Current Clinical Aspects of Androgen Deprivation Therapy for Locally Advanced and Metastatic Prostate Cancer: A Scoping Review for Urologists and Medical Providers.

Prostate cancer (PCa) currently stands as the most common malignancy and the second most common cause of death in men worldwide. Dr. C. Huggins revolutionized the field of PCa treatment through his work investigating the therapeutic effects of androgen deprivation. These early surgical castration methods were expanded upon by integrating reversible pharmacologic castration via biologic agonists. Following this, intermittent ADT (iADT) became a medical substitute for its continuous counterpart. This data synthesis aims to highlight and assess the pertinent adverse effects of ADT, to compare mortality for PCa treatment plans, and consequently provide direction for clinicians in choosing the suitable systemic ADT approach. We performed a thorough systematic search across the PubMed database to identify prospective randomized clinical trials (RCTs) comparing continuous and intermittent androgen deprivation therapy (cADT and iADT). Our qualitative analysis aimed to evaluate the potential of iADT as an alternative treatment approach, emphasizing recent clinical outcomes. The analysis of randomized control trials in the literature revealed no discernable statistical difference in PCa-specific mortality in comparison of iADT and cADT treatments. Further, in the analysis of mortality due to non-PCa causes, iADT patients fared more favorably compared to cADT. Due to iADT's characteristics of being more cost-efficient and less likely to cause undesirable side effects, urologic healthcare professionals should be made aware of these findings when counseling patients on the optimal form of ADT and consulting for future treatment guidelines.

The m6A regulators in prostate cancer: molecular basis and clinical perspective.

Prostate cancer (PCa) is the second leading cause of cancer-related death among men in western countries. Evidence has indicated the significant role of the androgen receptor (AR) as the main driving factor in controlling the development of PCa, making androgen receptor inhibition (ARI) therapy a pivotal management approach. In addition, AR independent signaling pathways also contribute to PCa progression. One such signaling pathway that has garnered our attention is N6-Methyladenosine (m6A) signaling, which refers to a chemical modification on RNA with crucial roles in RNA metabolism and disease progression, including PCa. It is important to comprehensively summarize the role of each individual m6A regulator in PCa development and understand its interaction with AR signaling. This review aims to provide a thorough summary of the involvement of m6A regulators in PCa development, shedding light on their upstream and downstream signaling pathways. This summary sets the stage for a comprehensive review that would benefit the scientific community and clinical practice by enhancing our understanding of the biology of m6A regulators in the context of PCa.

Influences on androgen deprivation therapy prescribing before surgery in high-risk prostate cancer.

Objectives: To understand how best to further reduce the inappropriate use of pre-surgical androgen deprivation therapy (ADT), we investigated the determinants (influences) of ADT prescribing in urologists in two European countries using an established behavioural science approach. Additionally, we sought to understand how resource limitations caused by COVID-19 influenced this practice. Identification of key determinants, of undistributed and disrupted practice, will aid development of future strategies to reduce inappropriate ADT prescribing in current and future resource-limited settings. Participants and Methods: We conducted semi-structured qualitative interviews with urologists practicing in Italy and the UK from February to July 2022. Interviews focussed on undisrupted (usual) practice and disrupted practice (changes made during COVID-19 restrictions). Codes were generated inductively and were mapped to the 14 domains of the Theoretical Domains Framework. Relevant domains of influence were identified, and the similarities and differences between the UK and Italy were distinguished. Results: We identified 10 domains that were influential to ADT prescribing in the UK and eight in Italy. The role of guidance and evidence, the cancer care setting, the patients and the urologist's beliefs and experiences were identified as areas that were influential to ADT prescribing before surgery. Twenty-one similarities and 22 differences between the UK and Italy, for usual and COVID-19 practice, were identified across these 10 domains. Conclusion: Similarities and differences influencing ADT prescribing prior to surgery should be considered in behavioural strategy development and tailoring to reduce inappropriate ADT use. We gained an understanding of usual, undistributed care and resource-limited or disrupted care due to COVID-19 in two European countries. This gives an indication of how influences on ADT prescribing may change in future resource-limited circumstances and where efforts can be focused now and in future.

The Rapidly Evolving Treatment Landscape of Metastatic Hormone-Sensitive Prostate Cancer.

The management of metastatic hormone-sensitive prostate cancer (mHSPC) or castration-sensitive prostate cancer (mCSPC) has become increasingly complex with the tremendous progress that has been made in this space within the past few decades. In the early days of androgen deprivation therapy (ADT), ADT monotherapy was the mainstay for treatment of advanced prostate cancer. However, novel hormone therapies in the form of androgen receptor pathway inhibitors (ARPI) have emerged; vaccine therapy, chemotherapy with docetaxel and cabazitaxel, and radioactive ligands have shaped the treatment of metastatic prostate cancer in the last decade. Following the initial approval of several drugs for use in metastatic castration-resistant prostate cancer (mCRPC) in combination with primary ADT, these agents were studied and subsequently approved for use in mCSPC. Therefore, ADT monotherapy no longer constitutes an optimal therapeutic option for otherwise fit patients who present with mCSPC. We focus on the treatment of first-line de novo mHSPC or mCSPC and explore frontline doublet and triplet therapy and the pivotal trials that led to their United States Food and Drug Administration approval.

The risk of fragility fractures in men with prostate cancer treated with androgen deprivation therapy.

Androgen Deprivation Therapy (ADT) increases long-term fracture risk in prostate cancer. Our study showed a higher fracture risk within six months of ADT use, and current use was associated with a higher risk of fragility fractures. Attention is needed for the prevention of fragility fractures at the start of ADT. PURPOSE: Androgen Deprivation Therapy (ADT) is known to increase long-term fracture risk in men with prostate cancer (PCa), although the risk of fragility fractures remains unclear. This study aims to evaluate the risk of fragility and malignancy-related fractures in men with PCa treated with ADT. METHODS: We conducted a retrospective cohort study of men with PCa. Follow-up time was divided into 30-day intervals and exposure (current, past, or no-ADT use). Current ADT use was stratified by duration of ADT use (≤ 182 days, 183-730 days, and > 730 days). Cause-specific Cox proportional hazard models were used to estimate the risk of fractures. RESULTS: We included 471 patients (mean age 70.5 (± 8.3) years). The mean follow-up time was 5.0 (± 1.7) years in patients who never started ADT, 3.4 (± 2.3) years and 4.1 (± 2.0) years in patients who started ADT at baseline and during follow-up, respectively. In total, 60 patients had a fracture, 48 (80%) fragility, and 12 (20%) malignancy-related fractures. Current ADT use was associated with a higher risk of all fractures (HR 5.10, 95% CI 2.34-11.13) and fragility fractures (HR 3.61, 95% CI 1.57-8.30). The association with malignancy-related fractures could not be studied due to no events during no-ADT use. There was an increased risk of all fractures with longer duration of ADT use. CONCLUSIONS: Current ADT use was associated with a higher risk of fragility fractures than no-ADT use. A higher fracture risk was observed within the first six months of ADT use and persisted for longer durations.

Androgen Deprivation Therapy and the Risk of Newly Developed Dry Eye Syndrome in Patients with Prostate Cancer: A Nationwide Nested Case-Control Study in the Republic of Korea.

Background: We aimed to evaluate the association between androgen deprivation therapy (ADT) and newly developed dry eye syndrome (DES) in patients with prostate cancer. Methods: A nested case-control study was conducted. From the nationwide claims database of the Republic of Korea, 125,005 patients were included in the final analysis. Cases were defined as those newly diagnosed with DES during follow-up, and 12,654 patients were identified. The cases were matched with controls in a ratio of 1:4. Odds ratios (ORs) for newly developed DES associated with ADT were estimated using conditional logistic regression. Results: After matching, 7499 cases and 29,996 controls were selected. ADT was associated with a reduced risk of newly developed DES in patients with prostate cancer compared to no ADT (OR = 0.875; 95% confidence interval, 0.825-0.927; p < 0.0001). An accumulated dose of ADT < 1 year was associated with a reduced risk of incidental DES (OR = 0.811; 95% CI, 0.751-0.875; p < 0.0001), and a duration of 1-2 years was also associated with a reduced risk (OR = 0.890; 95% CI, 0.802-0.986; p = 0.026). No association was observed with an ADT duration of ≥2 years. Conclusions: The use of ADT, especially for shorter durations (<2 years), was associated with a reduced risk of newly developed DES in S. Korean patients with prostate cancer.

Temporal declines in bone mineral density and trabecular bone score during androgen deprivation therapy.

INTRODUCTION: The trabecular bone score (TBS) has emerged as a convenient measure for assessing the microstructure of trabecular bone in the second through fourth lumbar vertebrae (L2-4) and can be conducted concurrently with bone mineral density (BMD) assessment. This study was performed to evaluate changes in BMD and the TBS during ADT for prostate cancer. MATERIALS AND METHODS: Consecutive patients who had prostate cancer without bone metastases at Kobe University Hospital were studied from March 2020 to December 2021. BMD and TBS were measured every 6 months from the start of treatment using Hologic Horizon devices (Hologic, Inc., Marlborough, MA, USA). RESULTS: Thirty-four patients were followed for 2 years. Significant declines in BMD (-3.8% for femoral neck, -4.2% for total hip, and -6.1% for lumbar spine) and TBS (-16.6%) were noted after 2 years of ADT. Correlation analyses revealed a weak correlation between lumbar spine BMD and TBS at ADT initiation, but this correlation strengthened after 2 years. The multiple regression analysis results suggested that the rate of BMD loss may be slower in patients with a preserved pretreatment TBS. CONCLUSION: In patients without bone metastases undergoing ADT for prostate cancer, notable decreases were found in both BMD and TBS over a 2-year treatment period. Factors influencing the TBS decline remain unclear; however, patients with a lower pretreatment TBS exhibited a more rapid decline in BMD.

Dose modification in enzalutamide and abiraterone plus prednisolone for castration-resistant prostate cancer: A subanalysis from the ENABLE study for PCa.

BACKGROUND: A head-to-head comparison between enzalutamide (ENZ) and abiraterone plus prednisolone (ABI) revealed similar survival benefits for castration-resistant prostate cancer (CRPC) in the ENABLE study for PCa. Considering that a dose reduction of ENZ and ABI has demonstrated sufficient inhibitory ability of androgen receptor (AR) signaling, we analyzed the efficacy of modified doses of these agents in the ENABLE study for PCa. METHODS: This investigator-initiated, multicenter, randomized controlled trial that was conducted in Japan analyzed the prespecified survival endpoints, prostate-specific antigen (PSA) response rate ( ≥50% decline from baseline), and safety profile in patients treated with modified doses (ENZ ≤ 120 mg/day, ABI ≤ 750 mg/day) compared with those treated with a standard dose (ENZ 160 mg/day, ABI 1000 mg/day) as a starting dose. RESULTS: In total, 92 patients in each arm were treated and analyzed; 16 patients were treated with a modified dose in both the ENZ and ABI arms, respectively. Moreover, 32 patients treated with modified doses showed a significantly better time to PSA progression (TTPP) and overall survival (OS) compared with the 152 patients treated with a standard dose (HR 0.47, 95%CI 0.27-0.83, p = 0.0379, and HR 0.35, 95%CI 0.19-0.63, p = 0.0162). Despite a significantly longer TTPP in the modified ABI group than in the standard ABI group (HR 0.29, 95%CI 0.14-0.62, p = 0.0248), no significant difference was observed in the TTPP between the modified and standard ENZ groups (p = 0.5366). Furthermore, similar adverse event rates and grades were observed in each treatment dose group. CONCLUSIONS: The modified doses of ABI showed better TTPP than the standard dose of ABI and may be a potential treatment option for CRPC patients; however, its mechanism is still unclear, although its ability to suppress AR signaling is equivalent to that of a standard dose.

Testosterone Recovery Following Androgen Suppression and Prostate Radiotherapy (TRANSPORT): A Pooled Analysis of Five Randomized Trials from the Meta-Analysis of Randomized Trials in Cancer of the Prostate (MARCAP) Consortium.

BACKGROUND AND OBJECTIVE: Time to testosterone recovery (TR) following androgen deprivation therapy (ADT) with gonadotropin-releasing hormone agonists varies widely. We evaluate TR kinetics and the oncological impact of an effective castration period in patients receiving definitive radiotherapy and ADT for prostate cancer. METHODS: We obtained individual patient data from randomized controlled trials of radiotherapy with ADT and prospectively collected serial testosterone data from the MARCAP Consortium. We estimated the times to noncastrate TR (>1.7 nmol/l) and nonhypogonadal TR (>8.0 nmol/l) were estimated for each prescribed ADT duration, and developed corresponding nomograms. The association between effective castration period and metastasis-free survival (MFS) for any given ADT duration was evaluated via multivariable Cox regression. We conducted cubic spline analyses to assess nonlinear associations. KEY FINDINGS AND LIMITATIONS: We included 1444 men from five trials in the analysis, of whom 115 received 4 mo, 880 received 6 mo, 353 received 18 mo, 36 received 28 mo, and 60 received 36 mo of ADT. Times to noncastrate TR and to nonhypogonadal TR varied considerably by ADT duration. Higher baseline testosterone and lower age were associated with a higher likelihood of TR (p < 0.001 for both). Effective castration period was not linearly associated with MFS for any ADT duration on Cox regression. Cubic spline analysis revealed that the optimal effective castration period for an MFS benefit was 10.6 mo for men who received 6 mo of ADT and 18 mo for men who received 18 mo of ADT. CONCLUSIONS AND CLINICAL IMPLICATIONS: Time to TR varies according to the ADT duration, baseline testosterone, and age. The relationship between effective castration period and MFS may be nonlinear, with a longer effective castration period being helpful for men receiving 6 mo of ADT.

Comparative Cardiovascular Safety of Gonadotropin-releasing Hormone Antagonists and Agonists Among Patients Diagnosed with Prostate Cancer: A Systematic Review and Meta-analysis of Real-world Evidence Studies.

BACKGROUND AND OBJECTIVE: Gonadotropin-releasing hormone (GnRH) antagonists and agonists are cornerstone treatments in prostate cancer. However, evidence regarding the comparative cardiovascular safety of these drugs from clinical trials is inconclusive. The objective of this study was to systematically assess the risk of adverse cardiovascular events of GnRH antagonists compared with GnRH agonists across real-world evidence studies. METHODS: We conducted a systematic search of PubMed, Embase, Cochrane Library, Scopus, and Web of Science (2008-2023). We included real-world evidence studies comparing the risk of cardiovascular outcomes of GnRH antagonists with those of GnRH agonists among patients with prostate cancer. We conducted a meta-analysis of effect estimates across studies at a low or moderate risk of bias, assessed via the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool, using random-effect models. KEY FINDINGS AND LIMITATIONS: Among ten included studies, four were classified as having a moderate and six as having a serious risk of bias. Across three studies at a moderate risk of bias in the primary analysis, degarelix was associated with an increased risk (pooled relative risk [RR]: 1.31, 95% confidence interval [CI]: 1.14-1.51) of major adverse cardiovascular events (MACEs). An augmented risk was observed in two studies among patients with a history of cardiovascular disease (pooled RR: 1.31, 95% CI: 1.11-1.56) compared with one study among patients without a history of cardiovascular disease (RR: 1.15, 95% CI: 0.83-1.59). CONCLUSIONS AND CLINICAL IMPLICATIONS: Real-world evidence studies indicate that degarelix, compared with GnRH agonists, is associated with a modest increased risk of MACEs, particularly among patients with a history of cardiovascular disease. However, residual confounding due to the treatment of high-risk patients with degarelix may account for these findings. Additional large studies with detailed data on tumor characteristics and cardiovascular risk factors are needed to confirm these findings. PATIENT SUMMARY: In this systematic evaluation of evidence among patients diagnosed with prostate cancer in routine care, degarelix was associated with higher cardiovascular adverse outcomes than gonadotropin-releasing hormone agonists.