PSA doubling time 4.65 months as an optimal cut-off of Japanese nonmetastatic castration-resistant prostate cancer.

A multicenter study of nonmetastatic castration-resistant prostate cancer (nmCRPC) was conducted to identify the optimal cut-off value of prostate-specific antigen (PSA) doubling time (PSADT) that correlated with the prognosis in Japanese nmCRPC. Of the 515 patients diagnosed and treated for nmCRPC at 25 participating Japanese Urological Oncology Group centers, 450 patients with complete clinical information were included. The prognostic values of clinical factors were evaluated with respect to prostate specific antigen progression-free (PFS), cancer-specific survival (CSS), and overall survival (OS). The optimal cutoff value of PSADT was identified using survival tree analysis by Python. The Median PSA and PSADT at diagnosis of nmCRPC were 3.3 ng/ml, and 5.2 months, respectively. Patients treated with novel hormonal therapy (NHT) showed significantly longer PFS (HR: hazard ratio 0.38, p < 0.0001) and PFS2 (HR 0.45, p < 0.0001) than those treated with vintage nonsteroidal antiandrogen agent (Vintage). The survival tree identified 4.65 months as the most prognostic PSADT cutoff point. Among the clinical and pathological factors PSADT of < 4.65 months remained an independent prognostic factor for OS (HR 2.96, p = 0.0003) and CSS (HR 3.66, p < 0.0001). Current data represented optimal cut-off of PSADT 4.65 months for a Japanese nmCRPC.

Increased circulating polymorphonuclear myeloid-derived suppressor cells are associated with prognosis of metastatic castration-resistant prostate cancer.

Introduction: Myeloid-derived suppressor cell (MDSC) exhibits immunosuppressive functions and affects cancer progression, but its relationship with prostate cancer remains unclear. We elucidated the association of polymorphonuclear MDSC (PMN-MDSC) and monocytic MDSC (M-MDSC) levels of the total peripheral blood mononuclear cells (PBMCs) with prostate cancer progression and evaluated their roles as prognostic indicators. Methods: We enrolled 115 patients with non-metastatic hormone-sensitive prostate cancer (nmHSPC, n = 62), metastatic hormone-sensitive prostate cancer (mHSPC, n = 23), and metastatic castration-resistant prostate cancer (mCRPC, n = 30). Subsequently, the proportions of MDSCs in each disease progression were compared. Log-rank tests and multivariate Cox regression analyses were performed to ascertain the associations of overall survival. Results: The patients with mCRPC had significantly higher PMN-MDSC percentage than those with nmHSPC and mHSPC (P = 7.73 × 10-5 and 0.0014). Significantly elevated M-MDSC levels were observed in mCRPC patients aged <70 years (P = 0.016) and with a body mass index (BMI) <25 kg/m2 (P = 0.043). The high PMN-MDSC group had notably shorter median survival duration (159 days) than the low PMN-MDSC group (768 days, log-rank P = 0.018). In the multivariate analysis including age, BMI, and MDSC subset, PMN-MDSC was significantly associated with prognosis (hazard ratios, 3.48; 95% confidence interval: 1.05-11.56, P = 0.042). Discussion: PMN-MDSC levels are significantly associated with mCRPC prognosis. Additionally, we highlight the remarkable associations of age and BMI with M-MDSC levels in mCRPC, offering novel insights into MDSC dynamics in prostate cancer progression.

Plasma microRNA Signature as Companion Diagnostic for Abiraterone Acetate Treatment in Metastatic Castration-Resistant Prostate Cancer: A Pilot Study.

Abiraterone acetate (AA) serves as a medication for managing persistent testosterone production in patients with metastatic castration-resistant prostate cancer (mCRPC). However, its efficacy varies among individuals; thus, the identification of biomarkers to predict and follow treatment response is required. In this pilot study, we explored the potential of circulating microRNAs (c-miRNAs) to stratify patients based on their responsiveness to AA. We conducted an analysis of plasma samples obtained from a cohort of 33 mCRPC patients before and after three, six, and nine months of AA treatment. Using miRNA RT-qPCR panels for candidate discovery and TaqMan RT-qPCR for validation, we identified promising miRNA signatures. Our investigation indicated that a signature based on miR-103a-3p and miR-378a-5p effectively discriminates between non-responder and responder patients, while also following the drug's efficacy over time. Additionally, through in silico analysis, we identified target genes and transcription factors of the two miRNAs, including PTEN and HOXB13, which are known to play roles in AA resistance in mCRPC. In summary, our study highlights two c-miRNAs as potential companion diagnostics of AA in mCRPC patients, offering novel insights for informed decision-making in the treatment of mCRPC.

Increase of prostate-specific antigen doubling time predicts survival in metastatic castration-resistant prostate cancer patients undergoing radium therapy.

OBJECTIVE: Radium-223 (Ra-223) is an important treatment modality for bone-dominant metastatic castration-resistant prostate cancer (mCRPC). However, there is currently a lack of effective markers to monitor treatment response during treatment. We aim to investigate the response in prostate-specific antigen doubling time (PSADT) as a potential marker for assessing Ra-223 treatment in mCRPC patients. METHODS: We retrospectively collected data from mCRPC patients who underwent radium treatment at our institution between August 2020 and June 2023. Prostate-specific antigen (PSA) measurements prior to treatment and during treatment were collected. Baseline PSADT was calculated from PSA measurements prior to Ra-223 treatment; interim PSADT was calculated from PSA measurements before Ra-223 treatment and prior to the fourth course injection. Overall survival was calculated from the start of treatment to the date of death. Univariable and multivariable analysis using the Cox proportional hazards model were performed to examine the association of factors with overall survival. RESULTS: We included 35 patients from our institution, with a median overall survival of 13.3 months. Eighteen (51.4%) completed all six courses of treatment. PSA dynamic response (interim PSADT > baseline PSADT or decreased PSA) was observed in 20 patients. Overall survival was associated with a PSA dynamic response (HR = 0.318, 95% CI 0.133-0.762, p = 0.010) when compared to patients without response. CONCLUSIONS: Dynamic changes in PSADT were associated with survival in mCRPC patients receiving radium therapy. Comparing interim and baseline PSADT could serve as a valuable marker for determining treatment benefits.

Impact of Circulating Tumor Cell-Expressed Prostate-Specific Membrane Antigen and Prostate-Specific Antigen Transcripts in Different Stages of Prostate Cancer.

PURPOSE: Prostate-specific membrane antigen (PSMA)-based images, which visually quantify PSMA expression, are used to determine prostate cancer micrometastases. This study evaluated whether a circulating tumor cell (CTC)-based transcript platform, including PSMA mRNA, could help identify potential prognostic markers in prostate cancer. EXPERIMENTAL DESIGN: We prospectively enrolled 21 healthy individuals and 247 patients with prostate cancer [localized prostate cancer (LPCa), n = 94; metastatic hormone-sensitive prostate cancer (mHSPC), n = 44; and metastatic castration-resistant prostate cancer (mCRPC), n = 109]. The mRNA expression of six transcripts [PSMA, prostate-specific antigen (PSA), AR, AR-V7, EpCAM, and KRT 19] from CTCs was measured, and their relationship with biochemical recurrence (BCR) in LPCa and mCRPC progression-free survival (PFS) rate in mHSPC was assessed. PSA-PFS and radiological-PFS were also calculated to identify potential biomarkers for predicting androgen receptor signaling inhibitor (ARSI) and taxane-based chemotherapy resistance in mCRPC. RESULTS: CTC detection rates were 75.5%, 95.3%, and 98.0% for LPCa, mHSPC, and mCRPC, respectively. In LPCa, PSMA [hazard ratio (HR), 3.35; P = 0.028) and PSA mRNA (HR, 1.42; P = 0.047] expressions were associated with BCR. Patients with mHSPC with high PSMA (HR, 4.26; P = 0.020) and PSA mRNA (HR, 3.52; P = 0.042) expressions showed significantly worse mCRPC-PFS rates than those with low expression. Increased PSA and PSMA mRNA expressions were significantly associated with shorter PSA-PFS and radiological PFS in mCPRC, indicating an association with drug resistance. CONCLUSIONS: PSMA and PSA mRNA expressions are associated with BCR in LPCa. In advanced prostate cancer, PSMA and PSA mRNA can also predict rapid progression from mHSPC to mCRPC and ARSI or taxane-based chemotherapy resistance.

Genomic Correlates of Prostate-Specific Membrane Antigen Expression and Response to 177Lu-PSMA-617: A Retrospective Multicenter Cohort Study.

PURPOSE: While 177Lu-PSMA-617 (LuPSMA) is an effective therapy for many patients with metastatic castration-resistant prostate cancer (mCRPC), biomarkers associated with outcomes are not well defined. We hypothesized that prostate cancer mutational profile may associate with clinical activity of LuPSMA. We devised a study to evaluate associations between mCRPC mutational profile with LuPSMA clinical outcomes. METHODS: This was a multicenter retrospective analysis of patients with mCRPC with next-generation sequencing (NGS) who received LuPSMA. PSA50 response (ie, ≥50% decline in prostate-specific antigen [PSA]) rate, PSA progression free survival (PSA PFS), and overall survival (OS) were compared between genetically defined subgroups. RESULTS: One hundred twenty-six patients with NGS results who received at least one cycle of LuPSMA were identified. The median age was 73 (IQR, 68-78) years, 124 (98.4%) received ≥1 prior androgen receptor-signaling inhibitor, and 121 (96%) received ≥1 taxane-based chemotherapy regimen. Fifty-eight (46%) patients with a DNA damage repair gene mutation (DNA damage response group) and 59 (46.8%) with a mutation in TP53, RB1, or PTEN tumor suppressor genes (TSG group) were identified. After adjusting for relevant confounders, the presence of ≥1 TSG mutation was associated with shorter PSA PFS (hazard ratio [HR], 1.93 [95% CI, 1.05 to 3.54]; P = .034) and OS (HR, 2.65 [95% CI, 1.15 to 6.11]; P = .023). There was improved OS favoring the DNA damage response group (HR, 0.37 [95% CI, 0.14 to 0.97]; P = .044) on multivariable analysis. Univariate analysis of patients with ATM mutations had significantly higher rates of PSA50 response, PSA PFS, and OS. CONCLUSION: Outcomes on LuPSMA varied on the basis of mutational profile. Prospective studies to define the clinical activity of LuPSMA in predefined genomic subgroups are justified.

Clinical validation of circulating GDF15/MIC-1 as a marker of response to docetaxel and survival in men with metastatic castration-resistant prostate cancer.

BACKGROUND: Elevated circulating growth differentiation factor (GDF15/MIC-1), interleukin 4 (IL4), and IL6 levels were associated with resistance to docetaxel in an exploratory cohort of men with metastatic castration-resistant prostate cancer (mCRPC). This study aimed to establish level 2 evidence of cytokine biomarker utility in mCRPC. METHODS: IntVal: Plasma samples at baseline (BL) and Day 21 docetaxel (n = 120). ExtVal: Serum samples at BL and Day 42 of docetaxel (n = 430). IL4, IL6, and GDF15 levels were measured by ELISA. Monocytes and dendritic cells were treated with 10% plasma from men with high or low GDF15 or recombinant GDF15. RESULTS: IntVal: Higher GDF15 levels at BL and Day 21 were associated with shorter overall survival (OS) (BL; p = 0.03 and Day 21; p = 0.004). IL4 and IL6 were not associated with outcomes. ExtVal: Higher GDF15 levels at BL and Day 42 predicted shorter OS (BL; p < 0.0001 and Day 42; p < 0.0001). Plasma from men with high GDF15 caused an increase in CD86 expression on monocytes (p = 0.03), but was not replicated by recombinant GDF15. CONCLUSIONS: Elevated circulating GDF15 is associated with poor prognosis in men with mCRPC receiving docetaxel and may be a marker of changes in the innate immune system in response to docetaxel resistance. These findings provide a strong rationale to consider GDF15 as a biomarker to guide a therapeutic trial of drugs targeting the innate immune system in combination with docetaxel in mCRPC.

The treatment landscape of nonmetastatic castrate resistant prostate cancer: A contemporary perspective.

OBJECTIVES: The incidence of nonmetastatic castrate resistant prostate cancer (nmCRPC) is not well defined in contemporary practice. The aim of this study is to describe the incidence and patterns of treatment of nmCRPC over the last 6 years at a single high-volume Australian health institution. SUBJECTS AND METHODS: All men newly diagnosed with prostate cancer at Western Health, Melbourne from January 2016 to December 2021 were included in the study. Those diagnosed with nonmetastatic prostate cancer and treated with medical or surgical castration for biochemical failure post attempted curative therapy were retrospectively reviewed for signs of castration resistance using prostate specific antigen (PSA) and testosterone biochemical markers up until October 2022. RESULTS: From January 2016 to December 2021, 822 patients were diagnosed with prostate cancer, 590 had localized disease, 373 underwent definitive locoregional therapy, and 31 went on to have biochemical recurrence and were commenced on androgen deprivation therapy. Twenty-five patients had undetectable PSA levels and were classified as having nonmetastatic castrate sensitive prostate cancer (nmCSPC), whilst the remaining 6 patients experienced a rising PSA and were thus classified as nmCRPC. The incidence rate of nmCRPC was 228 cases per 100,000 person-years. The median age at the time of prostate biopsy was 74 years (interquartile range [IQR] 64-79) in the nmCRPC group and 62 years (IQR 57-69) in the nmCSPC group. The median prebiopsy PSA (ng/ml) in the nmCRPC and nmCSPC groups were 27.5 (IQR 19.9-50.4), and 16.5 (IQR 9.0-26.0), respectively. The median duration from prostate cancer diagnosis to onset of nmCRPC was 24 months (IQR 17-29) and the median PSA doubling time was 3.4 months (IQR 2.2-5.7). CONCLUSIONS: Thus, nmCRPC is an uncommon disease. Further population-based studies are required to better understand the incidence of nmCRPC.

Clinical Implementation of a Noninvasive, Multi-Analyte Droplet Digital PCR Test to Screen for Androgen Receptor Alterations.

Alterations of the androgen receptor (AR) are associated with resistance to AR-directed therapy in prostate cancer. Thus, it is crucial to develop robust detection methods for AR alterations as predictive biomarkers to enable applicability in clinical practice. We designed and validated five multiplex droplet digital PCR assays for reliable detection of 12 AR targets including AR amplification, AR splice variant 7, and 10 AR hotspot mutations, as well as AR and KLK3 gene expression from plasma-derived cell-free DNA and cell-free RNA. The assays demonstrated excellent analytical sensitivity and specificity ranging from 95% to 100% (95% CI, 75% to 100%). Intrarun and interrun variation analyses revealed a high level of repeatability and reproducibility. The developed assays were applied further in peripheral blood samples from 77 patients with advanced prostate cancer to assess their feasibility in a real-world scenario. Optimizing the reverse transcription of RNA increased the yield of plasma-derived cell-free RNA by 30-fold. Among 23 patients with castration-resistant prostate cancer, 6 patients (26.1%) had one or a combination of several AR alterations, whereas only 2 of 54 patients (3.7%) in the hormone-sensitive stage showed AR alterations. These findings were consistent with other studies and suggest that implementation of comprehensive AR status detection in clinical practice is feasible and can support the treatment decision-making process.

Determination of enzalutamide long-term safety and efficacy for castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy: a multicenter prospective DELC study.

BACKGROUND: Alternative anti-androgen therapy has been widely used as a first-line treatment for castration-resistant prostate cancer, and it may affect treatment outcome of subsequent agents targeting the androgen receptor axis. We conducted the prospective observational DELC (Determination of Enzalutamide Long-term safety and efficacy for Castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy) study to evaluate the efficacy of enzalutamide in patients with castration-resistant prostate cancer who underwent prior combined androgen blockade with bicalutamide and then alternative anti-androgen therapy with flutamide. METHODS: The DELC study enrolled 163 Japanese patients with castration-resistant prostate cancer who underwent alternative anti-androgen therapy with flutamide following failure of initial combined androgen blockade with bicalutamide in multiple institutions between January 2016 and March 2019. Primary endpoint was overall survival. Administration of enzalutamide was started at 160 mg orally once daily in all patients. RESULTS: The rate of decline of prostate-specific antigen by 50% or more was 72.2%, and median overall survival was 42.05 months. Multivariate analysis revealed that higher pretreatment serum levels of prostate-specific antigen (≥11.3 ng/mL; P = 0.004), neuron-specific enolase (P = 0.014) and interleukin-6 (≥2.15 pg/mL; P = 0.004) were independent risk factors for overall survival. Fatigue (30.0%), constipation (19.6%) and appetite loss (17.8%) were the most common clinically relevant adverse events. The enzalutamide dose was not reduced in any patient under the age of 70, but adherence was decreased in those over 70. CONCLUSIONS: In the DELC study, the safety of enzalutamide was comparable to that in previous reports. Serum levels of neuron-specific enolase and interleukin-6 were suggested as prognostic factors for castration-resistant prostate cancer with potential clinical utility.

Biomarcadores pronósticos en el uso del radio-223 en pacientes con cáncer de próstata metastásico resistente a la castración / Prognostic biomarkers in the use of radium-223 in patients with metastatic castration-resistant prostate cancer

Objetivos Establecer biomarcadores basales en pacientes con cáncer de próstata metastásico resistente a la castración (CPMRC) tratados con Ra-223 que predigan una mejor supervivencia global (SG), así como valorar la toxicidad hematológica y la respuesta. Materiales y métodos Estudio retrospectivo multicéntrico en 151 pacientes con CPMRC tratados con Ra-223 entre 2013 y 2020. Se valoró la SG de acuerdo a: los niveles basales de hemoglobina (Hb), el antígeno prostático específico (PSA), la fosfatasa alcalina (FA), la escala de dolor de la OMS, el Eastern Cooperative Oncology Group (ECOG), el número de lesiones en gammagrafía ósea (GO), el uso de agentes de protección ósea y las dosis recibidas. Se determinó el grado de toxicidad hematológica y la respuesta basada en los cambios de la FA y el dolor pre y postratamiento. Resultados Mediana de SG de 24meses (IC95%: 16,5-31). En el 70% que recibieron tratamiento completo (5-6dosis) la mediana de SG fue de 34,9meses, versus 5,8 en el tratamiento incompleto (1-4dosis). La SG fue mayor en los pacientes con menor PSA, FA, Hb>13g/dl, menor número de metástasis óseas y ECOG 0-1. 52/151pacientes (34%) fallecieron durante el seguimiento. Cerca del 70% de los pacientes presentaron disminución del dolor, y el 66%, reducción de la FA. La mitad de los pacientes presentaron eventos adversos hematológicos leves, y solo el 5%, severos. Conclusiones Los pacientes con CPMRC tratados con Ra-223 que presentan biomarcadores basales como Hb>13g/ml, ECOG 0-1, PSA<20ng/ml y menor número de lesiones en GO muestran mejor SG, con un adecuado perfil de seguridad (AU)

Objectives Establish basal biomarkers in patients with bone metastatic castration-resistant prostate cancer (mCRPC) treated with Ra-223 that predicted a better overall survival (OS), assess hematology toxicity and treatment response. Materials and methods Retrospective multicenter study in 151 patients with mCRPC between 2013 and 2020. OS was assessed according to basal hemoglobin (Hb), PSA, alkaline phosphatase (AP), WHO pain scale, Eastern Cooperative Oncology Group (ECOG), number of metastatic lesions on bone scan (BS), use of protective bone agents and received. Hematological toxicities were evaluated. Treatment response was based on changes in FA and pain. Results Median OS was 24months (95%CI: 16.5-31). OS in 70% of patients who received complete Ra-223 treatment (5-6 doses) was 34.9m vs. 5.8m in patients with incomplete treatment (1-4 doses). OS was longer in patients with lower PSA and AP, Hb>13g/dL, lesser bone metastasis on GO and ECOG 0-1. 52/151 patients (34%) died during follow-up. Nearly 70% of patients experienced decrease in pain and 66% reduction on AP. Half of patients had mild hematological adverse effects and only 5% had severe. Conclusions mCRPC patients treated with Ra-223 who had Hb>13g/mL, ECOG 0-1, low AP, PSA<20ng/ml and lesser bone metastasis on BS shown a better OS with adequate safety profile (AU)

Observation of Serological Index and Efficacy of Abiraterone Hydrochloride Tablets Combined with Endocrine Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer

Purpose: This study reviewed and analysed the serological indexes, clinical efficacy and common clinical indexes of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with combination of abiraterone hydrochloride tablets and endocrine therapy. Method: This study is a retrospective analysis. A total of 133 mCRPC patients who were admitted to our hospital from January 2019 to December 2021 were selected as the study subjects. The patients were categorised into the experimental group (n = 51) and control group (n = 82) according to their treatment method. The control group was treated with docetaxel combined with endocrine therapy, whilst the experimental group was treated with combination therapy with abiraterone hydrochloride tablets. Subsequently, the clinical data of the two groups, including serum insulin-like growth factor-1 (IGF-1), human glandular kallikrein 2 (hK2), prostate specific antigen (PSA), vascular endothelial growth factor (VEGF) and serum carcinoembryonic antigen (CEA), were analysed. Result: The overall response rate of the experimental group (84.3%) was higher than that of the control group (72.0%). The serum levels of CEA, total prostate specific antigen, free prostate specific antigen, testosterone and androgen receptor splice variant 7 in both groups were lower than those of before treatment, and the values obtained by the experimental group were lower than those of the control group (p < 0.05). After treatment, the levels of CD3+, CD4+ and CD4+/CD8+ in both groups were higher than those before treatment, and the levels of CD8+, IGF-1, hK2, PSA and VEGF in the two groups decreased after treatment (p < 0.05). Conclusions: The use of abiraterone hydrochloride tablet combined with endocrine therapy for patients with mCRPC is effective and can improve clinical symptoms and serum cytokine levels (AU)

Elevated serum CEA is associated with liver metastasis and distinctive circulating tumor DNA alterations in patients with castration-resistant prostate cancer.

BACKGROUND: Elevated serum carcinoembryonic antigen (CEA) is used to identify "treatment emergent" forms of castration-resistant prostate cancer (CRPC) such as aggressive variant prostate cancer (AVPC). However, its individual utility as a prognostic marker and the genetic alterations associated with its expression have not been extensively studied in CRPC. METHODS: This study retrospectively analyzed clinical outcomes and circulating tumor DNA profiles in 163 patients with CRPC and elevated or normal serum CEA. These same patients were then classified as AVPC or non-AVPC and compared to determine the uniqueness of CEA-associated gene alterations. RESULTS: Patients with elevated CEA demonstrated higher rates of liver metastasis (37.5% vs. 19.1%, p = 0.02) and decreased median overall survival from CRPC diagnosis (28.7 vs. 73.2 mo, p < 0.0001). In addition, patients with elevated CEA were more likely to harbor copy number amplifications (CNAs) in AR, PIK3CA, MYC, BRAF, CDK6, MET, CCNE1, KIT, RAF1, and KRAS. Based on variant allele frequency we also defined "clonal" single-nucleotide variants (SNVs) thought to be driving disease progression in each patient and found that CEA expression was negatively correlated with clonal AR SNVs and positively correlated with clonal TP53 SNVs. Of these genetic associations, only the increases in clonal TP53 SNVs and KRAS amplifications were recapitulated among patients with AVPC when compared to patients without AVPC. CONCLUSIONS: Together these findings suggest that CEA expression in CRPC is associated with aggressive clinical behavior and gene alterations distinct from those in AVPC.

Efficacy and safety of Androgen Deprivation Therapy (ADT) combined with modified docetaxel chemotherapy versus ADT combined with standard docetaxel chemotherapy in patients with metastatic castration-resistant prostate cancer: study protocol for a multicentre prospective randomized controlled trial.

BACKGROUND: Androgen deprivation therapy (ADT) combined with docetaxel chemotherapy is the standard treatment for metastatic castration-resistant prostate cancer (mCRPC) patients. However, mCRPC patients are mainly frail elderly men, constantly accompanied by comorbidities and showing poor tolerance to standard docetaxel chemotherapy. Some exploratory studies administering modified chemotherapy regimens have reported noninferior oncologic outcomes with fewer adverse events, yet most are retrospective or small studies, and prospective randomized controlled trials have rarely been conducted. Therefore, we designed this modified docetaxel chemotherapy regimen in patients with mCRPC, aiming to evaluate its efficacy and safety compared with the standard docetaxel chemotherapy regimen. METHODS: This is an open-label, multi-institutional, prospective, randomized non-inferiority trial. A total of 128 patients with mCRPC will be randomized to receive ADT combined with modified docetaxel chemotherapy (experimental group, n=64) or ADT combined with standard docetaxel chemotherapy (control group, n=64). Patients in the experimental group will receive a modified regimen with docetaxel 40 mg/m2 on the 1st day and 35 mg/m2 on the 8th day, repeated every 21 days. The primary endpoint is progression-free survival at 2 years. Secondary endpoints include overall survival, prostate-specific antigen response rate, pain response rate, toxicity and quality of life. DISCUSSION: The expected benefit for the patient in the experimental arm is noninferior efficacy with decreased toxicity and improved quality of life compared with that in the control arm. To the best of our knowledge, this will be the first multicentre prospective randomized study to assess the efficacy and safety of modified docetaxel chemotherapy in patients with mCRPC in China. The results of this trial may provide benefit to mCRPC patients, especially those with poor performance. TRIAL REGISTRATION: chictr.org.cn Identifier: ChiCTR2100046636 (May 24, 2021). Ongoing study.

Ra-223 and Ethinylestradiol Combination Therapy in Castration-resistant Prostate Cancer.

BACKGROUND/AIM: Ra-223 is a therapeutic agent for bone metastatic castration-resistant prostate cancer (mCRPC). We examined the efficacy of a treatment method using Ra-223 together with ethinylestradiol (EE). PATIENTS AND METHODS: Patients who received Ra-223 three or more times were included and two groups (with or without EE) were compared retrospectively. RESULTS: Eighteen patients were treated with Ra-223 and EE concomitantly (EstRadium therapy) and 13 patients were treated with Ra-223 alone or Ra-223 and agents other than EE (non-EstRadium therapy). The number of patients with decreased serum prostate-specific antigen level was significantly higher in the EstRadium therapy group than in the non-EstRadium therapy group (p=0.029). CONCLUSION: The combination of Ra-223 and EE, compared to Ra-223 alone, is an effective treatment option for bone mCRPC patients, in terms of PSA response.

[IMPACT OF GENERAL FATIGUE ON TREATMENT PERIOD AFTER INDUCTION OF ENZALUTAMIDE FOR CASTRATION-RESISTANT PROSTATE CANCER].

(Objectives) Enzalutamide is an effective therapeutic options for castration resistant prostate cancer (CRPC). General fatigue is a major adverse event after commencing of enzalutamide in CRPC patients; however, its precise impact remains uncertain, especially on the duration of enzalutamide therapy. This study evaluated the relationship of general fatigue with patient age and enzalutamide treatment duration using real-world clinical data. (Patients and methods) This investigation retrospectively included patients who received enzalutamide therapy for CRPC between 2014 and 2018 at Shinshu University School of Medicine or Nagano Municipal Hospital. We classified the patients into the general fatigue group and the non-general fatigue group, and analyzed the groups in with regard to age and the duration of enzalutamide treatment. (Results) Of the 98 patients with CRPC were enrolled, 40 (40.8%) complained of general fatigue after enzalutamide induction. The median age of the study group was 78.0 years (71.0 years in the general fatigue group and 75.0 years in the non-general fatigue group), with no significant difference between the groups. Mean treatment duration was also comparable at 265.9 days in the general fatigue group and 266.5 days in the non-general fatigue group. (Conclusions) General fatigue after commencing enzalutamide was not impacted by age and did not remarkably influence the duration of therapy for CRPC.

Plasma tumor DNA is associated with increased risk of venous thromboembolism in metastatic castration-resistant cancer patients.

Cancer is a risk factor for venous thromboembolism (VTE). Plasma tumor DNA (ptDNA) is an independent predictor of outcome in metastatic castration-resistant prostate cancer (mCRPC). We aimed to investigate the association between ptDNA and VTE in mCRPC. This prospective biomarker study included 180 mCRPC patients treated with abiraterone and enzalutamide from April 2013 to December 2018. We excluded patients with a previous VTE history and/or ongoing anticoagulation therapy. Targeted next-generation sequencing was performed to determine ptDNA fraction from pretreatment plasma samples. VTE risk based on survival analysis was performed using cumulative incidence function and estimating sub-distributional hazard ratio (SHR). At a median follow-up of 58 months (range 0.5-111.0), we observed 21 patients who experienced VTE with a cumulative incidence at 12 months of 17.1% (95% confidence interval [CI] 10.3-23.9). Elevated ptDNA, visceral metastasis, prior chemotherapy and lactate dehydrogenase (LDH) were significantly associated with higher VTE incidence compared to patients with no thrombosis (12-month estimate, 18.6% vs 3.5%, P = .0003; 44.4% vs 14.8%, P = .015; 24.7% vs 4.5%, P = .006; and 30.0% vs 13.5%, P = .05, respectively). In the multivariate analysis including ptDNA level, visceral metastases, number of lesions and serum LDH, high ptDNA fraction was the only independent factor associated with the risk of thrombosis (HR 5.78, 95% CI 1.63-20.44, P = .006). These results first suggest that baseline ptDNA fraction in mCRPC patients treated with abiraterone or enzalutamide may be associated with increased VTE risk. These patients may be followed-up more closely for the VTE risk, and the need for a primary thromboprophylaxis should be taken into account in mCRPC with elevated ptDNA.

A European, prospective, observational study of enzalutamide in patients with metastatic castration-resistant prostate cancer: PREMISE.

In randomized clinical trials, the androgen-receptor inhibitor enzalutamide has demonstrated efficacy and safety in metastatic castration-resistant prostate cancer (mCRPC). This study captured efficacy, safety and patient-reported outcomes (PROs) of enzalutamide in mCRPC patients in a real-world European setting. PREMISE (NCT0249574) was a European, long-term, prospective, observational study in mCRPC patients prescribed enzalutamide as part of standard clinical practice. Patients were categorized based on prior docetaxel and/or abiraterone use. The primary endpoint was time to treatment failure (TTF), defined as time from enzalutamide initiation to permanent treatment discontinuation for any reason. Secondary endpoints included prostate-specific antigen (PSA) response, time to PSA progression, time to disease progression and safety. PROs included EuroQol 5-Dimension, 5-Level questionnaire, Functional Assessment of Cancer Therapy-Prostate and Brief Pain Inventory-Short Form. Overall, 1732 men were enrolled. Median TTF with enzalutamide was 12.9 months in the chemotherapy- and abiraterone-naïve cohort (Cohort 1) and 8.4 months in the postchemotherapy and abiraterone-naïve cohort (Cohort 2). Clinical outcomes based on secondary endpoints also varied between cohorts. Cohorts 1 and 2 showed small improvements in health-related quality of life and pain status. The proportions of patients reporting treatment-emergent adverse events (TEAEs) were 51.0% and 62.2% in Cohorts 1 and 2, respectively; enzalutamide-related TEAEs were similar in both cohorts. The most frequent TEAE across cohorts was fatigue. These data from unselected mCRPC patients in European, real-world, clinical-practice settings confirmed the benefits of enzalutamide previously shown in clinical trial outcomes, with safety results consistent with enzalutamide's known safety profile.