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Background: Metastatic castration-resistant prostate cancer (mCRPC) is a genetically heterogeneous disease with a poor prognosis. The prevalence of mutations in homologous recombination repair (HRR) pathway genes, including BRCA1/2, as well as treatment patterns and clinical outcomes, are not well characterized among Japanese men with mCRPC., Methods: This multicenter, noninterventional cohort study enrolled Japanese men with mCRPC from 24 institutions between 2014 and 2018. Mutations in the 15 HRR-related genes were assessed using archival primary or metastatic tumor samples. Patterns of sequential therapies for mCRPC were investigated. Patients were followed up for survival evaluation including prostate-specific antigen progression-free survival (PSA-PFS) and overall survival (OS)., Results: Of the 143 patients analyzed, HRR-related mutations were detected in 51 patients (35.7%). The most frequently mutated genes were CDK12 (N = 19, 13.3%), followed by BRCA2 (N = 18, 12.6%), ATM (N = 8, 5.6%), and CHEK2 (N = 3, 2.1%). The most common type of first-line therapy for mCRPC was next-generation hormonal agents (NHA, 44.4%), followed by first-generation antiandrogens (FGA, 30.3%), and taxanes (22.5%). Commonly prescribed first-/second-line sequential regimens included FGA/NHA (17.6%), NHA/NHA (15.5%), and NHA/taxanes (14.1%). The median PSA-PFS and OS for the entire cohort were 5.6 and 26.1 months, respectively. Patients carrying BRCA1/2 mutations had numerically shorter PSA-PFS (median 3.3 vs. 5.9 months) and OS (median 20.7 vs. 27.3 months) than those without mutations., Conclusions: In conclusion, approximately one-third of Japanese patients with mCRPC carried mutations in HRR-related genes in this study. The real-world outcomes of mCRPC are poor with conventional therapy, warranting an expansion of treatment options based on genetic abnormalities of the disease., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: The PROPHET (Prostate Cancer: Prostate Health Index Trial) is a prospective study to clarify the diagnostic impact of laboratory based and prostate volume adjusted p2PSA ([-2] proenzyme prostate specific antigen) related indexes on prostate cancer and clinically significant prostate cancer with prostate specific antigen less than 10 ng/ml., Materials and Methods: Between April 2015 and March 2017, 421 men 50 to 79 years old in the prostate specific antigen range above age specific cutoffs and below 10 ng/ml were registered in the PROPHET. We investigated the diagnostic impacts of various clinical laboratory based free prostate specific antigen related and p2PSA related indexes on any grade and high Gleason grade group prostate cancer., Results: Of the 363 eligible participants 179, 141 and 80 were diagnosed with any grade, and Gleason Grade Group 2-5 and 3-5 prostate cancer, respectively. The AUC-ROCs distinguishing nonprostate cancer vs prostate cancer, nonprostate cancer plus low Gleason Grade Group and low volume vs remaining prostate cancer with a higher Gleason Grade group or a higher volume on the PHI (Prostate Health Index) were significantly superior to the AUC-ROCs of prostate specific antigen and free-to-total prostate specific antigen. At 90% sensitivity in all investigated p2PSA related indexes the false-positive rate was superior to that of prostate specific antigen and free-to-total prostate specific antigen in any group comparison in terms of the Gleason Grade Group and positive biopsy cores. In 35% to 42% of men without prostate cancer and/or those with less aggressive prostate cancer the PHI would avoid unnecessary biopsy., Conclusions: Laboratory based p2PSA related indexes were significantly superior for detecting clinically significant prostate cancer compared to free-to-total prostate specific antigen. The indexes those would avoid up to 42% of prostate biopsies in men without aggressive cancer while maintaining 90% sensitivity.

Background: Female urethral carcinoma is a very rare disease that accounts for 0.02% of malignant diseases in female patients., Case Presentation: A 70-year-old Asian Japanese woman with a urethral tumor was referred to our hospital to undergo further examination. Biopsy specimens showed urethral adenocarcinoma that was positive for prostate-specific antigen. Her serum prostate-specific antigen level before surgery was 34.4 ng/ml. Urethral tumor resection with pelvic lymph node resection was performed. Her serum prostate-specific antigen level decreased to < 0.01 ng/ml after surgery., Conclusions: We report a very rare case of Skene duct adenocarcinoma in a female patient with serum prostate-specific antigen elevation.

Objective: More accurate diagnostic procedures for prostate cancer are needed to avoid unnecessary biopsy due to the low specificity of prostate-specific antigen (PSA). Recent studies showed that the percentage of serum isoform [-2]proPSA (p2PSA) to free PSA (%p2PSA), the Prostate Health Index (PHI) and magnetic resonance imaging (MRI) were more accurate than PSA. The aim of this study was to test the accuracy of %p2PSA, PHI and MRI in discriminating patients with and without prostate cancer., Materials and Methods: The subjects were 50 consecutive men with a PSA level of 2.0-10.0 ng/ml, who underwent prostate biopsy from October 2012 to July 2014. These patients underwent multiparametric MRI before biopsy, and their serum samples were measured for PSA, free PSA and p2PSA. The sensitivity, specificity and accuracy of PHI, %p2PSA and MRI were compared with PSA in the diagnosis of biopsy-confirmed prostate cancer., Results: In a univariate analysis, %p2PSA [area under the curve (AUC): 0.811] and PHI (AUC 0.795) were more accurate than MRI (AUC: 0.583) and PSA (AUC: 0.554) for prostate cancer detection. At 60% sensitivity, the specificity of PHI (76.5%) was higher than that of MRI (52.9%). For significant cancer detection, %p2PSA (AUC: 0.745), PHI (AUC: 0.791) and MRI (AUC: 0.739) were marginally more accurate than PSA (AUC: 0.696). At 85% sensitivity, the specificity of MRI (62.1%) was higher than that of PHI (34.5%)., Conclusion: PHI and %p2PSA can be used for screening the general population and MRI can be used for detection of significant cancer in patients suspected, from screening tests, of having prostate cancer.

Background: Prostate-specific antigen (PSA) flare is a well-known phenomenon in patients with prostate cancer treated with luteinizing hormone-releasing hormone agonist and chemotherapy. However, its incidence and the significance for the clinical outcomes of patients treated with abiraterone acetate (AA) are uncertain., Patients and Methods: A multicenter retrospective analysis of chemotherapy-naive patients treated with AA for metastatic castration-resistant prostate cancer (mCRPC) was conducted. The baseline characteristics, treatment history of mCRPC, and serum PSA kinetics during AA treatment were collected. The log-rank test was applied to compare progression-free survival (PFS) between patient groups with a PSA flare according to the different definitions and immediate PSA declines., Results: The data from 83 patients were analyzed. An immediate PSA decline of any amount was observed in 59 patients (71.1%). According to the various definitions of PSA flare, its incidence ranged from 6.0% to 10.8%. Although the median interval to the peak PSA level was 0.95 month, regardless of the PSA flare definition, the interval to the PSA nadir showed a wide range of 2.8 to 7.6 months. In PSA flare subgroup, the median PFS in patients with any PSA decline to less than the baseline and > 30% decline from the baseline was 12.4 months. The PFS duration of PSA flare patients did not significantly differ from that of patients with an immediate PSA decline of any amount and immediate > 30% decline without PSA flare., Conclusion: The PSA flare phenomenon is not rare event during AA treatment. A PSA decline during AA treatment, with or without a PSA flare, was associated with favorable clinical outcomes. Thus, AA should not be withdrawn early in patients with mCRPC in whom an initial, isolated PSA increase has been observed., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We determined whether prostate specific antigen (PSA) would decrease with immediate antiandrogen switching from bicalutamide (BCL) to flutamide (FLT) in patients receiving combined androgen blockade for advanced prostate cancer. From 2002 to 2006, 20 patients who showed PSA failure after first-line hormonal therapy with a luteinizing hormone-release hormone (LH-RH) agonist and BCL were enrolled. All patients were immediately switched from BCL to FLT, administered with an LH-RH agonist, as second-line combined androgen blockade (CAB). We evaluated the PSA response to second-line CAB. Eight patients (40%) were responsive, showing PSA decreases of at least 50%. The median (range) duration of the PSA response was 18.4 (3-26) months. Second-line CAB using FLT was effective in 40% of patients who received first-line CAB using BCL. The lower Gleason scores at the initial prostate biopsy probably reflect the response to second-line CAB. Responders showed significantly better OS and CSS in the determination of any PSA decline and 40% PSA decline. The median OS duration in nonresponders and responders (40% PSA decline) was 1433 days versus 3617 days. It is concluded that an immediate switch from BCL to FLT is effective for some CRPC patients after first-line CAB using BCL.

Introduction. The neutrophil-to-lymphocyte ratio (NLR), which can be easily calculated from routine complete blood counts of the peripheral blood, has been suggested to serve as a prognostic factor for some solid malignancies. In the present study, we aimed to determine the relationship between NLR in prostate cancer patients undergoing radical prostatectomy (RP) and their prognosis. Materials and Methods. We assessed NLR in 73 men (patients) who received RP for their prostate cancer. We also performed immunohistochemistry for CD8 and CD66b in a separate set of RP specimens. Results. The median NLR in the 73 patients was 1.85. There were no significant correlations of NLR with tumor grade (p = 0.834), pathological T stage (p = 0.082), lymph node metastasis (p = 0.062), or resection margin status (p = 0.772). Based on the area under the receiver operator characteristic curve (AUROC) to predict biochemical recurrence after RP, potential NLR cut-off point was determined to be 2.88 or 3.88. However, both of these cut-off points did not precisely predict the prognosis. There were no statistically significant differences in the number of CD66b-positive neutrophils or CD8-positive lymphocytes between stromal tissues adjacent to cancer glands and stromal tissues away from cancer glands and between different grades or stages of tumors. Conclusions. There was no association between NLR and biochemical failure after prostatectomy.

Background: There is currently no consensus on the correlations between androgen concentrations in prostate tissue and blood and stage and pathological grade of prostate cancer. In this study, we used a newly-developed ultra-sensitive liquid-chromatography tandem mass spectrometry method to measure testosterone (T) and dihydrotestosterone (DHT) concentrations in blood and needle biopsy prostate specimens from patients with prostate cancer., Methods: We analyzed androgen levels in 196 men diagnosed with prostate cancer. All patients had undergone systematic needle biopsy, and an additional needle biopsy from the peripheral zone was conducted for the simultaneous determination of T and DHT. We analyzed the relationships between T and DHT levels in tissue and blood and Gleason score, clinical stage, and percentage of positive biopsy cores, using multivariate analysis., Results: The median T and DHT levels in blood were 3551.0 pg/mL and 330.5 pg/mL, respectively. There was a strong correlation between serum T and DHT. The median T and DHT levels in prostate tissue were 0.5667 pg/mg and 7.0625 pg/mg, respectively. In multivariate analysis, serum prostate-specific antigen and tissue T levels were significantly associated with poor prognosis; high T levels in prostate tissue were significantly related to high Gleason score (p = 0.041), advanced clinical stage (p = 0.002), and a high percentage of positive biopsy cores (p = 0.001)., Conclusions: The results of this study indicate that high T levels in prostate tissue are related to high Gleason score, advanced clinical stage, and a high percentage of positive biopsy cores in patients with prostate cancer. T level in needle biopsy specimens may therefore be a useful prognostic factor in prostate cancer patients.

Purpose: In the present study, we compared 12- with 16-core biopsy in patients with prostate- specific antigen (PSA) levels of 4.0-20.0 ng/mL., Materials and Methods: Between 2003 and 2010, 332 patients whose serum PSA level was between 4.0 and 20.0 ng/mL underwent initial transrectal ultrasound (TRUS)-guided needle biopsy. Of those patients, 195 underwent 12-core biopsy and 137 underwent 16-core biopsy., Results: In the 12-core prostate biopsy group, 66 (33.8%) patients were found to have prostate cancer. On the other hand, in the 16-core prostate biopsy group of 137 patients, 61 (44.5%) were found to have prostate cancer. Among all patients, the prostate cancer detection rate was slightly higher in the 16-core biopsy group than in the 12-core biopsy group. Moreover, in patients with prostate volume > 30 mL or PSA density (PSAD) < 0.2, the prostate cancer detection rate was significantly higher in the 16-core biopsy group than in the 12-core biopsy group. There was no significant difference in pathological tumor grade, indolent cancer probability, or biopsy complication rate between the two groups., Conclusion: In order to detect prostate cancer, 16-core prostate biopsy is safe and feasible for Japanese patients with serum PSA level of 4.0-20.0 ng/mL.

Background: To ascertain the anti-tumor effect of zoledronic acid (ZOL) treatment on clinical outcomes in patients with bone metastatic prostate cancer, we examined the effect of ZOL started simultaneously with hormonal therapy as initial treatment in these patients., Methods: Forty-seven patients with bone-metastatic prostate cancer who received a luteinizing hormone releasing-hormone (LHRH) analogue and an anti-androgen [maximal androgen blockade (MAB)] were assigned to receive ZOL (4 mg intravenous administration every month for 2 years). The time to progression (TTP) of the prostate-specific antigen (PSA), the overall survival (OS), and the rate of PSA decrease in patients with MAB and ZOL treatment (ZOL group) were compared with these parameters in patients who received only MAB at one institute as a control group (non-ZOL group)., Results: Although the nadir PSA level and the rate of PSA normalization showed no significant differences between the ZOL and non-ZOL groups, the time to nadir PSA in the ZOL group was significantly shorter than that in the non-ZOL group (P < 0.05, Mann-Whitney U-test). There was a significant difference in TTP (P = 0.017, log-rank test) between the ZOL and non-ZOL groups, and statistically significant differences in TTP and OS between the ZOL and non-ZOL groups (P = 0.044 and 0.035, log-rank test) were recognized particularly in patients with advanced disease (extension of disease, grade 3 and 4)., Conclusions: Simultaneous administration of ZOL and MAB as initial treatment delayed TTP in bone-metastatic prostate cancer patients. Initial treatment with ZOL has the possibility of anti-tumor activity to delay disease progression.

Angiotensin II and AT1 receptor could be involved in the growth of androgen independent prostate cancer since we found the higher expression of AT1 receptor in prostate cancer tissue than in normal tissue. Angiotensin II directly and indirectly stimulates the growth of prostate cancer cells and stromal cells including angiogenic cells. ARBs experimentally inhibited the proliferation of cancer cells and angiogenesis. The administration of ARBs for castration resistant prostate cancer (CRPC) induced the decline of serum prostate specific antigen (PSA) and the improvement of performance status in cachexic CRPC patients. These results support the hypothesis that an intrinsic RAS exists in the prostate gland and it is likely that ARBs are useful molecular targeting agents for CRPC.

Purpose: The aim of this study is to evaluate the potential and limitation of FDG-PET/CT for detecting prostate cancer in subjects with an elevated serum prostate-specific antigen (PSA) level. Although [¹⁸F]-2-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) has limited value in detecting prostate cancer, the potential of PET/CT has not been precisely evaluated, since positron emission tomography/computed tomography (PET/CT) provides accurate localization of functional findings obtained by PET., Methods: Subjects with an increasing PSA level suggestive of prostate cancer were enrolled in this study. FDG-PET/CT was performed prior to prostate biopsy and the findings were compared with the pathological results., Results: Fifty subjects with an elevated serum PSA level took part in this study. The sensitivity, specificity and positive predictive value (PPV) of FDG-PET/CT in the prostate were 51.9% (27/52 areas), 75.7% (112/148 areas) and 42.9% (27/63 areas), respectively; those in the peripheral zone were 73.3% (22/30 areas), 64.3% (45/70 areas) and 46.8% (22/47 areas), respectively; and those in the central gland were 22.7% (5/22 areas), 85.9% (67/78 areas) and 31.3% (5/16 areas), respectively. The estimated cut-off values according to the highest odds ratio (OR) were age of 70 years [OR: 7.00, 95% confidence interval (CI): 1.89-25.93] and a PSA value of 12.0 ng/ml (OR: 10.77, 95% CI: 2.78-41.74). The FDG-PET/CT could potentially detect cancer with 80.0% sensitivity and 87.0% PPV in cases with a Gleason score of 7 or greater., Conclusion: FDG-PET/CT was appropriate for detecting peripheral zone prostate cancer in patients at more than an intermediate risk.

Background: In the present study, we compared 12- with 8-core biopsy in patients with prostate-specific antigen (PSA) levels of 4.0-20.0 ng/ml. We also examined whether the free/total (F/T) PSA ratio is useful for cancer detection in 12-core biopsy., Methods: A total of 419 men with PSA level between 4.0 and 20.0 ng/ml underwent transrectal ultrasound-guided transperineal needle biopsies of the prostate. Of these men, 235 underwent 8-core biopsy and 184 underwent 12-core biopsy. We compared the cancer detection rate between the 8- and 12-core biopsy groups by analyzing the PSA value, and especially the F/T PSA ratio., Results: The cancer detection rate in the 12-core group (35.9%) was significantly higher than in the 8-core group (23.8%). In cases of PSA level of 4.0-20.0 ng/ml with F/T PSA ratio less than 0.11, the cancer detection rate was 53.1% in the 12-core biopsy group. Performing 12-core biopsy resulted in a marked difference of cancer detection rate between men with F/T PSA ratio less than 0.11 and those with more than 0.12 in gray zone PSA (48.2% and 17.5%, respectively)., Conclusions: Twelve-core biopsy can achieve a higher detection rate of prostate cancer than 8-core biopsy using F/T PSA ratio., (Copyright 2009 S. Karger AG, Basel.)

Background: We previously reported that angiotensin II (AII) activated the proliferation of prostate cancer cells, and its antagonist, an AII receptor type 1 (AT1R) blocker (ARB), inhibited the proliferation of prostate cancer in vitro and in vivo. In the present study, we investigated whether telmisartan, an ARB, has a unique feature as a peroxisome proliferator-activated receptor gamma (PPARgamma) ligand, and its suppressive potential on prostate cancer cells., Methods: Cell count or MTT assay were carried out for growth suppression of prostate cancer cells. Phosphorylation of mitogen-activated protein kinase (MAPK), specific expression of prostate specific antigen (PSA) and AT1R were investigated by western blot. To confirm the PPARgamma activity of ARBs, luciferase assay using PSA promoter and PPARgamma response elements (PPRE) plasmids was performed., Results: The results showed that cell proliferation and signal transduction were inhibited by telmisartan treatment. Also, inhibition of PSA expression by telmisartan was confirmed by western blot and luciferase assay, indicating that an ARB acted in a similar way such as an anti-androgenic agent in prostate cancer cells., Conclusion: The present study showed ARBs, especially those possessing a PPARgamma ligand-like structure, have a potential antagonistic effect on androgen-dependent and -independent prostate cancer.

Antiandrogen withdrawal syndrome (AWS) is a well-established phenomenon in prostate cancer. However, responses to AWS are usually of limited duration, and a complete response (CR) is extremely rare. We present two patients who exhibited a chemical CR for more than 2 years after the discontinuation of steroidal antiandrogen chlormadinone acetate use. Whether patients who respond to antiandrogen withdrawal include a group of patients with a better prognosis remains uncertain. However, considering that the usual survival period of patients with hormone-resistant prostate cancer is approximately 12 months, both of the patients reported here, who are present in excellent physical condition, exhibiting an improved quality of life, and attending their hospital as outpatients, obviously acquired a prolonged survival because of AWS.

Decrease in serum prostate specific antigen (PSA) concentration is inevitably associated with antiandrogen therapy for benign prostatic hyperplasia (BPH), and might mask the presence of prostate cancer or delay its diagnosis. To determine the appropriate timepoint for determination of correct PSA value, we sequentially measured serum PSA and testosterone levels after discontinuation of antiandrogen therapy for BPH. With informed consent, 12 patients (72.8 +/- 12.2* years old) with BPH were treated with allylestrenol 50 mg/day for 4 months. Serum testosterone and PSA concentrations were determined before and just after treatment, as well as every month after treatment up to 3 months. After treatment with allylestrenol for 4 months, mean serum testosterone and PSA levels were significantly decreased from 408 +/- 136* to 87.9 +/- 76.2* ng/dl, and from 2.81 +/- 0.87* to 2.04 +/- 0.82* ng/ml, respectively. The mean serum PSA level recovered to the pretreatment level within 2 months and mean serum testosterone concentration within one month after discontinuation of administration. In conclusion, during treatment of BPH with antiandrogen allylestrenol, a two-month washout is adequate for determination of correct PSA value (*: M +/- SD).

Background: In order to assess whether the prostate-specific antigen (PSA) nadir obtained with an ultrasensitive PSA assay can be used as a prognostic indicator for patients undergoing radical prostatectomy, we investigated it retrospectively., Methods: Between October 1997 and July 2003, 46 patients underwent radical prostatectomy for prostate cancer at our institution. None of them received preoperative treatment. Levels of PSA were measured with an ultrasensitive PSA assay every 1-3 months after prostatectomy. Biochemical recurrence was defined as a PSA level of 0.2 ng/mL or higher., Results: There was a significant difference in PSA nadir between the biochemical recurrence group and the no recurrence group (P < 0.001). The receiver operating characteristics (ROC) curve gave an optimal cut-off value for PSA nadir of 0.01 ng/mL, demonstrating a significant difference in biochemical recurrence after radical prostatectomy. No patient with a PSA nadir level <0.01 ng/mL showed biochemical failure, while 15 out of 22 patients with PSA nadir levels >or=0.01 ng/mL showed biochemical failure., Conclusion: The PSA nadir level obtained using an ultrasensitive PSA assay is an excellent predictor of biochemical recurrence after radical prostatectomy. Early detection of recurrence offers the possibility of early salvage therapy.

Background: The aim of this study was to identify predictors that can increase the accuracy of detecting prostate cancer on subsequent biopsies., Methods: Between 1998 and 2003, a total of 235 men with prostate specific antigen (PSA) levels between 4.0 and 20 ng/mL underwent one or more systematic needle biopsies of the prostate. Of these men, 73 (31.1%) underwent one repeat biopsy and 26 (11.1%) underwent two or more repeat biopsies. We evaluated the results of prostate biopsies in relation to the morbidity of prostate cancer detected on repeat biopsies., Results: Of the 73 men who underwent repeat biopsy, 16 (21.9%) had prostate cancer. Twenty-six men with one negative re-biopsy underwent two or more repeat biopsies, and five of these patients were found to have early stage prostate cancer. On repeat biopsy, there was a significant difference in percent free PSA between the cancer-detected group and the no-cancer-detected group (P < 0.01). A receiver operating characteristics (ROC) curve gave an optimal cut-off value for percent free PSA of 11%, demonstrating a significant difference in the cancer detection rate on repeat biopsy (P = 0.0009). Analysis of the data for re-biopsies showed that cancer-detected cases showed a raised PSA value and a simultaneously reduced percent free PSA (these differences were statistically significant)., Conclusions: A low percent free PSA level increased the probability of a positive result in repeat biopsy. An increase in the accuracy of detecting cancer, especially on repeat biopsy, will promote the detection of more early stage prostate cancer.

Background: Prostate cancer is one of the most common cancers among men worldwide and the fourth most common cause of death. The number of prostate cancer cases and deaths is increasing every year because of population aging. This study aimed to clarify the risk of developing prostate cancer due to fluctuations in Prostate Specific Antigen (PSA) levels in patients without a history of prostate cancer using large medical information data. Results: This retrospective cohort included 1707 male patients aged 60 years or older who had a PSA level measurement date (2-PSA) within 3 months or more and 2 years from the first PSA level measurement date (1-PSA) in the database between 2008 and 2019. We subtracted 1-PSA from 2-PSA and designated patients with a higher 2-PSA than 1-PSA to the "up" group (n = 967) and patients with a lower 2-PSA than 1-PSA to the "down" group (n = 740). By using Cox proportional hazards model, a significant increase in prostate cancer risk was observed in the up group compared with the down group (adjusted hazard ratio [HR] = 1.82, 95% confidence interval [CI] = 1.21–2.72; adjusted for patient background factors). Subgroup analysis showed that patients with PSA levels < 4 ng/mL had a significantly increased risk of developing prostate cancer if the next PSA level increases by approximately 20% (adjusted HR = 2.94, 95% CI = 1.14–7.58), and patients with PSA levels of 4 ng/mL or higher if the next PSA level is decreased by approximately 20% had a significantly reduced risk of developing prostate cancer (adjusted HR = 0.36, 95% CI = 0.18–0.74), compared to that with no change. Conclusions: This is the first study to clarify the association between PSA variability and risk of developing prostate cancer in patients without a history of prostate cancer. These results suggest that the suppression of elevated PSA levels may lead to the prevention of prostate cancer and that it would be better to perform a biopsy because the risk of developing prostate cancer may increase in the future if the PSA value increases above a certain level. [ABSTRACT FROM AUTHOR]

Background: Despite the widespread availability of medication choices for metastatic castration-resistant prostate cancer (mCRPC), biomarkers to predict the efficacy of each mCRPC treatment have not yet been established. This study developed a prognostic nomogram and a calculator to predict the prognosis of patients with mCRPC who received abiraterone acetate (ABI) and/or enzalutamide (ENZ). Methods: In total, 568 patients with mCRPC who underwent ABI and/or ENZ between 2012 and 2017 were enrolled. A prognostic nomogram based on the risk factors was developed using the Cox proportional hazards regression model and clinically important factors. The discriminatory ability of the nomogram was assessed according to the concordance index (C-index). A 5-fold cross-validation was repeated 2000 times to estimate the C-index, and the means of the estimated C-index for the training and validation sets were determined. A calculator based on this nomogram was then developed. Results: The median overall survival (OS) was 24.7 months. Multivariate analysis showed that the time to CRPC, pre-chemotherapy, baseline prostate-specific antigen, baseline alkaline phosphatase, and baseline lactate dehydrogenase levels were independent risk factors for OS (hazard ratio [HR]: 0.521, 1.681, 1.439, 1.827, and 12.123, p = 0.001, 0.001, < 0.001, 0.019, and < 0.001, respectively). The C-index was 0.72 in the training cohort and 0.71 in the validation cohort. Conclusions: We developed a nomogram and calculator to predict OS in Japanese patients with mCRPC who received ABI and/or ENZ. Reproducible prognostic prediction calculators for mCRPC will facilitate greater accessibility for clinical use. [ABSTRACT FROM AUTHOR]

Background: There is no consensus on the role of serum dehydroepiandrosterone (DHEA) concentrations in the detection of prostate cancer. This study examined the effectiveness of serum DHEA in predicting candidate patients for active surveillance (AS) prior to prostate biopsy.Methods: A systematic prostate needle biopsy was performed in 203 men with serum PSA levels of < 10 ng/mL to detect prostate cancer. Serum DHEA concentrations were measured with liquid chromatography-tandem mass spectrometry (LC-MS/MS) just before biopsy. Patient's age, serum prostate-specific antigen (PSA) levels, prostate volume, and serum DHEA concentrations were compared with pathological findings in multivariate analyses.Results: The median patient's age, PSA, serum DHEA concentration and prostate volume were 68 years, 5.5 ng/mL, 1654.7 pg/mL, and 31.2 mL, respectively. In a multivariate analysis, low PSA values, high serum DHEA concentrations, and large prostate volume were significant predictors of the patients with benign prostatic hyperplasia (BPH) or prostate cancer with a Gleason score of ≤ 3 + 4 who are candidate for AS. The DHEA cut-off point for predicting BPH or prostate cancer with a Gleason score of ≤ 3 + 4 was 2188 pg/mL, with a sensitivity, specificity, positive predictive value, and negative predictive value of 33.7%, 96.0%, 98.4%, and 16.9%, respectively.Conclusion: The study indicated that higher serum DHEA concentrations prior to prostate biopsy might predict the patients with BPH or prostate cancer with a Gleason score ≤ 3 + 4 who are candidate for AS, in men with PSA of < 10 ng/mL. [ABSTRACT FROM AUTHOR]

Objective: The prognosis of high‐risk metastatic hormone‐naïve prostate cancer is poor, and real‐world evidence of therapeutic options and sequences is lacking. The J‐ROCK study aimed to evaluate the outcomes in a real‐world setting in Japan. Methods: Patients with high‐risk metastatic hormone‐naïve prostate cancer diagnosed after May 2019 were eligible. Based on their treatment within 3 months after diagnosis, patients were allocated to either cohort 1 (androgen deprivation therapy alone or combined androgen blockade with bicalutamide) or cohort 2 (androgen deprivation therapy with abiraterone acetate+prednisolone, docetaxel, enzalutamide, or apalutamide). Results: In this first interim analysis (cut‐off January 2021), 410 patients were enrolled, including 163 patients in cohort 1 and 247 in cohort 2. The median follow‐up period was 7.6 (range 0.1–20.5) months. A higher proportion of patients in cohort 2 (42.5%) achieved nadir prostate‐specific antigen levels ≤0.2 ng/ml within a year, compared with cohort 1 (22.1%). Prostate‐specific antigen‐progression‐free survival was also more favorable in cohort 2 (adjusted hazard ratio 0.629 [95% confidence interval 0.345–1.147]). Conclusions: The higher proportion of cohort 2 suggest a paradigm shift has occurred in the real‐world treatment of high‐risk metastatic hormone‐naïve prostate cancer in Japan. Some factors including prostate‐specific antigen may affect treatment selection but need further observation. Most patients in cohort 2 received abiraterone acetate+prednisolone. The proportion of patients in cohort 1 receiving combined androgen blockade was lower than previously reported in Japan. This analysis suggest that more intensive therapy tends to prolong prostate‐specific antigen‐progression‐free survival in patients with high‐risk metastatic hormone‐naïve prostate cancer. [ABSTRACT FROM AUTHOR]

Background: The purpose of the study is to evaluate real-world effectiveness and safety of enzalutamide in men with nonmetastatic castration-resistant prostate cancer (nmCRPC) in Japan. Methods: This was a retrospective evaluation of medical records from men in Japan who started enzalutamide treatment from November 1, 2014, to March 31, 2018, and received androgen deprivation therapy throughout. The primary endpoint was time to prostate-specific antigen (PSA) progression. Secondary endpoints included PSA response rate, time to first use of new antineoplastic therapy, time to first use of cytotoxic chemotherapy, and enzalutamide treatment duration. An exploratory analysis of metastasis-free survival (MFS) was also performed. Adverse events (AEs) were analyzed to assess safety. Results: Based on data from medical records of 205 men in Japan, median time to PSA progression was 27 months (95% confidence interval [CI] 19–not reached [NR]), with 82.5% and 52.0% of men achieving PSA response rates of ≥ 50% and ≥ 90%, respectively. Median time to first use of new antineoplastic therapy was 36 months (95% CI 27−NR) and median enzalutamide treatment duration was 13 months (interquartile range: 7–24). Median time to first use of cytotoxic chemotherapy was NR (95% CI 41−NR). Median MFS was 29 months (95% CI 23−35). In total, 51.7% of men experienced AEs, with malaise (18.5%), decreased appetite (10.7%), and nausea (4.9%) the most frequently reported. Conclusions: This is the first study to demonstrate the real-world effectiveness and safety of enzalutamide in men with nmCRPC in Japan, further informing healthcare providers about available treatment options for this patient population. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of enzalutamide plus androgen deprivation therapy in Japanese men with metastatic hormone‐sensitive prostate cancer. Methods: A post‐hoc analysis of the Japanese subgroup in the phase III, randomized, multinational ARCHES study (NCT02677896) was carried out. Patients with metastatic hormone‐sensitive prostate cancer were randomized to receive enzalutamide or a placebo, plus androgen deprivation therapy, stratified by disease volume and prior docetaxel therapy. The primary end‐point was radiographic progression‐free survival. Secondary end‐points included time to prostate‐specific antigen progression and overall survival. Results: Of 1150 patients, 92 Japanese patients were randomized to enzalutamide (n = 36) or a placebo (n = 56), plus androgen deprivation therapy; none received prior docetaxel. Enzalutamide plus androgen deprivation therapy reduced the risk of radiographic progression or death in Japanese patients by 61% versus the placebo, similar to the overall population. Similar results were observed with secondary end‐points, showing clinical benefit of enzalutamide plus androgen deprivation therapy in Japanese patients. Overall survival data were immature. Grade 3–4 adverse events were reported in 47% and 25% of the enzalutamide and placebo groups, respectively. Nasopharyngitis, hypertension and abnormal hepatic function were reported more frequently in Japanese patients versus the overall population. Conclusions: Enzalutamide plus androgen deprivation therapy has clinical benefit with a tolerable safety profile in Japanese men with metastatic hormone‐sensitive prostate cancer, consistent with the overall population. [ABSTRACT FROM AUTHOR]

Background: Apalutamide, a nonsteroidal potent androgen receptor antagonist, was safe and effective in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and metastatic-CRPC (mCRPC) in global studies. In this phase 1 study, safety, pharmacokinetics (PK), and efficacy of apalutamide were evaluated in Japanese patients with mCRPC. Methods: In this open-label, multi-center study, patients received apalutamide 240 mg (once-daily, orally) for first 1 week (PK week) during which PK parameters were assessed. 1 week later (Cycle 1 Day1), after reassessing safety, continuous daily dosing (4 weeks/cycle; once-daily orally) was initiated. Endpoints evaluated were: safety, tolerability, PK and antitumour efficacy of apalutamide. Dose-limiting toxicities (DLTs) were evaluated during PK week and Cycle 1. Results: All six patients received apalutamide. The most common treatment-emergent adverse events (TEAEs) were abdominal discomfort, nasopharyngitis, dysgeusia, rash, and hot flush [2/6 patients (33.3%) each]. No death or DLTs were reported. Grade 3 TEAEs were spinal-cord compression and renal disorder (1/6 patient each). In continuous daily dosing period, PK steady-state of apalutamide was reached approximately by week 4. A significant accumulation of apalutamide was observed (mean accumulation index 3.55), based on AUC0–24. Median (range) serum prostate-specific antigen level decreased from 54.42 (8.92–310.11) ng/mL at baseline to 11.70 (0.37–47.74) ng/mL at week 12 with ≥ 50% reduction in 4/6 (66.7%) patients and 90% reduction in 2/6 (33.3%) patients. Conclusion: Apalutamide had manageable safety profile, without any DLT or any new safety signals, and favourable efficacy in Japanese mCRPC patients. Thus, it was ascertained to be an adequate dosage regimen in Japanese mCRPC patients. Trial registration: ClinicalTrials.gov identifier: NCT02162836. [ABSTRACT FROM AUTHOR]

This open‐label, phase I dose‐finding study evaluated the gonadotropin‐releasing hormone antagonist, TAK‐385, in Japanese patients with nonmetastatic prostate cancer. In a two‐part design, patients received daily oral TAK‐385 at doses of 320 (loading, day 1)/80 (maintenance, day 2 and thereafter), 320/120, 320/160, or 360/120 mg for 28 days in a dose‐escalation phase (part A, n = 13), and at 320/80 or 320/120 mg for up to 96 weeks in a randomized expansion phase (part B, n = 30). Primary endpoint in both parts was safety, including dose‐limiting toxicity in part A. Secondary endpoints included pharmacokinetics, pharmacodynamics, and prostate‐specific antigen concentration. Ten (77%) patients in part A and all patients in part B experienced an adverse event; hot flush (part A, n = 4; part B, n = 15), viral upper respiratory tract infection (part A, n = 1; part B, n = 10), and diarrhea (part B, n = 8) were most frequent. No dose‐limiting toxicities were observed (part A). In 12 evaluable patients (part A), TAK‐385 was rapidly absorbed after a single loading dose; on day 28 (maintenance dose), median steady‐state Tmax was ~1‐2 hours and mean t1/2z was 67‐79 hours. All doses rapidly reduced testosterone concentrations to castration levels within 1 week. Durable reductions in prostate‐specific antigen of >90% from baseline were observed through 96 weeks. TAK‐385 appeared tolerable and resulted in sustained reductions in testosterone to castration levels at all doses. The lowest loading/maintenance dose required for a clinical effect was 320/80 mg. ClinicalTrials.gov: NCT02141659. [ABSTRACT FROM AUTHOR]

Background: Automated bone scan index (aBSI) change (ΔBSI) after treatment and survival in men with prostate cancer remains unclear. We evaluated the correlation between ΔBSI after cabazitaxel and overall survival (OS) in men with bone metastatic castration-resistant prostate cancer (CRPC). Methods: We retrospectively enrolled 32 men with bone metastatic CRPC who had received cabazitaxel. The correlation between ΔBSI from baseline to 16 weeks after starting cabazitaxel and OS was analyzed by multivariate analysis. Results: Median age and time to CRPC were 70.7 years and 9.5 months, respectively. The median cycles of docetaxel before cabazitaxel were eight. Ten (31.2%) patients had visceral metastases at baseline. Median baseline prostate-specific antigen (PSA) was 123.0 ng/mL. The median aBSIs at baseline and 16 weeks after cabazitaxel were 3.2 and 4.4%, respectively. Improvements in aBSI and PSA after 16 weeks of cabazitaxel occurred in 7 (21.9%) and 12 patients (37.5%), respectively. There were no correlations between ΔBSI and OS (p = 0.55), but PSA change was significantly correlated with OS (p = 0.03) by multivariate analysis. Conclusions: This study demonstrated that ΔBSI from baseline to16 weeks after starting cabazitaxel was not correlated with OS among men with bone metastatic CRPC. Further prospective studies may be warranted to confirm the limited utility of aBSI in this setting. [ABSTRACT FROM AUTHOR]

Introduction. Nearly 80% of advanced prostate cancer patients respond to initial androgen deprivation therapy (ADT). However, ADT does not prevent the progression of prostate cancer over the long term, and the disease eventually progresses to castration-resistant prostate cancer (CRPC). Prior to the development of enzalutamide (ENZ) and abiraterone acetate, docetaxel was the only established treatment with life-prolongation for CRPC. ENZ is a second-generation anti-androgen receptor drug that has contributed to improving the prognosis of CRPC. Several studies have reported factors predicting the efficacy of ENZ; however, there are no confirmed biomarkers. The neutrophil-to-lymphocyte ratio (NLR) is an easily calculated biomarker that is associated with the prognosis of several solid malignancies. However, there were few studies investigated NLR for ENZ in patients with mCRPC. We examined the usefulness of the NLR as a predictive tool for ENZ. Methods. We retrospectively examined a total of 106 CRPC patients who were treated with ENZ until September 2016 in Yokohama City University Hospital, Yokohama City University Medical Center, and National Cancer Center Hospital East. ENZ was routinely started as a dose of 160 mg per day; the dosage was reduced in some patients due to side effects. Drug holiday for 1-2 weeks or dose reduction to 80-120mg was done and no patients discontinued ENZ treatment due to adverse effects. ENZ was stopped when cancer progression was detected based on PSA elevation, radiographic findings, and deterioration of the patient's performance status. The cut-off NLRs for overall survival (OS) and cancer-specific survival (CSS) were determined based on the receiver-operator curves. Kaplan-Meier curves were used to analyze the factors associated with OS or CSS and a log-rank test was performed. A multivariate analysis was also performed to analyze the factors associated with the prognosis. Results. We retrospectively reviewed 106 consecutive CRPC patients who were both treated with ENZ and were able to be counted before ENZ NLR. Cut-off point was 2.14 for both OS and CSS by receiver operator characteristic curve. The patients were then divided into the higher NLR group (≥2.14) and lower NLR group (<2.14). Multivariate analysis showed that NLR and predocetaxel chemotherapy were independent risk factors for both overall and cancer-specific survival. Conclusions. The NLR might be a useful biomarker for predicting the prognosis of mCRPC patients who are treated with ENZ. [ABSTRACT FROM AUTHOR]

Background: Female urethral carcinoma is a very rare disease that accounts for 0.02% of malignant diseases in female patients.Case Presentation: A 70-year-old Asian Japanese woman with a urethral tumor was referred to our hospital to undergo further examination. Biopsy specimens showed urethral adenocarcinoma that was positive for prostate-specific antigen. Her serum prostate-specific antigen level before surgery was 34.4 ng/ml. Urethral tumor resection with pelvic lymph node resection was performed. Her serum prostate-specific antigen level decreased to < 0.01 ng/ml after surgery.Conclusions: We report a very rare case of Skene duct adenocarcinoma in a female patient with serum prostate-specific antigen elevation. [ABSTRACT FROM AUTHOR]

Background: In most cases, prostate cancer metastasizes to the lymph nodes, bone, and liver. In very rare cases, it metastasizes to the ureter. Due to the difficulty in making a preoperative diagnosis, ureteral metastasis from prostate cancer is typically diagnosed after nephroureterectomy.Case Presentation: A 77-year-old Asian Japanese man with right hydronephrosis and hydroureter was referred to our hospital to undergo further examination due to the suspicion of ureteral cancer. He had been diagnosed 2 years previously with prostate cancer with a Gleason score of 4+5=9. He received radiotherapy and androgen deprivation therapy. A nephroureterectomy was performed for suspected right ureteral cancer. On the basis of a histopathological examination, poorly differentiated adenocarcinoma was suspected, and the tumor cells were positive for prostate-specific antigen immunohistochemically.Conclusions: We herein report a rare case of ureteral metastasis in castration resistant prostate cancer. [ABSTRACT FROM AUTHOR]

Background. Although patients with prostate cancer with metastatic lesions initially respond to androgen ablation therapy, most patients ultimately develop a hormone-refractory state. Effective treatment for men with hormone-refractory prostate cancer (HRPC) has not been established. We performed a clinical study of docetaxel in HRPC patients, and evaluated its efficacy. Methods. Nine patients with HRPC were administered 55mg/m² docetaxel, every 3 weeks, simultaneously with hormonal therapy, with a luteinizing hormone-releasing hormone analog, and daily oral dexamethasone. Change in serum prostate-specific antigen (PSA) was determined as the primary endpoint. Results. The mean age of the patients was 64 years (range, 49 to 76 years). Median follow-up time was 8.5 months (range, 5.3 to 16.7 months). In eight patients whose pretreatment serum PSA was elevated, six patients (75.0%) had a PSA decline of more than 50%, and four (50.0%) had a PSA decline of more than 75%. Median time to progression for all patients was 7.9 months (range, 0.0 to 11.6 months; 95% confidence interval [CI], 0.0 to 26.3). The median overall survival was 8.5 months (range, 5.3 to 16.7 months; 95% CI, 8.1 to 13.8). Four of six patients (66.7%) with pain before treatment obtained pain relief and were able to discontinue analgesic agents. This regimen was well tolerated. Grade 3 or 4 neutropenia or leukocytopenia without fever was seen in three patients (33.3%). Only one patient required administration of granulocyte-colony stimulating factor because of neutropenia. No other grade 3 or 4 toxicity was observed. Conclusion. Docetaxel was an active agent in Japanese HRPC patients, and was well tolerated in this population. To establish its efficacy and safety in Japanese HRPC patients, a large-scale study in Japan is warranted. [ABSTRACT FROM AUTHOR]

Background: Metastatic spinal cord compression (MSCC) from prostate cancer (PC) influences not only patients' prognosis but also their quality of life. However, little is known about the clinical outcome of surgery for MSCC from PC. We evaluated both the oncological and functional outcomes of decompression and reconstruction surgery for patients with symptomatic MSCC from PC.Methods: We assessed 19 patients who underwent decompression and reconstruction surgery for symptomatic MSCC from PC. Of these 19 patients, 8 had metastatic hormone-naïve PC (mHNPC) and 11 had metastatic castration-resistant PC (mCRPC).Results: The median age of the patients with mHNPC and mCRPC was 72 and 65 years, respectively. The median prostate-specific antigen level at the time of diagnosis of MSCC in patients with mHNPC and mCRPC was 910 and 67 ng/mL, respectively. Although two of eight patients (25.0%) with mHNPC were ambulatory preoperatively, six patients (75.0%) were ambulatory postoperatively. Among 11 patients with mCRPC, only 3 (27.3%) were ambulatory preoperatively, while 6 (54.5%) were ambulatory postoperatively. The median postoperative overall survival among patients with mHNPC and mCRPC were not reached and 8 months, respectively.Conclusions: Decompression and reconstruction surgery for symptomatic MSCC from PC might contribute to a favorable functional outcome among men with mHNPC and mCRPC. However, its role in improving the oncological outcome remains unclear. The treatment strategy should be chosen by shared decision-making among patients, urologists, radiation oncologists, and orthopedic surgeons. [ABSTRACT FROM AUTHOR]

The phase 3 SPARTAN study evaluated apalutamide versus placebo in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) and prostate-specific antigen doubling time of ≤10 mo. At primary analysis, apalutamide improved median metastasis-free survival (MFS) by 2 yr and overall survival (OS) data were immature. We report the prespecified event-driven final analysis for OS. A total of 1207 patients with nmCRPC (diagnosed by conventional imaging) were randomised 2:1 to apalutamide (240 mg/d) or placebo, plus on-going androgen deprivation therapy. After MFS was met and the study was unblinded, 76 (19%) patients still receiving placebo crossed over to apalutamide. OS and time to cytotoxic chemotherapy (TTChemo) were analysed by group-sequential testing with O'Brien-Fleming-type alpha spending function. At median 52-mo follow-up, 428 deaths had occurred. The median treatment duration was 32.9 mo for apalutamide group and 11.5 mo for placebo group. Median OS was markedly longer with apalutamide versus placebo, reaching prespecified statistical significance (73.9 vs 59.9 mo, hazard ratio [HR]: 0.78 [95% confidence interval {CI}, 0.64–0.96]; p = 0.016). Apalutamide also lengthened TTChemo versus placebo (HR: 0.63 [95% CI, 0.49–0.81]; p = 0.0002). Discontinuation rates in apalutamide and placebo groups due to progressive disease were 43% and 74%, and due to adverse events 15% and 8.4%, respectively. Subsequent life-prolonging therapy was received by 371 (46%) patients in the apalutamide arm and by 338 (84%) patients in the placebo arm including 59 patients who received apalutamide after crossover. Safety was consistent with previous reports; when adverse events were adjusted for treatment exposure, rash had the greatest difference of incidence between the apalutamide and placebo groups. Extension of OS with apalutamide compared with placebo conferred impactful benefit in patients with nmCRPC. There was a 22% reduction in the hazard of death in the apalutamide group despite 19% crossover (placebo to apalutamide) and higher rates of subsequent therapy in the placebo group. With data presented herein, all primary and secondary study end points of SPARTAN were met; findings demonstrate the value of apalutamide as a treatment option for nonmetastatic castration-resistant prostate cancer. Apalutamide increased overall survival and delayed time to initiation of cytotoxic chemotherapy versus placebo in patients with nonmetastatic castration-resistant prostate cancer. Prior analyses had demonstrated clinically impactful improvement in metastasis-free survival, time to symptomatic progression, and second progression-free survival with apalutamide. [ABSTRACT FROM AUTHOR]

Background: Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic castration-resistant prostate cancer who were at high risk for the development of metastasis.Methods: We conducted a double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned, in a 2:1 ratio, to receive apalutamide (240 mg per day) or placebo. All the patients continued to receive androgen-deprivation therapy. The primary end point was metastasis-free survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death.Results: A total of 1207 men underwent randomization (806 to the apalutamide group and 401 to the placebo group). In the planned primary analysis, which was performed after 378 events had occurred, median metastasis-free survival was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (hazard ratio for metastasis or death, 0.28; 95% confidence interval [CI], 0.23 to 0.35; P<0.001). Time to symptomatic progression was significantly longer with apalutamide than with placebo (hazard ratio, 0.45; 95% CI, 0.32 to 0.63; P<0.001). The rate of adverse events leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7.0% in the placebo group. The following adverse events occurred at a higher rate with apalutamide than with placebo: rash (23.8% vs. 5.5%), hypothyroidism (8.1% vs. 2.0%), and fracture (11.7% vs. 6.5%).Conclusions: Among men with nonmetastatic castration-resistant prostate cancer, metastasis-free survival and time to symptomatic progression were significantly longer with apalutamide than with placebo. (Funded by Janssen Research and Development; SPARTAN ClinicalTrials.gov number, NCT01946204 .). [ABSTRACT FROM AUTHOR]