Androgen Blockade Research Articles

Abstract 5327: KPG-121, a novel CRBN modulator, potently inhibits growth of metastatic castration resistant prostate cancer as a single agent or in combination with androgen receptor signaling inhibitors both in vitro and in vivo

Abstract Prostate cancer is the common cancer in men and the second leading cause of cancer-related deaths in men. This disease depends on dihydrotestosterone (DHT) which activates the androgen receptor (AR) signal. Endocrine therapy (including castration surgery, anti-androgen deprivation therapy or combined androgen blockade therapy) is a preferred treatment for prostate cancer. The treatment is very effective for the majority of patients at the initial stage, but after a median period of treatment for 14 to 30 months, most patients will gradually develop metastatic castration resistant prostate cancer (mCRPC) with a median survival of less than 20 months, and urgently need a further treatment. Androgen receptor antagonists in combination with anti-androgen drugs are currently the most effective drug treatment to manage mCRPC where castration has failed. Enzalutamide, Abiraterone Acetate, Apalutamide and Darolutamide belong to this class of androgen receptor or androgen synthesis inhibitors. Here we show that KPG-121, a small molecule immunomodulator, significantly enhances the therapeutic effects of Enzalutamide, Abiraterone Acetate, Apalutamide and Darolutamide in pre-clinical mCRPC tumor models. The phase 1 trials were initiated to evaluate the safety, PK profile and preliminary efficacy of the combinatorial therapy in the patients with metastatic castration resistant prostate cancer in the US (IND 134979). KPG-121 is a novel generation of Lenalidomide analogue. KPG-121 is structurally similar to lenalidomide but with stronger binding with CRBN target, enhanced immunomodulatory activity, better anti-proliferative and anti-angiogenic properties compared to lenalidomide. Results from in vivo metastatic castration resistant prostate cancer xenograft models demonstrated that KPG-121 at tested daily dose levels ranging from 1.0 mg/kg to 10 mg/kg in combination with Enzalutamide, Abiraterone Acetate, Apalutamide or Darolutamide significantly improved anti-tumor efficacy compared to the AR signaling inhibitors alone. In addition, KPG-121 showed favorable DMPK profiles and potentially manageable toxicity in pre-clinical IND enabling study. Citation Format: Chuansheng Ge, Lei Zhang, Baisong Liao. KPG-121, a novel CRBN modulator, potently inhibits growth of metastatic castration resistant prostate cancer as a single agent or in combination with androgen receptor signaling inhibitors both in vitro and in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5327.

A Retrospective Study of Patients with Castrate Resistant Prostate Cancer at Muhimbili National Hospital, Tanzania

Background: Prostate cancer (PC) is a common health problem among men globally with high incidence and mortality. The mortality following PC is associated with advanced disease progressing to castrate resistance following androgen ablation therapies. While advances to addresscastrate resistant prostatic cancer (CRPC) have shown good results, the burden of castrate resistant cancer in Tanzania has remained unknown hence our patients cannot benefit from such advances. This study therefore aimed to determine the magnitude and clinical presentation among patients with a diagnosis of castrate resistant cancer at Muhimbili National Hospital in 2018-2019.
 Methods: This was a retrospective descriptive hospital based study carried out at Muhimbili National Hospital. Patients who were treated with androgen blockade, had evidence of attainment of castrate levels of testosterone with a diagnosis of castrate resistant prostate cancer were identified. Information regarding primary prostatic cancer treatment, clinical disease progression symptoms, and age of the patients were collected. Descriptive statistics were prepared and summarized as tables and figures.
 Results: We recruited 293 patients with prostate cancer treated by androgen deprivation therapy. Bilateral orchiectomy was the most common treatment modality offered for advanced PC. Castrate levels of testosterone were achieved in 189 (95.5%) of the patients who had testosterone levels checked. Ninety-Six (50.8%) had met the criteria for diagnosis of castrate resistant prostate cancer with mean age of 71.23±4.2 years. Patients presented with lower urinary tract symptoms and metastatic features. Most of the patients had a poorly differentiated histology with prostate specific antigen (PSA) over 100ng/l. Only 13.5% of the patients had spine magnetic resonance imaging (MRI) for their work up.
 Conclusion and recommendation: Half of patients treated for advanced PC at MNH will progress to castrate resistance following androgen deprivation therapy. More studies are needed to understand the predictors of CRPC and related treatment strategies.
 Key words: Castrate Resistant Prostate cancer, androgen deprivation therapy, advanced prostate cancer

Prescribing practices for tumour aggressiveness and castration resistance in risk-stratified prostate cancer patients

Capturing real-world prescription data is important for evaluating clinical practice in prostate cancer. The aim of this study was to evaluate prescribing practices in prostate cancer. This was a cross-sectional study in which four groups were identified based on tumour aggressiveness (bone metastasis absent and bone metastasis presnt) and castration response (castration-sensitive prostate cancer and castration-resistant prostate cancer). Drug utilisation methodology and core indicators of World Health Organization were used. A total of 150 patients were stratified into the four groups. The most common regime was complete androgen blockade in both bone metastasis groups and castration-sensitive prostate cancer. Palliative radiotherapy was part of the management in the bone metastasis (present) group. In castration-resistant prostate cancer, abiraterone, fosfestrol, docetaxel, and enzalutamide were prescribed. Approximately 78% of prescriptions contained medicines from the National List of Essential Medicines, India, 2015. Polypharmacy was not a common practice, antibiotics and antidepressant medicines were rarely prescribed. The prescribing trend for prostate cancer conformed to National Comprehensive Cancer Network guidelines.

Prognostic Value of the LATITUDE and CHAARTED Risk Criteria for Predicting the Survival of Men with Bone Metastatic Hormone-Naïve Prostate Cancer Treated with Combined Androgen Blockade Therapy: Real-World Data from a Japanese Multi-Institutional Study.

Background The CHAARTED and LATITUDE trials demonstrated a prolonged overall survival (OS) for metastatic hormone-naïve prostate cancer (mHNPC) patients who receive up-front docetaxel or abiraterone acetate. These studies used their own risk criteria: CHAARTED trial defines high- and low-volume diseases and LATITUDE trial targeting a high-risk disease. The present study explored whether or not the CHAARTED and LATITUDE criteria were useful for predicting the outcome in Japanese bone mHNPC patients, including elderly patients (≥70 years). Methods A total of 532 mHNPC patients diagnosed from 2004 to 2014 in multithird referral cancer centers were enrolled in this study. All patients had bone metastasis and received combined androgen blockade treatment as an initial hormonal therapy. Results The number of patients with CHAARTED low-volume and high-volume diseases was 178 (33.5%) and 354 (66.5%), respectively. On the contrary, the number of patients with LATITUDE low-risk and high-risk diseases was 157 (29.5%) and 375 (70.5%), respectively. A total of 307 (57.7%) patients were defined as having both CHAARTED high-volume and LATITUDE high-risk disease. The median castration-resistant prostate cancer- (CRPC-) free survival was 12.5 months for the CHAARTED high volume, 56.9 months for the CHAARTED low volume, 13.6 months for the LATITUDE high risk, and 37.3 months for the LATITUDE low risk, respectively. The OS was 50.1 months in patients with CHAARTED high-volume disease, 95.1 months in patients with CHAARTED low-volume disease, 54.0 months in patients with LATITUDE high-risk disease, and 92.7 months in patients with LATITUDE low-risk disease, respectively. This trend was also observed in elderly (≥70 years old) patients. Conclusions The patients with CHAARTED high-volume disease or LATITUDE high-risk disease showed a shorter CRPC-free survival and a shorter OS than those in the CHAARTED low-volume disease group or in the LATITUDE low-risk group among Asian Japanese bone metastatic HNPC patients.

Phase II trial of bicalutamide in combination with palbociclib for the treatment of androgen receptor (+) metastatic breast cancer.

1017 Background: Genome-wide transcriptional analysis has identified a unique subset of androgen receptor (AR) +, estrogen receptor (ER)/progesterone receptor (PR)- breast cancer (BC). The functional role of AR was confirmed initially in preclinical models demonstrating that androgen-driven growth could be abrogated by antiandrogen therapy. TBCRC011 established the safety and efficacy of inhibiting AR with bicalutamide (B) in patients (pts) with AR+/ER/PR- metastatic BC (MBC) with a median progression free survival (PFS) of 12 weeks (wks) (95% CI, 11–22 wks). In preclinical data, palbociclib (P) has been shown to reduce growth of AR+/ER/PR- MDA-MB-453 BC cells. It has been shown that AR+ triple negative BC (TNBC) expresses a luminal profile and has intact Rb protein, the target of P activity. We conducted this Phase I/II trial of the AR inhibitor B in combination with the CDK4/6 inhibitor P in pts with AR+/ER/PR/HER2- BC (NCT02605486) to test the hypothesis that androgen blockade, paired with CDK4/6 inhibition would have increased efficacy in pts with androgen-dependent BC. Methods: Postmenopausal pts with AR+ TN MBC defined as IHC ≥ 1% nuclear staining (DAKO, Clone AR441 (5/2016-11/2016) then Ventana AR SP107 (11/2016-6/2018), ECOG ≤2, measurable/non-measurable disease were eligible for enrollment. Any number of prior regimens was permitted. Pts received B 150 mg daily and P 125 mg daily 3 wks on 1 wk off. Pts were evaluated for toxicity every 2-4 wks and for response every 8-12 wks. Primary endpoint: 6 month (mo) PFS. Secondary endpoints: clinical benefit rate, toxicity, correlative studies to better characterize AR+ TNBC. A Simon 2-stage minimax design that discriminates between 6 mo PFS rates of 20% and 40% was used. If ≥ 11/33 pts were PF at 6 mo then B+P would warrant further study. Results: As of 1.1.20 33 pts were enrolled on study with median (med) age 67 (42-79), performance status 0 (0-1). Number of pts with visceral metastases: 20, measurable disease: 22. AR% 1-9: 3, 10-50: 6; 51-100: 24. Med prior lines for MBC: 3 (0-9). Best response: (31 evaluable pts): 11 pts PF at 6mo: 10 SD > 6mo, 1 PR. Med wks on study: 14 (2-101). Toxicity > 10% grade >3 related: Number of pts with leukopenia: 21, neutropenia: 21, lymphocytopenia: 6, thrombocytopenia: 3. One pt with febrile neutropenia. One death due to disease progression within 30 days off study. Conclusions: In this selected subset of pts with AR+ TN MBC, this study met its prespecified endpoint with 11 pts PF at 6 mo on B 150 mg + P 125 mg. B+P has been well tolerated with no unexpected toxicity observed. Clinical trial information: NCT02605486 .

Colina 111 PET results in a nonmetastatic castration-resistant cancer (nmCRPC) in population that is negative by conventional imaging: True incidence from real-world evidence data.

e17522 Background: Nonmetastatic Castration-Resistant Prostate Cancer (nmCRPC) is characterized by a rising prostate-specifing antigen (PSA) level, castrate testosterone levels,and no evidence of distant metastases by conventional bone scan and croos-sectional image of the chest,abdomen and pelvis. SPARTAN and PROSPER trials recently demonstrated metastasis free survival in patients with nmCPRC treated with apalutamide with androgen blockade therapy and enzalutamide respectively, Real incidence of nmCPRC in latinoamerican population is unknown. Therefore, patients with negative conventional imaging could be metastatic with PET use, fall the percentage of non metastatic setting PET Colina demonstrated improved sensitivity and specificity used for biochemically recurrent hormone – sensitive patients and staging advanced disease. Colina – PET performance in nmCPRC remain largely unknown and requires evaluation. In this study we examined the incidence of nmCPRC in an Argentinian population by conventional imaging studies and the impact of use of Colina Pet. Methods: Overall 300 patients from public and private insitutions were assessed. Real World Evidence Prostate cancer database were retrospectively screened for records of patients with nmCPRC. Results: Three hundred medical records of consecutive patients with prostate cancer were assessed. All patients were evaluated by multidisciplinary team Localized disease 214 patients and metastatic Prostate Cancer Castration Sensitive 86 patients. With a median a six years of median follow up, 43 patients developed Prostate Cancer Castration Resistant. Six patients showed nmCPRC criteria, in all of them Colina Pet was indicated. After PET colina 5 cases were positives and only one patient were negative. Conclusions: The incidence or nmCPRC is 0,02% in argentine cohort and drop out to 0,003% with PET use. Colina-PET detected loco-regional of M1 disease in nearly all patients with CPRC and no detectable metastasis by conventional imaging. Further epidemiologic with real world evidence data studies with cost-efective evaluations should be launched to put in context the rol of PET in this setting.

Bicalutamide Elicits Renal Damage by Causing Mitochondrial Dysfunction via ROS Damage and Upregulation of HIF-1.

Combined androgen blockade using bicalutamide (Bic) is a therapeutic choice for treating prostate cancer (PCa). However, even at regular clinical dosages, Bic frequently shows adverse effects associated with cardiovascular and renal damage. Previously, we found that Bic selectively damaged mesangial cells compared to tubular cells and in an in vivo rat model, we also found renal damage caused by Bic. In the present study, a rat mesangial cell model was used to further the investigation. Results indicated that Bic enhanced lactate dehydrogenase release, reactive oxygen species (ROS) production, lysosome population and kidney injury molecule-1 and decreased N-cadherin. Bic elicited mitochondrial swelling and reduced the mitochondrial potential, resulting in severe suppression of the oxygen consumption rate (OCR), maximum respiration and ATP production. The hypoxia-inducible factor (HIF)-1α transcriptional activity and messenger RNA were significantly upregulated in dose-dependent manners. The HIF-1α protein reached a peak value at 24 h then rapidly decayed. BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 and cleaved caspase-3 were dose-dependently upregulated by Bic (60 μM) and that eventually led to cell apoptosis. It is suggested that Bic induces renal damage via ROS and modulates HIF-1α pathway and clinically, some protective agents like antioxidants are recommended for co-treatment.

MP74-05 OUTCOMES OF NEOADJUVANT CHEMOHORMONAL THERAPY WITH COMPLETE ANDROGEN BLOCKADE, FOLLOWED BY TREATMENT WITH DOCETAXEL AND ESTRAMUSTINE PHOSPHATE BEFORE RADICAL PROSTATECTOMY IN PATIENTS WITH HIGH-RISK LOCALIZED PROSTATE CANCER: A PROPENSITY-SCORE MATCHING ANALYSIS

You have accessJournal of UrologyProstate Cancer: Localized: Surgical Therapy IV (MP74)1 Apr 2020MP74-05 OUTCOMES OF NEOADJUVANT CHEMOHORMONAL THERAPY WITH COMPLETE ANDROGEN BLOCKADE, FOLLOWED BY TREATMENT WITH DOCETAXEL AND ESTRAMUSTINE PHOSPHATE BEFORE RADICAL PROSTATECTOMY IN PATIENTS WITH HIGH-RISK LOCALIZED PROSTATE CANCER: A PROPENSITY-SCORE MATCHING ANALYSIS Shintaro Narita*, Hiromi Sato, Mizuki Kobayashi, Akane Kikuchi, Taketoshi Nara, Sohei Kanda, Kazuyuki Numakura, Atsushi Koizumi, Ryuhei Yamamoto, Mitsuru Saito, Takamitsu Inoue, Shigeru Satoh, Koji Mitsuzuka, Norihiko Tsuchiya, Chikara Ohyama, Yoichi Arai, Hiroshi Nanjo, and Tomonori Habuchi Shintaro Narita*Shintaro Narita* More articles by this author , Hiromi SatoHiromi Sato More articles by this author , Mizuki KobayashiMizuki Kobayashi More articles by this author , Akane KikuchiAkane Kikuchi More articles by this author , Taketoshi NaraTaketoshi Nara More articles by this author , Sohei KandaSohei Kanda More articles by this author , Kazuyuki NumakuraKazuyuki Numakura More articles by this author , Atsushi KoizumiAtsushi Koizumi More articles by this author , Ryuhei YamamotoRyuhei Yamamoto More articles by this author , Mitsuru SaitoMitsuru Saito More articles by this author , Takamitsu InoueTakamitsu Inoue More articles by this author , Shigeru SatohShigeru Satoh More articles by this author , Koji MitsuzukaKoji Mitsuzuka More articles by this author , Norihiko TsuchiyaNorihiko Tsuchiya More articles by this author , Chikara OhyamaChikara Ohyama More articles by this author , Yoichi AraiYoichi Arai More articles by this author , Hiroshi NanjoHiroshi Nanjo More articles by this author , and Tomonori HabuchiTomonori Habuchi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000960.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: To investigate the clinical outcomes in patients with high-risk prostate cancer (PCa) treated with neoadjuvant chemohormonal therapy (NCHT) before radical prostatectomy (RP). METHODS: Our NCHT protocol involved complete androgen blockade (CAB) followed by 6 cycles of docetaxel (30 mg/m2) plus estramustine phosphate (560 mg). NCHT was given to 60 patients with PCa before RP, and we compared the clinical and pathological outcomes with those of 349 patients with high-risk PCa who underwent RP alone, using propensity score matching (PSM). The data for those who underwent RP alone were obtained from the Michinoku Japan Urological Cancer Study Group database. RESULTS: In the NCHT group, 10.0% achieved pathological complete response, 3.3% had positive surgical margins, and 13.3% developed severe complications (Clavien–Dindo grade ≥III) after RP. The median follow-up duration was 42.5 months and the 5-year biochemical recurrence (BCR)-free survival was 60.1%. In multivariate analysis, pN+ was an independent prognostic factor for BCR (hazard ratio = 5.25, 1.30–21.20; P = 0.020). In PSM, the BCR rate in the NCHT group was significantly lower than that in the RP alone group (P = 0.021). In subgroup analyses, the BCR rate in patients with a single high-risk factor was significantly lower in the NCHT group than in the RP alone group (P = 0.027). CONCLUSIONS: NCHT before RP can reduce the risk of BCR in patients with high-risk PCa, particularly if a single high-risk factor is present. However, the potential for perioperative complications should be considered. Source of Funding: None © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1133-e1133 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Shintaro Narita* More articles by this author Hiromi Sato More articles by this author Mizuki Kobayashi More articles by this author Akane Kikuchi More articles by this author Taketoshi Nara More articles by this author Sohei Kanda More articles by this author Kazuyuki Numakura More articles by this author Atsushi Koizumi More articles by this author Ryuhei Yamamoto More articles by this author Mitsuru Saito More articles by this author Takamitsu Inoue More articles by this author Shigeru Satoh More articles by this author Koji Mitsuzuka More articles by this author Norihiko Tsuchiya More articles by this author Chikara Ohyama More articles by this author Yoichi Arai More articles by this author Hiroshi Nanjo More articles by this author Tomonori Habuchi More articles by this author Expand All Advertisement PDF downloadLoading ...

Case Report: A castration-resistant terminal prostate cancer patient’s survival prolonged after practicing Falun Gong

Background: Most metastatic prostate cancer patients receive combined androgen blockade (CAB) as the mainstay of treatment. Unfortunately, patients ultimately progress to castration resistance. Clinical finding and diagnosis: We describe a man in his eighties who developed stage IV, M1b prostate cancer, multiple (≥5) bone metastases, and required the aid of a walker to ambulate. Without treatment, his treating physician predicted he would survive 6 months. Interventions and outcomes: The patient initially responded well to treatment with CAB, but during the 68-80th week of treatment he developed castration resistance. Bicalutamide was then discontinued. He subsequently began practicing Falun Gong (FLG) as an alternative form of care. Within one year of constant practice, he became able to walk independently, his bone metastases disappeared, and he also enjoyed better psychosocial functioning. His treating physician assessed that his prostate malignancy was “clinically, under control” and “his overall functional status is excellent.” The patient survived a total of 263 weeks (61.4 months) post diagnosis, including 174 weeks (40.6 months) after developing castration resistance. Conclusion: This castration-resistant terminal prostate cancer patient gained significant clinical benefits after practicing Falun Gong.

PROTEUS: A randomized, double-blind, placebo (PBO)-controlled, phase III trial of apalutamide (APA) plus androgen deprivation therapy (ADT) versus PBO plus ADT prior to radical prostatectomy (RP) in patients with localized high-risk or locally advanced prostate cancer (PC).

TPS383 Background: Patients (pts) with localized high-risk PC have disease progression rates of ~50% after RP (Kane et al. J Urol. 2007). Neoadjuvant studies show that androgen blockade can improve local disease control at the time of RP (McKay et al. Prostate Cancer Prostatic Dis. 2017; Taplin et al. JCO. 2014; Efstathiou et al. Eur Urol. 2019). This study will determine if treatment with APA + ADT before RP in pts with localized high-risk or locally advanced PC improves pathologic complete response (pCR) rate and if neoadjuvant and adjuvant peri-operative treatment with APA + ADT improves metastasis-free survival (MFS) compared with PBO + ADT. Methods: This international multicenter trial is enrolling candidates for RP with localized high-risk or locally advanced PC. Eligibility criteria: any combination of Gleason score (GS) 4 + 3 (= Grade Group [GG] 3) and GS 8 (4 + 4 or 5 + 3) from ≥ 6 systematic biopsy cores (SB) or targeted biopsy cores (TB) (with ≥ 1 core GS 8 [4 + 4 or 5 + 3] included); any combination of GS 4 + 3 (= GG 3) and GS 8 (4 + 4 or 5 + 3) from ≥ 3 SB or TB (with ≥ 1 core GS 8 [4 + 4 or 5 + 3]) included and prostate-specific antigen (PSA) ≥ 20 ng/mL; GS ≥ 9 (GG 5) in ≥ 1 SB or TB; or ≥ 2 SB or TB with continuous GS ≥ 8 (GG 4), each with ≥ 80% involvement. Stratification: GS (7 or ≥ 8), cN0 or N1, and region. Randomization: 1:1 to APA (240 mg) + ADT or PBO + ADT. Pts will receive 6 months neoadjuvant treatment and RP + 6 months adjuvant treatment. Dual primary end points: pCR rate (assessed by blinded independent central pathology review) and MFS (assessed by blinded independent central radiology review). Secondary end points: PSA-free survival and progression-free survival. Imaging with CT or MRI and bone scan at screening, after RP, and then every 6 months following biochemical failure until documented distant metastasis, or death. ~1500 pts will be enrolled globally over 3 years at 240 sites in 19 countries. An independent data monitoring committee is commissioned to review trial data. Clinical trial information: NCT03767244.

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.

Effects of endocrine therapy on lipid metabolism and nutritional status in elderly patients with prostate cancer

Objective To analyze effects of androgen deprivation therapy on lipid metabolism and nutritional status in patients with prostate cancer. Methods The clinical data of 255 elderly patients (≥ 65 years old) with prostate cancer who received endocrine therapy and complete follow-up data from January 2010 to December 2018 were analyzed retrospectively. The median age of the 255 patients was 76 years(65-92). The average PSA of patients was (58.15±9.62) ng/ml, where 101 patients had PSA 20 ng/ml. All patients were diagnosed pathologically by prostate biopsy. As for Gleason score, Gleason score≤6, Gleason score=7 and Gleason score≥ 8 had 62, 103 and 90 patients, respectively. Endocrine therapy included maximum androgen blockade (197 cases) and drug castration (58 cases), and continued for at least 1 year. Among them, 123 cases had complete blood lipid index data, and the subgroup analysis was based on the age of 80 years old, including 98 cases aged 65 to 80 years old and 25 cases over 80 years old. A total of 186 cases had complete data of total protein and albumin, of which 147 cases were 65 years old and 80 years old and 39 cases were more than 80 years old. Before treatment, cholesterol was (4.08±0.87)mmol/L, including (4.14±0.86) mmol/L in the 65-80 years old group, (3.82±0.88) mmol/L in >80 years old group; triglyceride was (1.23 ±0.56) mmol/L, 65-80 age group was (1.26±0.56) mmol/L and >80 years old group was (1.11±0.57) mmol/L; High density lipoprotein cholesterol was(1.09±0.24)mmol/L, 65-80 age group was (1.10±0.25) mmol/L and >80 years group was (1.04±0.21) mmol/L. Low density lipoprotein cholesterol was (2.50±0.78)mmol/L, 65~80 age group was (2.55±0.77)mmol/L and (2.34±0.83) mmol/L in >80 years old group.The total protein before endocrine therapy was (63.81±5.93) g/L, including (63.95±5.79) g/L in the 65-80 years old group, (63.30±6.49) g/L in >80 years old group. In terms of pre-treatment albumin (39.68±3.50) g/L, including (39.82±3.60) g/L in the 65-80 years old group and (39.21±3.12) g/L in >80 years old group. The differences of various indexes before and after treatment were analyzed. Results The results of blood lipid data analysis of 123 cases showed that, there were increased significant differences(P 0.05). The results of data analysis of 186 cases of total protein and albumin showed that, the total protein after treatment was (62.81±7.34) g/L, which was not significantly different from that before treatment (P>0.05). The total protein in 65-80 years old group after treatment was (62.36±7.36) g/L, which decrease and have statistical significantly different from that before treatment (P 80 years old group after treatment was (64.49±7.12) g/L, it was higher than that before treatment, but the difference was not statistically significant (P>0.05). The level of albumin after endocrine therapy was (38.34±4.48) g/L, which was significantly different from that before treatment (P 80 years old group after treatment were (38.32±4.54) g/L and (38.44±4.30) g/L respectively, but only in the group of 65 to 80 years old, there were significant differences compared with those before treatment (P<0.05). Conclusion Endocrine therapy can not only significantly increase total cholesterol, triglyceride, low density lipoprotein cholesterol and high density lipoprotein cholesterol in elderly patients with prostate cancer, but also significantly reduce albumin after treatment. Key words: Prostate cancer; Endocrine therapy; Lipid metabolism; Nutritional status

Adjuvant androgenic blockade after teleradiotherapy for prostate cancer: long-term results of phase III rtog 85-31 study

Adjuvant androgenic blockade after teleradiotherapy for prostate cancer: long-term results of phase III rtog 85-31 study

A Case of Primary Central Nervous System Lymphoma that Developed during the Treatment of Castration-Resistant Prostate Cancer

A 64-year-old man was diagnosed with metastatic prostate cancer (cT3bN0M1b) and treated with combined androgen blockade. After two years and three months, he developed castration-resistant prostate cancer. Multiple lung metastases appeared after the administration of five courses of docetaxel and four courses of cabazitaxel therapy. Pulmonary metastases disappeared following rechallenge with docetaxel. Enzalutamide administration was initiated because docetaxel had to be discontinued due to adverse events. Although enzalutamide lowered the prostate specific antigen value, the patient staggered while walking and developed homonymous hemianopsia. Magnetic resonance imaging revealed a brain tumor. Although the brain tumor was considered to have metastasized from the prostate cancer, it was diagnosed as a primary central nervous system lymphoma using open-ended tumor biopsy. The brain tumor was eliminated with whole-brain irradiation. Thereafter, he has been treated with enzalutamide for 3 years without clinical progression of either disease.

United in Fight against prOstate cancer (UFO) registry: first results from a large, multi-centre, prospective, longitudinal cohort study of advanced prostate cancer in Asia.

ObjectivesTo document the management of advanced prostate cancer including diagnosis, prognosis, treatment, and care, in real‐world practice in Asia using the United in Fight against prOstate cancer (UFO) registry.Patients and MethodsWe established a multi‐national, longitudinal, observational registry of patients with prostate cancer presenting to participating tertiary care hospitals in eight Asian countries. A total of 3636 eligible patients with existing or newly diagnosed high‐risk localised prostate cancer (HRL), non‐metastatic biochemically recurrent prostate cancer (M0), or metastatic prostate cancer (M1), were consecutively enrolled and are being followed‐up for 5 years. Patient history, demographic and disease characteristics, treatment and treatment decisions, were collected at first prostate cancer diagnosis and at enrolment. Patient‐reported quality of life was prospectively assessed using the European Quality of Life‐five Dimensions, five Levels (EQ‐5D‐5L) and Functional Assessment of Cancer Therapy for Prostate Cancer questionnaires. In the present study, we report the first interim analysis of 2063 patients enrolled from study start (15 September 2015) until 18 May 2017.ResultsOf the 2063 enrolled patients, 357 (17%), 378 (19%), and 1328 (64%) had HRL, M0 or M1 prostate cancer, respectively. The mean age at first diagnosis was similar in each group, 56% of all patients had extracapsular extension of their tumour, 28% had regional lymph node metastasis, and 53% had distant metastases. At enrolment, 62% of patients had at least one co‐morbidity (mainly cardiovascular disease or diabetes), 91.8% of M1 patients had an Eastern Cooperative Oncology Group performance score of <2 and the mean EQ‐5D‐5L visual analogue score was 74.6–79.6 across cohorts. Treatment of M1 patients was primarily with combined androgen blockade (58%) or androgen‐deprivation therapy (either orchidectomy or luteinising hormone‐releasing hormone analogues) (32%). Decisions to start therapy were mainly driven by treatment guidelines and disease progression. Decision to discontinue therapy was most often due to disease progression (hormonal drug therapy) or completion of therapy (chemotherapy).ConclusionIn the UFO registry of advanced prostate cancer in Asia, regional differences exist in prostate cancer treatment patterns that will be explored more deeply during the follow‐up period; prospective follow‐up is ongoing. The UFO registry will provide valuable descriptive data on current disease characteristics and treatment landscape amongst patients with prostate cancer in Asia.

Clinical outcomes and prognostic factors in patients with newly diagnosed metastatic prostate cancer initially treated with androgen deprivation therapy: a retrospective multicenter study in Japan.

Clinical outcomes of patients with newly diagnosed metastatic hormone-naïve prostate cancer (mHNPC) and initially treated with androgen deprivation therapy (ADT) were evaluated. The medical records of 605 consecutive mHNPC patients with initial ADT or combined androgen blockade (CAB) at nine study centers between 2008 and 2016 were retrospectively reviewed. Castration-resistant prostate cancer (CRPC)-free and overall survival (OS) were estimated by the Kaplan-Meier method. The association of pretreatment risk factors with CRPC-free survival and OS was evaluated by Cox proportional hazard models and differences in survival were classified by the number of risk factors. Median follow-up was 2.95years, median CRPC-free survival was 21.9months and median OS was 5.37years. Multivariable analysis found that four risk factors, a Gleason score ≥ 9, lymph node metastasis, an extent of disease score ≥ 2, and serum LDH of > 220IU were independently associated with both CRPC-free survival and OS. Median CRPC-free survival of low-risk patients with no or one factor was 86.5months, 17.9months in intermediate-risk patients with two or three factors, and 11.0months in high-risk patients with four factors. Median OS was 4.72years in intermediate- and 2.44years in high-risk patients. It was not reached in low-risk patients. In this series, CRPC-free and OS of a subset of mHNPC patients in Japan who were treated with ADT or CAB had better CRPC-free and overall survivals in Japan. Risk-adapted treatment based on the presence of novel prognostic factors may be beneficial for selected mHNPC patients.

Different androgen deprivation therapies might have a differential impact on cognition - An analysis from a population-based study using time-dependent exposure model

BackgroundAndrogen deprivation therapy (ADT) remains the mainstay treatment for locally advanced or metastatic prostate cancer (PC). However, potential effects of ADT treatment on neurocognitive dysfunction remain unclear. The present study was conducted to assess the relation between ADT treatment and risk of cognitive decline in Asian men with PC. MethodsA population-based cohort of 24,464 men with PC, each newly diagnosed between 2000 and 2008, was selected from the Taiwan National Health Insurance Database. Subjects were further grouped by treatment as non-ADT (n = 4685) or ADT (n = 12,740), members of the latter subjected to bilateral orchiectomy or medical treatment (ie, luteinizing hormone-releasing hormone agonists, antiandrogens, or combination therapy). A multivariable Cox proportional hazard model with ADT as time-dependent covariate was used to generate adjusted hazard ratios (HRs) of subsequent cognitive decline, including dementia, Alzheimer's disease (AD), and Parkinson’s disease (PD). ResultsADT showed a significant association with overall risk of cognitive decline (HR = 1.51, 95 % CI: 1.31–1.74), especially for PD, dementia, and non-Alzheimer dementia (non-AZD). When stratified by various ADT regimens, antiandrogen-only recipients displayed significantly heightened risks of subsequent AD, non-AZD, and PD. However, combined androgen blockade also imposed an increased risk of PD. There was no apparent correlation between duration of ADT exposure and cognitive dysfunction. ConclusionsVarious ADT therapies may have disparate impacts on cognitive function. Prospective studies exploring pertinent clinical characteristics more fully are needed to confirm these findings.

Favorable response to combined androgen blockade for metastatic cutaneous apocrine carcinoma: a case report

Introduction: Most cases of cutaneous apocrine carcinoma (CAC) express androgen receptor. Androgen signal is thought to have a relationship on the survival and cell growth of the tumor. Presentation of Case: A 53-year-old man with a red superficial nodule on the left axilla and a back pain was diagnosed with CAC in the left axilla with multiple bone and bone marrow metastases. After cytotoxic chemotherapy for around 4 years, severe anemia, thrombocytopenia, and disseminated intravascular coagulation progressed. We started combined androgen blockade by bicaltamide and degarelix, and the therapy had successfully maintained stable disease for more than 6 months. Discussion: Most cases of CAC express androgen receptor. Androgen signal could have a relationship on the survival and cell growth of the tumor. Conclusion: Antiandrogen therapy for androgen-receptor positive CAC is a promising therapeutic option.

Role of androgen receptor expression in non-muscle-invasive bladder cancer: a systematic review and meta-analysis.

In order to evaluate the potential prognostic/predictive role of androgen receptor (AR) expression in non-muscle-invasive bladder cancer (NMIBC), and whether it may represent a therapeutic target, we conducted a systematic search of the literature using 'androgen receptor or AR', 'testosterone', 'bladder cancer' and 'non-muscle invasive bladder cancer or NMIBC' as keywords. Eleven studies met the inclusion/exclusion criteria. No significant association was found between AR status and patients' gender (p=0.232), tumor size (p=0.975), tumor stage (p=0.237), tumor grade (p=0.444), tumor multicentricity (p=0.397), concomitant CIS (p=0.316) and progression of disease (p=0.397). On the other hand, relative lack of AR expression was significantly correlated to recurrent disease (p=0.001). Evidence for a direct correlation between AR expression and recurrence-free survival of patients with NMIBC indicate ARs as potential markers of BC behavior; moreover, the finding of a role of androgen blockade therapy in improving survival highlights the potential clinical application of this pathway, which deserves to be further explored.

Abstract LB-A10: ORIC-101 overcomes glucocorticoid-driven resistance to enzalutamide in castration-resistant prostate cancer

Abstract Prostate cancer is the second leading cause of cancer-related death in men. Androgen deprivation is commonly used to treat hormone-sensitive prostate cancer, while second-generation antiandrogens, including enzalutamide and abiraterone, benefit patients with castration-resistant prostate cancer (CRPC). New therapeutic strategies are needed for patients who relapse with metastatic CRPC. The glucocorticoid receptor (GR) has been implicated as a major bypass mechanism to escape androgen blockade in patients with CRPC, indicating that GR-targeted therapies may provide an avenue to overcome therapeutic resistance in this clinical setting. We discovered a novel, selective, oral GR antagonist, ORIC-101, which fully reverses GR-driven resistance to enzalutamide in a dose-dependent manner in preclinical models. Specifically, we show that GR is widely expressed in prostate cancer cell lines, organoids, and tumor tissue, and that GR levels are upregulated upon enzalutamide treatment. We demonstrate in preclinical studies that physiological levels of glucocorticoids promote tumor cell growth, stimulate androgen-regulated gene expression, and drive resistance to enzalutamide. Importantly, these effects were completely reversed by ORIC-101, suggesting ORIC-101 overcomes GR-driven resistance to enzalutamide. To inform the clinical development of ORIC-101 in combination with enzalutamide, we identified FKBP5 and KLK3 as direct transcriptional targets of both androgen receptor and GR. We subsequently validated that secreted PSA, a product of the KLK3 gene, can be induced by glucocorticoids and this induction is fully inhibited by ORIC-101. These findings confirm that targeting GR may help overcome resistance to enzalutamide in CRPC, and that FKBP5 and KLK3 are rational PD biomarkers that may be used in clinical trials of ORIC-101, along with PSA. Citation Format: Haiying Zhou, Shravani Barkund, Aleksandr Pankov, Sharvani Sinha, Dena Sutimantanapi, Lori S. Friedman, Omar Kabbarah. ORIC-101 overcomes glucocorticoid-driven resistance to enzalutamide in castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A10. doi:10.1158/1535-7163.TARG-19-LB-A10