Androgen Suppression Therapy Research Articles

Efficacy of leuprorelin in spinal and bulbar muscular atrophy: a 3-year observational study.

This study aimed to investigate the long-term effects and functional outcomes of androgen suppression therapy using leuprorelin among Korean patients with spinal and bulbar muscular atrophy (SBMA). This observational study enrolled patients with genetically confirmed SBMA who provided informed consent. Leuprorelin was administered via subcutaneous injection every 12weeks. The primary outcome measure was the change in total Spinal and Bulbar Muscular Atrophy Functional Rating Scale (SBMAFRS) scores. A total of 48 SBMA patients were evaluated in this study. Among them, 39 patients underwent androgen suppression therapy over a 3-year period. The total SBMAFRS score decreased from 41.72 ± 5.55 to 36.74 ± 7.74 (p < 0.001) in patients who completed their treatment. The subgroup with a baseline SBMAFRS score of ≥ 42 had a significantly lower decline in SBMAFRS score than did those with a baseline SBMAFRS score of ≤ 41. We determined that at a baseline, SBMAFRS cutoff value of 41.5 could predict good prognosis, with a corresponding area under the curve of 0.689. Despite androgen suppression therapy, all enrolled participants exhibited a decrease in the overall SBMAFRS score. However, those with a baseline SBMAFRS of ≥ 42 showed a mild decrease in scores, indicating a more favorable prognosis. These findings suggest that a higher baseline motor function was a key prognostic indicator in SBMA treatment and that initiating early leuprorelin treatment in patients with high baseline function may lead to good clinical outcomes.

Selection of prostate cancer therapy strategy under early androgen suppression treatment

Intermittent androgen suppression therapy is increasingly employed as an alternative method of advanced prostate cancer. However, it remains controversial whether intermittent therapy is superior to continuous therapy in controlling cancer progression. In this paper, we study the mathematical model for early treatment of prostate cancer that incorporates the individual differences and the pharmacodynamics of drugs. The mathematical criteria for selection of better treatment are established on the basis of stability of periodic solution induced by treatment. Numerical results further explore the optimal design of intermittent treatment. The results provide valuable insights for clinical practice.

Quality of life comparison based on testosterone recovery after androgen deprivation therapy in patients cured from high-risk prostate cancer: Long term data from a phase III trial.

333 Background: Using data from a randomized Phase III trial and based on testosterone recovery after androgen suppression therapy (ADT), we compared quality of life (QOL) between patients (pts) considered cured of high-risk prostate cancer (HRPC). Methods: 630 pts with HRPC were randomised to pelvic and prostate radiotherapy plus either 36 or 18 months (m) of ADT (10-2000 / 01-2008). Serum testosterone (T) was measured at baseline then at each visit. Abnormal T was defined as below the normal level. We considered cured pts those with a PSA nadir &lt; 2 ng/ml, QOL was assessed by the validated EORTC30 (30 items). Patient-reported outcomes were filled out before treatments, every 6 m during ADT, 4 m after ADT and then once a year for 5 years. The 30 items were regrouped into 9 scales. All items and scales scores were linearly transformed to a 0-100 points scale. We analysed all items and scales scores with general linear model and repeated measures to evaluate changes between pts who did versus those who did not recover normal levels of T over time. Effect of T recovery was adjusted in multivariable model including age, initial normal/abnormal T and ADT duration (18 or 36 m). P-value &lt; 0.01 was considered statistically significant to account for multiple comparisons and a difference in mean scores of ≥ 10 points was considered clinically relevant. Results: We selected those pts considered cured to avoid subsequent T variations due to reintroduction of ADT for recurrence. We excluded 361 pts: not receiving exactly 18 or 36 m of ADT (63), survival &lt; 1 year (15), no T measured at baseline or during follow-up (55), biochemical failure (105) or evidence of metastatic/recurrent disease (92), no QOL questionnaire (31). 269 pts were retained for the analysis. With a median follow-up of 14 years, 140/269 (52%) pts recovered T to a normal level: 94/166 (56.6%) in 18 m and 46/103 (44.7%) in 36 m ADT, p=0.056. Among pts regaining a normal T, the median time to recovery was 3 years (IQR: 2.5 to 3.6) for 18 m vs. 5 years (IQR: 4.5 to 6.0) for 36 m, p&lt;0.001. The global adherence to QOL questionnaires was 83.9% (2649/3156) and it was higher for 36m than for 18 m [86.4% (1255/1452) vs. 81.8% (1394/1704) p&lt;0.001]. When comparing EORTC30 between pts who recovered with those who did not recover T, pts with T recovery had a better QOL: 15/30 items and 6/9 scales were statistically significant principally scale and items related to physical, role, emotional, fatigue, pain, dyspnoea, insomnia, diarrhoea, and financial difficulties. 2 items were also clinically relevant, trouble to take a long walk and feeling tense. Conclusions: In pts cured from HRPC, T recovery is associated with a betterQOL. 18 m of ADT should be the preferred duration since a significantly faster and a higher proportion of pts recover a normal T level with the shorter schedule without detriment in long term outcomes, as previously reported.

Risk of prostate cancer death after radical radiotherapy with neoadjuvant and adjuvant therapy with bicalutamide or gonadotropin-releasing hormone agonists

Background Oncological outcome after radical radiotherapy (RRT) combined with neoadjuvant and adjuvant androgen suppression therapy (AST) may differ according to type of AST. The aim of this nationwide register-based study was to investigate risk of prostate cancer (Pca) death after different neoadjuvant and adjuvant ASTs; (i) bicalutamide, (ii) gonadotropin-releasing hormone agonists (GnRH) or (iii) combined bicalutamide and GnRH (CAB), together with RRT. Materials and Methods Data for 6882 men diagnosed with high-risk Pca between 2007 and 2020 and treated with primary RRT was retrieved from Prostate Cancer data Base Sweden (PCBaSe) 5.0. Time to Pca death according to type of neoadjuvant and adjuvant AST was assessed by use of Kaplan–Meier plots and Cox proportional hazard models adjusted for putative confounders. Results Data were stratified by RRT type since the effect of AST in risk of Pca death differed according to type of RRT. Compared with the reference RRT combined with neoadjuvant CAB/adjuvant GnRH, risk of Pca death for men treated with CAB/bicalutamide and conventionally fractionated external beam radiotherapy (CF-EBRT) was hazard ratio (HR) 0.73 (95% CI: 0.50–1.04), hypofractionated EBRT (HF-EBRT), HR 1.35 (95% CI: 0.65–2.81) and EBRT with high dose rate brachytherapy (EBRT-HDRBT), HR 0.85 (95% CI: 0.37–1.95). Risk of Pca death for men treated with bicalutamide/bicalutamide and: (i) CF-EBRT was HR 2.35 (95% CI: 1.42–3.90), (ii) HF-EBRT, HR 0.70 (95% CI: 0.26–1.85), (iii) HF-EBRT, HR 4.07 (95% CI: 1.88–8.77) vs the reference. Conclusion In this observational study, risk of Pca death between men receiving different combinations of AST varied according to RRT type. No difference was found in risk of Pca death for men treated with bicalutamide or GnRH as adjuvant therapy to RRT following neoadjuvant CAB. Risk of Pca death was increased for men with monotherapy neo-/adjuvant bicalutamide in combination with CF-EBRT or EBRT-HDRBT.

Long-Term Outcomes Following Fairly Brief Androgen Suppression and Stereotactic Radiation Therapy in High-Risk Prostate Cancer: Update From the FASTR/FASTR-2 Trials

There is limited data on the long-term outcomes of ultrahypofractionated radiation therapy in high-risk prostate cancer. The FASTR and FASTR-2 trials were designed to assess the tolerability of stereotactic ablative radiation therapy (SABR) in this context. Herein, the long-term results are reported. Eligible patients had localized high-risk prostate cancer and were either ≥70 years old, had a score of ≥3 on the Vulnerable Elderly Scale, or declined standard therapy. Nineteen patients from a single institution were enrolled on FASTR between 2011 and 2015. They received 40 Gy to the prostate and 25 Gy to the pelvic lymph nodes in 5 weekly fractions, with 12 months of androgen deprivation therapy (ADT). Thirty patients from the same institution were enrolled on FASTR-2 between 2015 and 2017. They received 35 Gy to the prostate alone in 5 weekly fractions, with 18 months of ADT. Updated toxicity and outcomes were assessed retrospectively. Kaplan-Meier estimates were calculated for biochemical failure-free survival, freedom from distant metastases, prostate cancer-specific survival, and overall survival. Forty-four patients were eligible for analysis, 16 from FASTR and 28 from FASTR-2. Thirty-four patients (77%) were >70 years old. High-risk features included Gleason score ≥8 (n=20, 46%), T3-T4 disease (n=12, 27%), and baseline prostate-specific antigen > 20 (n=22, 50%). Median follow-up was 6.4 years. The 5-year cumulative incidence of late grade ≥3 genitourinary/gastrointestinal toxicity was 32% in FASTR and 11% in FASTR-2. At 5 years, the combined rates of biochemical failure-free survival, freedom from distant metastases, prostate cancer-specific survival, and overall survival were 72%, 90%, 92%, and 83%, respectively. SABR can be safely delivered in high-risk prostate cancer by optimizing technical delivery, particularly with adherence to strict dose constraints for organs at risk. The clinical outcomes in FASTR and FASTR-2 were largely comparable to more standard fractionation schemes plus ADT, but further modifications may improve disease control. Larger randomized trials are necessary to better understand the efficacy and tolerability of this approach.

Long-Term Outcomes Following Fairly Brief Androgen Suppression and Stereotactic Radiation Therapy in High-Risk Prostate Cancer: Update from the FASTR/FASTR-2 Trials.

There has been emerging interest in the role of ultra-hypofractionated radiotherapy for high-risk prostate cancer, especially given its low α/β ratio. However, there is limited data on the long-term outcomes of this treatment strategy. The FASTR and FASTR-2 clinical trials were designed to assess the tolerability of stereotactic ablative body radiotherapy (SABR) in high-risk prostate cancer. FASTR was discontinued early due to unacceptable acute toxicity, whereas the acute toxicities in FASTR-2 were minimal. Herein, the long-term results from these trials are reported. Eligible patients had at least 1 high-risk feature as per the National Comprehensive Cancer Network criteria for high-risk prostate cancer, no evidence of metastatic disease, and either a score of 3+ on the Vulnerable Elderly Scale or declined standard therapy. A total of 19 patients from a single institution were enrolled on FASTR between 2011 and 2015. They received 40 Gy to the prostate and 25 Gy to the pelvic lymph nodes in 5 fractions delivered once weekly for 5 weeks, along with 1 year of androgen deprivation therapy (ADT). The excessive acute toxicity in FASTR prompted several modifications in FASTR-2, including the omission of nodal irradiation. A total of 30 patients from the same institution were enrolled on FASTR-2 between 2015 and 2017. They received 35 Gy to the prostate alone in 5 fractions delivered once weekly for 5 weeks, along with 18 months of ADT. A total of 44 patients were eligible for analysis, 16 from FASTR and 28 from FASTR-2. Most patients were >70 years old (77%). High-risk features included Gleason score ≥8 (46%), T3-T4 disease (27%) and baseline PSA >20 (50%). With a median follow-up of 6.4 years, the cumulative incidence of grade ≥3 genitourinary/gastrointestinal toxicity was 50% among FASTR patients and 7% among FASTR-2 patients. At 5 years, the combined rates of biochemical failure-free survival, freedom from distant metastases, prostate cancer-specific survival and overall survival were 72%, 90%, 92% and 83%, respectively. A total of 12 patients (27%) required further treatment. No significant differences in clinical outcomes were noted between the FASTR and FASTR-2 cohorts. SABR for high-risk prostate cancer is an attractive option for reducing treatment burden. Clinical outcomes and toxicity with the FASTR-2 protocol were comparable to conventionally-fractionated radiotherapy plus ADT. Larger prospective, randomized trials exploring the role of SABR with ADT in high-risk disease are necessary to better understand the efficacy and tolerability of this approach.

The Participation of Trans Women in Competitive Fencing and Implications on Fairness: A Physiological Perspective Narrative Review.

Debate has surrounded whether the participation of trans women in female sporting categories is fair, specifically the retained male physiological advantage due to increased testosterone compared to cisgender females. Recently, individual sporting organisations have been investigating and assessing policies regarding trans women athlete participation in female categories, resulting in several banning participation. This review aims to discuss the scientific evidence and provide appropriate guidance for the inclusion of trans women in elite competitive female fencing categories. Fencing is an intermittent sport, where competitions can span 1 to 3 days. The lunge is the most common movement used to attack opponents, where a successful hit relies on the speed of the action. Male puberty induced increased circulating testosterone promotes a greater stature, cardiovascular function, muscle mass, and strength compared to cisgender females, culminating in a ~12-40% sport performance advantage. Elite cisgender male fencers perform significantly higher, ~17-30%, jump heights and leg power measures compared to elite cisgender female fencers, resulting in faster lunges. Trans women receiving androgen-suppression therapy for 12 months showed significant reductions in strength, lean body mass, and muscle surface area, but even after 36 months, the measurements of these three indices remained above those for cisgender females. Previous male muscle mass and strength can be retained through continuation of resistance training. The literature reviewed shows that there is a retained physiological advantage for trans women who have undergone male puberty when participating in the elite competitive female fencing category. A proposed solution of an open or third gender category for elite fencing competition promotes fair competition, while allowing trans women to compete in their chosen sport.

Saw Palmetto may fight prostate cancer.

Saw Palmetto may fight prostate cancer.

Management of cancer treatment-induced bone loss (CTIBL) in patients with breast cancer or prostate cancer.

Breast cancer and prostate cancer are sex hormone-dependent cancers, and estrogen or androgen suppression therapy is the standard treatment. Cancer treatment-induced bone loss (CTIBL): bone loss and osteoporosis have become important side effects of these therapies. To summarize the current evidences, (1) Endocrine therapy for breast cancer and prostate cancer is associated with a significant decrease in bone mineral density. (2) Aromatase inhibitors (AI) for breast cancer are associated with a significant increase in fractures, and androgen deprivation therapy (ADT) for prostate cancer is likely to be associated with an increase in fractures. (3) Administration of bisphosphonates and denosumab increases bone mass in patients undergoing endocrine therapy for breast cancer. Administration of bisphosphonates, denosumab, and SERMs increased bone mass in patients undergoing ADT therapy for prostate cancer. (4) Bisphosphonates and denosumab reduce fracture risk in patients on AI for breast cancer, and toremifene and denosumab in patients on ADT for prostate cancer.

Impact of Finasteride on Survival in Bladder Cancer: A Retrospective Multi-institutional Database Analysis.

Androgen suppression therapy has been associated with a lower incidence of bladder cancer (BCa) or improved overall/cancer-specific survival. Results are ofent conflicting; therefore, we aim to assess the impact of use of finasteride on overall survival (OS) for BCa using multi-institutional database. The South Texas Veterans Healthcare System from 5 medical centers was queried for patients with BCa with or without use of finasteride after diagnosis of BCa. The primary outcome was the impact of finasteride use after diagnosis on the OS in BCa and in the high-risk Non-muscle invasive BCa (NMIBC) cohort. A total of 1890 patients were included, amongst which 619 (32.8%) men were classified as finasteride users and 1271 (67.2%) men as controls. At a median (IQR) follow up of 53.8 (27.4, 90.9) months, death due to any cause was noted in 272 (43.9%) finasteride-treated, and 672 (49.3%) control groups (P=.028). The patients in the finasteride group had significantly better OS in overall cohort (112.1 months vs. 84.8 months, P < .001) as well as in the NMIBC cohort (129.3months vs. 103.2 months, P=.0046). The use of finasteride was independently associated with improved OS in both, overall cohort (HR 0.74, 95% CI 0.63-0.86; P < .001) and in the NMIBC cohort (HR=0.71, 95% CI 0.55-0.93; P=.011). Finasteride use is associated with the improved overall survival in patients with BCa, specifically in patients with NMIBC. We, further, propose a randomized clinical trial to investigate the use of finasteride in BCa patients.

Anti-oncogenic effects of dutasteride, a dual 5-alpha reductase inhibitor and a drug for benign prostate hyperplasia, in bladder cancer

BackgroundThe incidence of bladder cancer (BCa) is approximately four times higher in men than in women. To develop effective BCa treatments, there is an urgent need to understand the differences in the BCa control mechanisms based on gender. Our recent clinical study showed that androgen suppression therapy using 5α-reductase inhibitors and androgen deprivation therapy affects BCa progression, but the underlying mechanisms are still unknown.MethodsmRNA expression levels of the androgen receptor (AR) and SLC39A9 (membrane AR) in T24 and J82 BCa cells were evaluated by reverse transcription-PCR (RT-PCR). The effect of dutasteride, a 5α-reductase inhibitor, in BCa progression was determined in cells transfected with control and AR-overexpressing plasmids. In addition, cell viability and migration assays, RT-PCR, and western blot analysis were performed to analyze the effect of dutasteride on BCa in the presence of testosterone. Finally, steroidal 5α-reductase 1 (SRD5A1), one of the dutasteride target genes, was silenced in T24 and J82 BCa cells using control and shRNA-containing plasmids, and the oncogenic role of SRD5A1 was evaluated.ResultsDutasteride treatment led to significant inhibition of the testosterone-induced increase dependent on AR and SLC39A9 in cell viability and migration of T24 and J82 BCa cells and induced alterations in the expression level of cancer progression proteins, such as metalloproteases, p21, BCL-2, NF-KB, and WNT in AR-negative BCa. Furthermore, the bioinformatic analysis showed that mRNA expression levels of SRD5A1 were significantly higher in BCa tissues than in normal paired tissues. A positive correlation between SRD5A1 expression and poor patient survival was observed in patients with BCa. Also, Dutasteride treatment reduced cell proliferation and migration via blocking the SRD5A1 in BCa.ConclusionsDutasteride inhibited testosterone-induced BCa progression dependent on SLC39A9 in AR-negative BCa and repressed oncogenic signaling pathways, including those of metalloproteases, p21, BCL-2, NF-KB, and WNT. Our results also suggest that SRD5A1 plays a pro-oncogenic role in BCa. This work provides potential therapeutic targets for the treatment of BCa.

An adaptive information-theoretic experimental design procedure for high-to-low fidelity calibration of prostate cancer models.

The use of mathematical models to make predictions about tumor growth and response to treatment has become increasingly prevalent in the clinical setting. The level of complexity within these models ranges broadly, and the calibration of more complex models requires detailed clinical data. This raises questions about the type and quantity of data that should be collected and when, in order to maximize the information gain about the model behavior while still minimizing the total amount of data used and the time until a model can be calibrated accurately. To address these questions, we propose a Bayesian information-theoretic procedure, using an adaptive score function to determine the optimal data collection times and measurement types. The novel score function introduced in this work eliminates the need for a penalization parameter used in a previous study, while yielding model predictions that are superior to those obtained using two potential pre-determined data collection protocols for two different prostate cancer model scenarios: one in which we fit a simple ODE system to synthetic data generated from a cellular automaton model using radiotherapy as the imposed treatment, and a second scenario in which a more complex ODE system is fit to clinical patient data for patients undergoing intermittent androgen suppression therapy. We also conduct a robust analysis of the calibration results, using both error and uncertainty metrics in combination to determine when additional data acquisition may be terminated.

High Accuracy Indicators of Androgen Suppression Therapy Failure for Prostate Cancer-A Modeling Study.

Simple SummaryHormonal therapy for prostate cancer is often applied past the point of resistance, hence losing any future clinical value to the evolution of resistant strains. If the undesirable outcome of the treatment is forewarned, then clinicians can have an opportunity to adjust the treatment, which can result in better management of the cancer. Using a mechanistic mathematical model, we introduce two methods to enhance the accuracy of classical biomarkers for hormonal therapy failure. Our results show the value in measuring both prostate-specific antigen and androgen during hormonal treatment, which can potentially allow for better management of prostate cancer.Prostate cancer is a serious public health concern in the United States. The primary obstacle to effective long-term management for prostate cancer patients is the eventual development of treatment resistance. Due to the uniquely chaotic nature of the neoplastic genome, it is difficult to determine the evolution of tumor composition over the course of treatment. Hence, a drug is often applied continuously past the point of effectiveness, thereby losing any potential treatment combination with that drug permanently to resistance. If a clinician is aware of the timing of resistance to a particular drug, then they may have a crucial opportunity to adjust the treatment to retain the drug’s usefulness in a potential treatment combination or strategy. In this study, we investigate new methods of predicting treatment failure due to treatment resistance using a novel mechanistic model built on an evolutionary interpretation of Droop cell quota theory. We analyze our proposed methods using patient PSA and androgen data from a clinical trial of intermittent treatment with androgen deprivation therapy. Our results produce two indicators of treatment failure. The first indicator, proposed from the evolutionary nature of the cancer population, is calculated using our mathematical model with a predictive accuracy of 87.3% (sensitivity: 96.1%, specificity: 65%). The second indicator, conjectured from the implication of the first indicator, is calculated directly from serum androgen and PSA data with a predictive accuracy of 88.7% (sensitivity: 90.2%, specificity: 85%). Our results demonstrate the potential and feasibility of using an evolutionary tumor dynamics model in combination with the appropriate data to aid in the adaptive management of prostate cancer.

Abstract 4068: The potent quadruplex-binding compound SOP1812 shows potent anti-proliferative activity in a prostate cancer cell panel and anti-tumor activity in an in vivo model of metastatic prostate cancer

Abstract The compound SOP1812, a tetra-substituted naphthalene diimide (ND) derivative has been designed as a potent compound for targeting quadruplex sequences in cancer genes. It has been previously disclosed to have single-digit nM anti-proliferative activity in a panel of human cancer cell lines (Ahmed et al., ACS Med Chem Lett, 2020, 11, 1634-1644). It also has significant anti-tumor activity in several models for pancreatic cancer. We have also previously shown that two early-generation ND derivatives are active in both androgen-positive and negative prostate cancer cell lines (Mitchell et al, Biochemistry, 2013, 32, 1429-1436) and that these compounds down-regulate the transcription of quadruplex-containing genes such as c-MYC. We now report that this compound also shows significant anti-proliferative activity in several prostate cancer cell lines, notably with a GI50 value of 3 nM in the PC3 cell line. Abiraterone has a GI50 in this line of 4820 nM. By contrast SOP1812 has a GI50 of 247 nM in the LNCaP line, which is also derived from a patient with metastatic prostate cancer but is androgen positive. The PC3 line is derived from a metastatic carcinoma following androgen suppression therapy and is thus androgen independent and is a model for castration-resistant prostate cancer when hormone therapies are no longer effective. We have evaluated the activity of SOP1812 in the PC3 xenograft model using a twice-weekly 1 mg/kg dose regimen IV administered, against a saline control and abiraterone, at a daily dose of 200 mg/kg, administered by the PO route, both over a 28-day period. No weight loss was observed in treated animals with either drug. SOP1812 produced statistically significant tumor shrinkage (P value of 0.0008) relative to the controls, with a T/C value of 33.5% on day 28. Abiraterone treatment resulted in a T/C value of 61.6%, with a P value of 0.0382. SOP1812 is bio-available at therapeutic doses and is well tolerated at these levels in this animal model. It is currently being evaluated as a candidate for clinical development by Qualigen Therapeutics Inc. Citation Format: Nicole Williams, Jenny Worthington, Stephen Neidle, Ahmed Ahmed. The potent quadruplex-binding compound SOP1812 shows potent anti-proliferative activity in a prostate cancer cell panel and anti-tumor activity in an in vivo model of metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4068.

Radiation Therapy for Prostate Cancer Using HYpofractionation Directed by UltraSound (RAPHYDUS): A Brazilian Public Health Care System Study

PurposeThis study evaluated the toxicity associated with a short course dose-escalated hypofractionated radiation therapy (HFRT) using image guided RT with or without androgen suppression therapy in patients with prostate cancer. Methods and MaterialsThis single-center prospective observational study included 132 patients with prostate cancer from 2016 to 2020. Patients received HFRT using image guided RT (84%) with 3-dimensional (91%) or intensity modulated RT (9%). Total prescribed doses were 66 Gy (63%), 63 Gy (12%), and 60 Gy (24%) in 22, 21, or 20 daily fractions depending on organ-at-risk dose constraints. Acute toxicity was scored using Radiation Therapy Oncology Group criteria and the international prostate symptom index. The expanded prostate cancer index composite questionnaire was used to collect quality of life data (ranging from 0-100). ResultsThe study population consisted of 111 patients who completed RT during a period of 3 years. The risk groups were as follows: low risk (12%), intermediate (32%), and high (56%). None of the patients had suspicious lymph nodes. Ninety percent received androgen suppression therapy. Maximum acute genitourinary and gastrointestinal toxicity peaked at grade 3 in 4 of 111 evaluated patients (4%) and at grade 2 in 7 of 111 evaluated patients (8%), respectively. The average international prostate symptom score increased from 4.8 at pretreatment to 14.0 during week 4 and normalized (5.7) 3 months after treatment completion. ConclusionsThe current HFRT dose-escalation trial has demonstrated the feasibility of administering 66 Gy in 22 fractions with low acute gastrointestinal and genitourinary toxicities. Further follow-up will report late toxicities and outcomes.

Degarelix for treating advanced hormone-sensitive prostate cancer.

Degarelix is a gonadotropin-releasing hormone antagonist that leads to medical castration used to treat men with advanced or metastatic prostate cancer, or both. It is unclear how its effects compare to standard androgen suppression therapy. To assess the effects of degree compared with standard androgen suppression therapy for men with advanced hormone-sensitive prostate cancer. We searched multiple databases (CENTRAL, MEDLINE, Embase, Scopus, Web of Science, LILACS until September 2020), trial registries (until October 2020), and conference proceedings (until December 2020). We identified other potentially eligible trials by reference checking, citation searching, and contacting study authors. We included randomized controlled trials comparing degarelix with standard androgen suppression therapy for men with advanced prostate cancer. Three review authors independently classified studies and abstracted data from the included studies. The primary outcomes were overall survival and serious adverse events. Secondary outcomes were quality of life, cancer-specific survival, clinical progression, other adverse events, and biochemical progression. We used a random-effects model for meta-analyses and assessed the certainty of evidence for the main outcomes according to GRADE. We included 11 studies with a follow-up of between three and 14 months. We also identified five ongoing trials. Primary outcomes Data to evaluate overall survival were not available. Degarelix may result in little to no difference in serious adverse events compared to standard androgen suppression therapy (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.62 to 1.05; low-certainty evidence; 2750 participants). Based on 114 serious adverse events in the standard androgen suppression group, this corresponds to 23 fewer serious adverse events per 1000 participants (43 fewer to 6 more). We downgraded the certainty of evidence for study limitations and imprecision. Secondary outcomes Degarelix likely results in little to no difference in quality of life assessed with a variety of validated questionnaires (standardized mean difference 0.06 higher, 95% CI 0.05 lower to 0.18 higher; moderate-certainty evidence; 2887 participants), with higher scores reflecting better quality of life. We downgraded the certainty of evidence for study limitations. Data to evaluate cancer-specific survival were not available. The effects of degarelix on cardiovascular events are very uncertain (RR 0.15, 95% CI 0.04 to 0.61; very low-certainty evidence; 80 participants). We downgraded the certainty of evidence for study limitations, imprecision, and indirectness as this trial was conducted in a unique group of high-risk participants with pre-existing cardiovascular morbidities. Degarelix likely results in an increase in injection site pain (RR 15.68, 95% CI 7.41 to 33.17; moderate-certainty evidence; 2670 participants). Based on 30 participants per 1000 with injection site painwith standard androgen suppression therapy, this corresponds to 440 more injection site pains per 1000 participants (192 more to 965 more). We downgraded the certainty of evidence for study limitations. We did not identify any relevant subgroup differences for different degarelix maintenance doses. We did not find trial evidence foroverall survival or cancer-specific survival comparing degarelix to standard androgen suppression, but serious adverse events and quality of life may be similar between groups. The effects of degarelixon cardiovascular events are very uncertain as the only eligible study had limitations, was small withfew events, and was conducted in a high-risk population.Degarelix likely results in an increase in injection site pain compared to standard androgen suppression therapy. Maximum follow-up of included studies was 14 months, which is short.There is a need for methodologically better designed and executed studies with long-term follow-up evaluating men with metastatic prostate cancer.

A new role of GRP75-USP1-SIX1 protein complex in driving prostate cancer progression and castration resistance.

Prostate cancer (PC) is the second most common cancer with limited treatment option in males. Although the reactivation of embryonic signals in adult cells is one of the characteristics of cancer, the underlying protein degradation mechanism remains elusive. Here, we show that the molecular chaperone GRP75 is a key player in PC cells by maintaining the protein stability of SIX1, a transcription factor for embryonic development. Mechanistically, GRP75 provides a platform to recruit the deubiquitinating enzyme USP1 to inhibit K48-linked polyubiquitination of SIX1. Structurally, the C-terminus of GRP75 (433-679 aa) contains a peptide binding domain, which is required for the formation of GRP75-USP1-SIX1 protein complex. Functionally, pharmacological or genetic inhibition of the GRP75-USP1-SIX1 protein complex suppresses tumor growth and overcomes the castration resistance of PC cells in vitro and in xenograft mouse models. Clinically, the protein expression of SIX1 in PC tumor tissues is positively correlated with the expression of GRP75 and USP1. These new findings not only enhance our understanding of the protein degradation mechanism, but also may provide a potential way to enhance the anti-cancer activity of androgen suppression therapy.

Prostate-specific antigen nadir and testosterone level at prostate-specific antigen failure following radiation and androgen suppression therapy for unfavorable-risk prostate cancer and the risk of all-cause and prostate cancer-specific mortality.

Although both PSA nadir (PSAn) and testosterone levels at PSA failure are known prognostic factors in men undergoing radiation therapy (RT) and androgen deprivation therapy (ADT) for unfavorable-risk prostate cancer (PC), it is unclear whether their prognostic significance is independent or overlapping. Seventy-five men treated with RT with or without 6months of ADT for unfavorable-risk nonmetastatic PC enrolled in 2 prospective clinical trials between 1986 and 2001 formed the study cohort. Competing risks and Cox multivariable regression were used to assess whether low versus normal serum testosterone at the time of PSA failure and higher PSAn after initial therapy were independently associated with the risk of PC-specific (PCSM) and all-cause mortality (ACM) adjusting for PC prognostic factors. After a median follow-up of 15.34years (interquartile range, 6.66-16.88years), there were 53 deaths (73.3%): 30 (56.6%) were from PC. Low testosterone at PSA failure was significantly associated with an increased risk of PCSM (adjusted HR [AHR], 7.77; 95% CI, 1.14-52.99; P=.04) and ACM (AHR, 3.01; 95% CI, 1.01-8.96; P=.05), as was higher PSAn (PCSM AHR, 1.03; 95% CI, 1.01-1.05; P<.01; ACM AHR, 1.04; 95% CI, 1.02-1.07; P<.01), although the prognostic significance of PSAn was only noted in men with a normal testosterone at PSA failure. Low testosterone level at PSA failure in high-risk patients with PC treated with RT is associated with increased PCSM and ACM risk. In men with normal testosterone levels at the time of PSA failure, an elevated PSAn was associated with worse PCSM and ACM risk. This study investigates whether the prostate-specific antigen (PSA) nadir and normal versus low testosterone at the time of PSA failure provide mutually exclusive or overlapping prognostic information following treatment with radiation and androgen deprivation therapy for unfavorable-risk patients with prostate cancer using data from 2 prospective clinical trials. It was found that both provided prognostic information; however, higher PSA nadir was only found to be of prognostic significance in men with normal testosterone levels at PSA failure.

Clinical Outcomes of the CHIRP Trial: A Phase II Prospective Randomized Trial of Conventionally Fractionated Versus Moderately Hypofractionated Prostate and Pelvic Nodal Radiation Therapy in Patients With High-Risk Prostate Cancer

PurposeHypofractionated radiation therapy (HFRT) may offer treatment advantages for patients with prostate cancer. However, HFRT may also increase the risk of gastrointestinal (GI) or genitourinary (GU) toxicity compared with conventionally fractionated radiation therapy (CFRT). Several large trials have found that HFRT is well tolerated in mixed risk population studies. Here, we report on a phase II, randomized controlled study conducted to evaluate these endpoints in exclusively high-risk patients with prostate cancer treated with prostate and pelvic nodal radiation. Methods and MaterialsAfter giving informed consent, patients with high-risk prostate cancer were randomly assigned to prostate plus pelvic nodal radiation therapy with either HFRT (68 Gy in 25 fractions) or CFRT (78 Gy in 39 fractions) and 18 months of androgen suppression therapy. Toxicity was scored using the Common Terminology Criteria for Adverse Events (version 4.0). Biochemical failure was determined by the Phoenix definition. Patients were analyzed on an intention-to-treat basis. ResultsFrom 2012 to 2018, 111 patients with high-risk prostate cancer were enrolled and 109 patients were treated. The cumulative incidence of grade 2 or higher acute GI toxicity was not significantly different between the arms (HFRT 18.9% vs CFRT 21.8%; P = .812). Similarly, acute GU (HFRT 30.2% vs CFRT 30.9%; P = 1.00), late GI (HFRT 16.0% vs CFRT 10.0%; P = .554), and late GU (HFRT 16.0% vs CFRT 6.0%; P = .200) were not significantly different between the arms. Median follow-up was 38.0 months (4.8-77.8 months). The 3-year biochemical recurrence-free survival was not significantly different between the 2 arms (97.3% for HFRT vs 91.0% for CFRT; P = .606). The 3-year overall survival was 94.8% in the HFRT arm and 100.0% in the CFRT arm (P = .116). ConclusionsHFRT and CFRT using intensity modulated radiation therapy were both well tolerated for patients with high-risk prostate cancer and resulted in similar 3-year biochemical recurrence-free survival and overall survival.

Effect of leuprorelin inbulbar function of spinal and bulbar muscular atrophypatients: observational study for 1year.

This study aimed to investigate the effect of androgen suppression therapy using leuprorelin focused on the bulbar function of patients with spinal and bulbar muscular atrophy (SBMA). Genetically confirmed SBMA patients who consented to participate in this observational study were enrolled. Leuprorelin was subcutaneously injected every 12weeks. Videofluoroscopic swallowing study was performed at baseline and after androgen suppression therapy for 1 year. The primary outcome measures were the changes in the vallecular residue and pyriform sinus residue. The videofluoroscopic swallowing study data were analyzed and interpreted by two experienced physiatrists. A total of 40 patients with SBMA were analyzed in this study. The inter-rater reliability testing showed good agreement for the pharyngeal residue (ICC = 0.84) and videofluoroscopic dysphagia scale (ICC = 0.75). The vallecular residue and pyriform sinus residue after swallowing 9mL yogurt were significantly reduced (26.8 ± 22.6 to 14.6 ± 14.5, p < 0.001, 14.9 ± 16.9 to 7.6 ± 9.9, p < 0.001, respectively). The swallowing subscore of amyotrophic lateral sclerosis functional rating scale-revised improved after androgen suppression therapy (3.3 ± 0.5 to 3.5 ± 0.6, p = 0.041). Leuprorelin significantly reduced the pharyngeal residue in patients with SBMA after 1 year of treatment without any serious adverse events and longitudinal studies are needed to confirm these results.