manage the aforementioned complications. In patients with local progressive CRPCA and lower urinary tract symptoms, palliative TUR-P, radical prostatectomy or radical cystoprostatectomy with urinary diversion and even anterior and posterior exenteration can be performed in selected patients, requiring a preoperative multiparametric MRI of the prostate and the pelvic floor along with a laboratory examination to optimise surgical techniques and perioperative outcomes. In case of symptomatic involvement of the upper urinary tract system, the placement of endoluminal DJ stents or percutaneous nephrostomy in men with a poor performance status and a short life expectancy is the treatment of choice. In men with an ECOG performance status of 0 to 1, reconstructive surgery such as ureteral reimplantation, ileal ureteral replacement or placement of a subcutaneous pyelovesical bypass is an appropriate treatment option. To summarise, the aforementioned palliative surgical treatment options should be provided for selected patients and performed by well-experienced urologists.

No Relationship of Anti-Androgens to Alzheimer's Disease or Cognitive Disorder in the MedWatch Database.

Background:Two large studies suggest that risk is not increased. But other studies have found increased risk of Alzheimer’s disease and impaired cognition.Objective:To determine whether androgen deprivation therapy increases the risk of impaired cognition or Alzheimer’s disease in men with prostate cancer.Methods:We used data from MedWatch, the Food and Drug Administration (FDA) Safety Information and Adverse Event Reporting Program. Machine-readable data from MedWatch, including adverse drug reaction reports from manufacturers, are part of a public database. We used the online tool OpenVigil 2.1 to query the database. OpenVigil calculates proportional reporting ratios (PRRs) from adverse drug reaction reports to determine whether the combination of drug and adverse event are related. For example, PRR = 2 indicates that the adverse reaction is two times more frequent in users of the drug than in the general population.Results:We analyzed adverse event reporting data for these androgen-deprivation drugs: The luteinizing hormone releasing hormone (LHRH) agonists leuprolide, goserelin triptorelin, histrelin; the anti-androgens flutamide, nilutamide, enzalutamide, and bicalutamide; the LHRH antagonist degarelix; the CYP17 inhibitor abiraterone; the anti-fungal ketoconazole, which is also an anti-androgen administered to men with advanced prostate cancer.Conclusion:Our analysis of FDA MedWatch adverse event data reports does not support the idea that androgen deprivation therapy per se is associated with Alzheimer’s disease or cognitive dysfunction. Perhaps the prostate cancer itself, or the stress it imposes on the man who has it, may be detrimental to mood and intellect, increasing susceptibility to Alzheimer’s disease and cognitive disorder.

Patterns of Bicalutamide Use in Prostate Cancer Treatment: A U.S. Real-World Analysis Using the SEER-Medicare Database.

IntroductionBicalutamide (BIC), a non-steroidal anti-androgen, is FDA-indicated for use in combination with a luteinizing hormone-releasing hormone (LHRH) analog for treatment of Stage D2 metastatic carcinoma of the prostate. Lack of consensus exists regarding the clinical benefit of BIC use, either alone or combined use of BIC with an LHRH analog or antagonist (combined androgen blockade or CAB), versus treatment with androgen deprivation therapy (ADT) alone.MethodsThe SEER-Medicare database was used to identify prostate cancer patients aged ≥ 66 years diagnosed between 2007 and 2011 and who filled at least one prescription for BIC. Duration of BIC treatment was assessed in relation to ADT use; either alone (monotherapy), as part of CAB only, and as part of CAB followed by monotherapy. Additionally, we assessed use of BIC during or outside a potential testosterone flare prevention period (initiation within 2 months of an LHRH agonist).ResultsA total of 7521 prostate cancer patients who filled a prescription for BIC were identified. Eighteen percent of the cohort used BIC alone, over half the patients (54%) used BIC as part of CAB and 27% used BIC as part of CAB followed by monotherapy. Among men treated with BIC as part of CAB, 58% received BIC only within the potential flare period.ConclusionsAlthough there is no FDA indication for BIC use as monotherapy, > 44% of patients in this study used BIC alone or as part of CAB followed by monotherapy. Further research is necessary to understand the outcomes of BIC utilization in these settings, particularly compared with newer second-generation anti-androgens.FundingMedivation LLC, a Pfizer company, and Astellas, Pharma, Inc.Electronic supplementary materialThe online version of this article (10.1007/s12325-018-0738-5) contains supplementary material, which is available to authorized users.

Neoadjuvant degarelix with or without apalutamide followed by radical prostatectomy for intermediate and high-risk prostate cancer: ARNEO, a randomized, double blind, placebo-controlled trial

BackgroundRecent retrospective data suggest that neoadjuvant androgen deprivation therapy can improve the prognosis of high-risk prostate cancer (PCa) patients. Novel androgen receptor pathway inhibitors are nowadays available for treatment of metastatic PCa and these compounds are promising for early stage disease. Apalutamide is a pure androgen antagonist with a very high affinity with the androgen receptor. The combination of apalutamide with degarelix, an LHRH antagonist, could increase the efficacy compared to degarelix alone.ObjectiveThe primary objective is to assess the difference in proportions of minimal residual disease at prostatectomy specimen between apalutamide + degarelix vs placebo + degarelix. Various secondary endpoints are assessed: variations of different biomarkers at the tumour level (tissue microarrays to evaluate DNA-PKs, PARP, AR and splice variants, PSMA, etc.), whole transcriptome sequencing, exome sequencing and clinical (PSA and testosterone kinetics, early biochemical recurrence free survival, quality of life, safety, etc.) and radiological endpoints.MethodsARNEO is a single centre, phase II, randomized, double blind, placebo-controlled trial. The plan is to include at least 42 patients per each of the two study arms. Patients with intermediate/high-risk PCa and who are amenable for radical prostatectomy with pelvic lymph node dissection can be included. After signing an informed consent, every patient will undergo a pelvic 68Ga -PSMA-11 PSMA PET/MR and receive degarelix at standard dosage and start assuming apalutamide/placebo (60 mg 4 tablets/day) for 12 weeks. Within thirty days from the last study medication intake the same imaging will be repeated. Every patient will undergo PSA and testosterone testing the day of randomization, before the first drug intake, and after the last dose. Formalin fixed paraffin embedded tumour samples will be collected and used for transcriptome analysis, exome sequencing and immunohistochemistry.DiscussionARNEO will allow us to answer, first, whether the combined treatment can result in an increased proportion of patients with minimal residual disease. Secondly, It will enable the study of the molecular consequences at the level of the tumour. Thirdly, what the consequences are of new generation androgen receptor pathway inhibitors on 68Ga -PSMA-11 PET/MR. Finally, various clinical, safety and quality of life data will be collected.Trial RegistrationEUDRaCT number: 2016–002854-19 (authorization date 3rd August 2017).clinicalTrial.gov: NCT03080116.

Intergroup study EORTC-1532-gucg: A phase 2 randomized open-label study of oral darolutamide (ODM-201) vs. androgen deprivation therapy (ADT) with LHRH agonists or antagonist in men with hormone naive prostate cancer (PCa).

TPS406 Background: Androgen deprivation therapy (ADT) by LHRH analogues aims to lower serum testosterone. ADT is associated with several side effects that include hot flushes, depression, loss of libido, metabolic disturbances leading to an increase risk of cardiovascular disease, increased bone resorption leading to increased risk of osteoporosis and skeletal fracture. AR antagonists may circumvent these side effects by suppressing AR transcription by competitive inhibition of AR, without lowering systemic testosterone. In Europe, first generation AR antagonists bicalutamide 150 mg is registered for the treatment of non-metastatic hormone-naïve PCa. is a novel AR antagonist that is structurally distinct with higher AR-binding affinity compared to bicalutamide, enzalutamide, and apalutamide. The aim of this trial is to investigate the activity, safety and tolerability of darolutamide as single agent, as an alternative to LHRH analogues in men requiring ADT. Methods: EORTC-1532-GUCG (NCT02972060) will randomize 250 men with hormone-naïve PCa 1:1 to 600 mg (2× 300-mg tablets) bid of darolutamide1 or LHRH agonist or antagonist, stratified for type of ADT (agonist vs. antagonist), disease extent (measurable, non-measurable, vs. no metastasis) and age (≥70 vs < 70 years). Key inclusion criteria include histologically confirmed asymptomatic PCa (all stages) for whom continuous ADT is indicated for a minimum period of 24 weeks. Patients with up to 4 confirmed not visceral metastases, are allowed. Baseline total testosterone should be ≥ 8 nmol/L or 230 ng/dL. Primary endpoint is PSA response assessed at 24 weeks, defined as a ≥ 80% decline in PSA at week 24 in the darolutamide study arm. The ADT arm is used as an internal non comparative control. Key secondary endpoints include: Change in hormone-treatment related symptoms scale of the EORTC QLQ-PR25 at 24 weeks (comparison between arms); objective response rate at 24 weeks in patients with measurable disease at baseline, safety according to NCI-CTC version 4.0. Clinical trial information: NCT02972060.

A phase II study of degarelix prior to radiation on prostatic tissue androgens.

103 Background: Optimizing androgen suppression may provide better treatment outcomes for localized prostate cancer (PCa). Numerous trials have supported the benefit of combining androgen deprivation (ADT) with definitive radiotherapy in men with locally advanced or high-grade disease. LHRH agonist (LHRHa) is most commonly used. The LHRH antagonist degarelix may provide more robust androgen suppression. The impact on tissue androgens following use of degarelix prior to radiation has not been reported. We examined the impact on androgens in serum and tissue after 12 weeks of degarelix in this phase II study. Methods: A prospective, phase II study was conducted in men with localized PCa treated with 6 months of neoadjuvant and concurrent degarelix with radiation. Prostate biopsies were obtained at the time of fiducial placement before radiotherapy. Serum and tissue androgen levels were measured by liquid chromatography-tandem mass spectrometry. Needle biopsies from a separate analysis of untreated men or those receiving LHRHa prior to prostatectomy were used as tissue androgen level controls. Results: 16 men with intermediate (4) and high-risk (12) PCa received study therapy. 14 men completed degarelix and planned radiation to 77.4-81 Gy. Serum and tissue androgens after 12 weeks of therapy are compared to untreated control and LHRHa treated patients (12 weeks). Serum levels of dihydrotestosterone (DHT) and testosterone were similarly suppressed by LHRHa or degarelix compared to untreated controls, without statistically significant differences. Degarelix provided statistically greater reduction in androsterone than LHRHa. Conclusions: In this phase II study degarelix and LHRHa achieved similar serum and tissue androgen levels at 12 weeks; however, there was a greater suppression of tissue androsterone with degarelix. The clinical significance of this difference remains uncertain. Clinical trial information: NCT01731912. [Table: see text]

Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury.

There is a substantial unmet clinical need for new strategies to protect the hematopoietic stem cell (HSC) pool and regenerate hematopoiesis after radiation injury from either cancer therapy or accidental exposure. Increasing evidence suggests that sex hormones, beyond their role in promoting sexual dimorphism, regulate HSC self-renewal, differentiation, and proliferation. We and others have previously reported that sex-steroid ablation promotes bone marrow (BM) lymphopoiesis and HSC recovery in aged and immunodepleted mice. Here we found that a luteinizing hormone (LH)-releasing hormone antagonist (LHRH-Ant), currently in wide clinical use for sex-steroid inhibition, promoted hematopoietic recovery and mouse survival when administered 24 h after an otherwise-lethal dose of total-body irradiation (L-TBI). Unexpectedly, this protective effect was independent of sex steroids and instead relied on suppression of LH levels. Human and mouse long-term self-renewing HSCs (LT-HSCs) expressed high levels of the LH/choriogonadotropin receptor (LHCGR) and expanded ex vivo when stimulated with LH. In contrast, the suppression of LH after L-TBI inhibited entry of HSCs into the cell cycle, thus promoting HSC quiescence and protecting the cells from exhaustion. These findings reveal a role of LH in regulating HSC function and offer a new therapeutic approach for hematopoietic regeneration after hematopoietic injury.

Recovery of Serum Testosterone Levels and Sexual Function in Patients Treated With Short-term Luteinizing Hormone-releasing Hormone Antagonist as a Neoadjuvant Therapy Before External Radiotherapy for Intermediate-risk Prostate Cancer: Preliminary Prospective Study.

External beam radiation therapy (EBRT) with short-term androgen deprivation therapy is the standard of care for intermediate-risk prostate cancer patients. However, no study to date has evaluated the hormonal kinetics or sexual and hormonal function recovery after cessation of short-term luteinizing hormone (LH)-releasing hormone (LHRH) antagonist treatment. Ten intermediate-risk prostate cancer patients (mean age, 69.9 years) were included. All patients received 4 months of LHRH antagonist (degarelix) treatment followed by EBRT. The testosterone, luteinizing hormone (LH), follicle-stimulating hormone, and prostate-specific antigen levels were measured and Expanded Prostate Cancer Index Composite questionnaires were completed before LHRH antagonist therapy at baseline; 1, 2, 3, and 4 months after the first injection of LHRH antagonist treatment; and every 2 months thereafter until 18 months. The testosterone levels were at the castration level at 1 month after the first LHRH antagonist injection. The median interval to recover a normal testosterone level (> 7.2 nmol/L) was 7 months after the last LHRH antagonist administration. The LH and follicle-stimulating hormone levels decreased but had increased more than twice above baseline at 15 months after the last LHRH antagonist injection. The sexual function and hormonal bother subdomain scores and sexual and hormonal domain scores decreased once after LHRH antagonist treatment but had significantly recovered thereafter (P< .05). In most patients, the testosterone level had normalized within 9 months after the last LHRH administration. Sexual and hormonal function recovered after short-term LHRH antagonist administration for neoadjuvant therapy before EBRT.

Abstract CT058: A phase 2 open-label study to evaluate the efficacy and safety of VT-464 in patients with androgen receptor positive triple-negative breast cancer patients, and men with ER positive breast cancer

Abstract Background: The androgen receptor (AR) is expressed in 20-30% of patients with triple negative breast cancer (TNBC). In phase 2 trials androgen blockade with bicalutamide demonstrated a clinical benefit rate (CBR = Partial Response + Complete Response + Stable Disease) of 19% at 24 weeks and enzalutamide showed a CBR of 35% at 16 weeks. VT-464 is an oral non-steroidal, small molecule that is a potent anti-androgen through both inhibition of CYP17 lyase and through direct inhibition of AR. Studies in breast cancer cell lines have shown that VT-464 inhibits growth in a soft agar assay of MCF7 (ER positive/low AR expression), tamoxifen-resistant MCF7, and MDA-MB-453 (ER negative/AR positive) cells in a dose dependent manner and with higher potency than enzalutamide. Patients with AR+ TNBC may benefit from treatment with VT-464. In addition, since VT-464 will deplete androgen available for aromatization, men with ER-positive (ER+) breast cancer may benefit from use of VT-464. Methods: This is a Phase 2, open label study evaluating the potential benefit of VT-464 in female patients with TNBC with AR 1 to 9% (cohort 1) and AR ≥ 10% (cohort 2), and men with ER+ breast cancer (cohort 3) (NCT02130700; NIH 14-c-0090). VT-464 will be administered once daily in continuous 28-days cycles. Due to differences in drug metabolism, women with TNBC will receive VT-464 450mg by mouth daily while men with ER+ breast cancer will receive VT-464 600mg by mouth daily. In the two female TNBC cohorts the primary endpoint is CBR at 16 weeks. In the ER+ male breast cancer cohort the primary endpoint is progression free survival at 24 weeks. Secondary objectives include evaluation of response rate and the safety profile of the drug in both populations. Women with TNBC with &amp;gt; 1% AR expression per IHC are eligible. Males with ER+ breast cancer, who have failed at least one prior endocrine therapy and are undergoing gonadal suppression using LHRH agonists or antagonists are eligible for the study. All patients must be at least 18 years old and have a ECOG of 0 to 1. Consenting patients must have biopsiable disease which will be used for genomic and transcriptomic evaluation before and after treatment with VT-464. Correlative studies including serum hormone levels, circulating tumor cells, and immune subset will be analyzed. Patients must also have adequate hematopoietic, hepatic and renal function. Exclusions include symptomatic CNS metastases, radiotherapy within 28 days of study entry and active HIV, hepatitis B or hepatitis C infection. This trial opened in December 2016. While no patients have been enrolled at this time, multiple patients are currently being screened. Citation Format: Alexandra Zimmer, Margaret E. Gatti-Mays, Stan Lipkowitz, Fatima Karzai, James Gulley, William Dahut, Seth Steinberg, William D. Figg, Ravi Madan. A phase 2 open-label study to evaluate the efficacy and safety of VT-464 in patients with androgen receptor positive triple-negative breast cancer patients, and men with ER positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT058. doi:10.1158/1538-7445.AM2017-CT058

Suppressing the irrepressible; the use of LHRH antagonist, degarelix, where maximal androgen blockade had failed to achieve effective testosterone suppression in node-positive prostate cancer treated with potentially curative intent

Suppressing the irrepressible; the use of LHRH antagonist, degarelix, where maximal androgen blockade had failed to achieve effective testosterone suppression in node-positive prostate cancer treated with potentially curative intent

Is chemical/surgical castration necessary during docetaxel chemotherapy for castration-resistant prostate cancer?

e16530 Background: Docetaxel is the standard treatment for castration-resistant prostate cancer (CRPC). However, the role of chemical/surgical castration during docetaxel chemotherapy is unclear. The purpose of this study was to analyze the impact of castration during docetaxel chemotherapy. Methods: Data from 43 patients diagnosed with CRPC and treated at our institute with docetaxel chemotherapy, from January 2007 to September 2016, were analyzed retrospectively. They were divided into two groups according to the continuation of chemical castration during docetaxel chemotherapy: a continuation group and a discontinued group. Patients’ background data (age and serum prostate-specific antigen [PSA] level), PSA decline, progression-free survival, and overall survival were compared between the two groups. Results: The continuation group included 19 patients, and the discontinued group included 24 patients. Castration included surgical castration (15.8%), use of a luteinizing hormone-releasing hormone (LH-RH) agonist (68.4%), and use of an LH-RH antagonist (15.8%). There were no significant differences in patient age (73.5 years vs. 73.5 years; p = 0.878) and baseline serum PSA levels (14.25 ng/ml vs. 31.1 ng/ml, p = 0.745) between the two groups at the start of chemotherapy. PSA declines of ≥50% were observed in 7/14 patients and in 9/20 patients, respectively. There were no significant differences between the two groups with respect to the median progression-free survival (5.7 months vs. 9.9 months, p = 0.406) and overall survival. (52.1 months vs. 44.1 months, p = 0.776). Conclusions: Continuing chemical/surgical castration during docetaxel chemotherapy did not affect progression and prognosis of CRPC. Our results might suggest that chemical castration is not necessary during docetaxel chemotherapy.

PD24-05 IMPACT OF ABIRATERONE ACETATE IN THE POST-DOCETAXEL SETTING ON THE SURVIVAL OF METASTATIC CASTRATION-RESISTANT PROSTATE CANCER PATIENTS: A POPULATION-BASED STUDY IN QUEBEC

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) I1 Apr 2017PD24-05 IMPACT OF ABIRATERONE ACETATE IN THE POST-DOCETAXEL SETTING ON THE SURVIVAL OF METASTATIC CASTRATION-RESISTANT PROSTATE CANCER PATIENTS: A POPULATION-BASED STUDY IN QUEBEC Alice Dragomir, Joice Rocha, Marie Vanhuyse, Fabio Cury, Jason Hu, Noémie Prévost, and Armen Aprikian Alice DragomirAlice Dragomir More articles by this author , Joice RochaJoice Rocha More articles by this author , Marie VanhuyseMarie Vanhuyse More articles by this author , Fabio CuryFabio Cury More articles by this author , Jason HuJason Hu More articles by this author , Noémie PrévostNoémie Prévost More articles by this author , and Armen AprikianArmen Aprikian More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1082AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Abiraterone was introduced in Quebec in 2012 for metastatic castration-resistant prostate cancer (mCRPC) in the post-docetaxel setting. This study described abiraterone utilization in the early post-approval period and its clinical effectiveness in Quebec, for both post-chemotherapy patients and patients unfit for chemotherapy. METHODS A retrospective cohort study was conducted using Quebec public healthcare administrative databases. The study population consisted of men 40 years and older with a diagnosis of prostate cancer (PCa), and who received androgen-deprivation therapy (ADT) (orchiectomy or luteinizing hormone-releasing hormone analogs or antagonists (LHRHa)) between January 2001 and July 2013. In addition, patients should have received a first treatment of abiraterone between 2012 and 2013. Treatment groups were defined as: 1) Abiraterone post chemotherapy and 2) Abiraterone “exception patient”, for chemotherapy-ineligible patients treated with abiraterone authorized by the “exception patient” measure category. Study outcomes included overall survival since abiraterone initiation, abiraterone duration, and hospitalization days. Cox proportional hazard regression was used to estimate the effectiveness of abiraterone in the post-docetaxel setting adjusted for several covariates. RESULTS Our cohort consisted of 303 mCRPC patients treated with abiraterone (abiraterone post-chemotherapy: 99 and abiraterone “exception patient”: 204). The median age was 75.0 for the abiraterone post-chemotherapy group and 80.0 for the abiraterone “exception patient” group. The corresponding median survivals were 12 and 14 months, respectively (log-rank test p-value=0.815). Risk of death was similar in the abiraterone post-chemotherapy and abiraterone “exception patient” groups (hazard ratio (HR): 0.89; 95%CI 0.57-1.38). CONCLUSIONS Effectiveness of abiraterone in older patients who were chemotherapy ineligible was similar to that of patients with prior docetaxel exposure. Overall, real-world survival benefits of abiraterone were similar to the results of the COU-AA-301 trial. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e453 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Alice Dragomir More articles by this author Joice Rocha More articles by this author Marie Vanhuyse More articles by this author Fabio Cury More articles by this author Jason Hu More articles by this author Noémie Prévost More articles by this author Armen Aprikian More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...