'Just because I have prostate cancer doesn't mean that I can't do things' - men's experiences of the acceptability of an exercise intervention for prostate cancer during treatment.

BACKGROUND: Structured exercise has an important role in mitigating the extensive side effects caused by ongoing prostate cancer treatments, specifically androgen deprivation therapy (ADT) and radiation therapy (RT). Little is known about men's experiences of, and preferences for, structured exercise programmes during active cancer treatment. This study aimed to inform the acceptability of a 6-month supervised intervention that emphasised increasing and varied intensities of aerobic and resistance exercise, by exploring the experiences of men who participated. METHODS: Individual semi-structured interviews were conducted with an interviewer independent of the exercise study and data was analysed using a descriptive qualitative design. RESULTS: Twelve prostate cancer patients were interviewed including participants who completed (n = 9) and withdrew from (n = 3) the intervention. Four main themes captured how men experienced the intervention: (1) Navigating the Unknown: Building confidence amidst vulnerability (subtheme- pushing the limits), (2) Building Trust: The credibility and approach of the exercise instructor (subtheme- appropriateness of supervised vs. independent exercise), (3) Flexibility in Delivery, (4) Finding Purpose: Exercise as a means of escapism and regaining control during treatment. CONCLUSION: While an initial lack of self-confidence can be a barrier to exercise participation, exercise programmes have the potential to provide psychosocial benefits, rebuild confidence and empower men throughout their cancer treatment and into recovery. Structured exercise is acceptable during treatment including RT and can offer a form of escapism and sense of control for men navigating their cancer journey. Trust building, flexible delivery and credibility alongside a challenging exercise prescription are important facilitators of acceptability for men. Strategies to embed exercise from the point of diagnosis through ADT and RT should reflect men's experiences of exercise during treatment. TRIAL REGISTRATION: The trial has been registered on ClinicalTrials.gov as of the 14th of December 2021 (NCT05156424).

[Urogeriatric thinking using the example of antiandrogen therapy for prostate cancer]. / Urogeriatrisches Denken am Beispiel der antiandrogenen Therapie des Prostatakarzinoms.

The geriatric patient is defined by an age of over 75 years and multimorbidity or by an age of over 80 years. These patients exhibit a particular vulnerability, which, in the incidence of side effects or complications, leads to a loss of autonomy. Treatment sequalae, once they have arisen, can no longer be compensated. It is important to recognize and document treatment requirements among geriatric patients with the help of screening instruments such as the Identification of Seniors at Risk (ISAR) and Geriatric 8 (G8) scores. If a treatment requirement is identified, oncologic treatment should not be commenced uncritically but rather a focus placed on identification of functional deficits relevant to treatment, ideally using a geriatric assessment but at least based on a detailed medical history. These deficits can then be presented in a structured, examiner-independent, and forensically validated manner using special assessments. A planned treatment requires not only consideration of survival gains, but also knowledge of specific side effects and, in geriatric patients in particular, their impact on everyday life. These considerations should be compared with the patient's individual risk profile in order to prevent side effects from negating the effect of the treatment, for example by worsening the patient's self-help status. With regard to androgen deprivation in prostate cancer-which often is used uncritically-it is important to consider possible side effects such as osteoporosis, sarcopenia, anemia, and cognitive impairment in terms of a possible fall risk; an increase in cardiovascular mortality and the triggering of a metabolic syndrome on the basis of preexisting cardiac diseases or risk constellations; and to carry out a careful risk-benefit analysis.

Protocol for Evaluating the Efficacy and Safety of Radiotherapy for Prostate and Oligometastatic Lesions in Patients With Low-Burden Sensitive Oligometastatic Prostate Cancer: An Open, Exploratory Pilot Clinical Trial.

INTRODUCTION: The existing large prospective study demonstrates the benefits of primary radiotherapy in patients with low-volume oligometastatic prostate cancer (OMPC), and there is additional evidence of the benefits of local metastasis-directed therapy (MDT) for metastatic lesions. However, there are no results from a prospective study to demonstrate the efficacy of radiotherapy for prostate and oligometastases. Therefore, the aim of the protocol is to illustrate the efficacy of radiotherapy for prostate and oligometastatic lesions in patients with low-volume de novo hormone-sensitive OMPC. METHODS AND ANALYSIS: This study involves a prospective, single-center, limited-sample, single-arm exploration of radiotherapy for prostate and oligometastatic lesions in patients diagnosed with low-volume hormone-sensitive OMPC. Eligible participants undergo thorough assessments and treatment involving endocrine therapy alongside radiation targeting metastatic lesions and the pelvic region. The primary site is treated with volumetric modulated arc therapy (VMAT), while metastatic sites are treated with either VMAT or stereotactic body radiation therapy (SBRT) depending on their location. All patients received radiation therapy for both the primary and metastatic lesions combined with endocrine therapy. Endocrine therapy with an antiandrogen (bicalutamide, for 4 weeks) androgen deprivation therapy combined with novel hormonal agents (acetate abiraterone) will be continued for 2 years. The primary objective is to evaluate progression-free survival-2 (PFS-2), while secondary endpoints include androgen deprivation therapy (ADT)-free survival, quality of life (QoL), overall survival, time to castration-resistant prostate cancer (CRPC), radiation-related complications, and endocrine therapy-related adverse events. ETHICS AND DISSEMINATION: Approval was obtained from the ethics committee of the First Affiliated Hospital of Naval Medical University (CHEC2023-220). This is a single-arm exploration pilot trial evaluating radiotherapy for prostate and oligometastatic lesions in patients with OMPC. It aims to disseminate its findings through peer-reviewed journals and relevant medical conferences, with the intention of publication and presentation at these events. TRIAL REGISTRATION NUMBERS: Clinicaltrials.gov identifier NCT06198387.

HSD3B1 genotype and outcomes in metastatic hormone-sensitive prostate cancer with androgen deprivation therapy and enzalutamide: ARCHES.

HSD3B1 encodes 3ß-hydroxysteroid dehydrogenase-1, which converts adrenal dehydroepiandrosterone to 5α-dihydrotestosterone and is inherited in adrenal-permissive (AP) or adrenal-restrictive forms. The AP allele is linked to castration resistance, mainly in low-volume tumors. Here, we investigate the association of HSD3B1 alleles with outcomes in ARCHES, a multinational, double-blind, randomized, placebo-controlled phase 3 trial that demonstrated clinical benefit with enzalutamide plus androgen deprivation therapy (ADT) in men with metastatic hormone-sensitive prostate cancer (mHSPC) compared to those treated with placebo plus ADT. There are no significant differences between genotypes for clinical efficacy endpoints. Enzalutamide significantly improves radiographic progression-free survival and overall survival vs. placebo irrespective of HSD3B1 status. Men with the AP genotype have higher post-progression mortality and treatment-emergent adverse events, including hypertension, cardiovascular events, and gynecomastia, but a lower fracture rate. Overall, enzalutamide is beneficial in men with mHSPC independent of the HSD3B1 genotype. Inherited polymorphisms of HSD3B1 may account for differential toxicities.

Targeting adenocarcinoma and enzalutamide­resistant prostate cancer using the novel anti­androgen inhibitor ADA­308.

Prostate cancer (PCa) is the leading cause of cancer­related death among men worldwide. PCa often develops resistance to standard androgen deprivation therapy and androgen receptor (AR) pathway inhibitors, such as enzalutamide (ENZ). Therefore, there is an urgent need to develop novel therapeutic strategies for this disease. The efficacy of ADA­308 was evaluated through in vitro assessments of AR activity and cell proliferation, alongside in vivo studies. ADA­308 has emerged as a promising candidate, demonstrating potent inhibition of AR­sensitive adenocarcinoma as well as ENZ­resistant PCa cell lines. The results of the study revealed that ADA­308 effectively blocked AR activity, including its nuclear localization, and inhibited cell proliferation in vitro. Furthermore, ADA­308 demonstrated notable efficacy in vivo, with a robust antitumor response in ENZ­resistant models. These findings establish the role of ADA­308 as a potent AR inhibitor that overcomes resistance to AR­targeted therapies and highlights its potential as a novel therapeutic approach in advanced PCa management.

How We Treat Metastatic Castration-Sensitive Prostate Cancer.

The treatment of metastatic castration-sensitive prostate cancer (mCSPC) has seen remarkable breakthroughs over the last few years. Diagnostic and therapeutic advances have given rise to debates about risk stratification and optimal first-line treatment selection, as well as to concerns about potential overtreatment in a disease state with a highly heterogeneous clinical behavior. Here, we use case reports from our practice to review the clinical trials exploring intensified triplet regimens combining androgen deprivation therapy with second-generation androgen receptor signaling inhibitors and docetaxel, and we offer our recommendations on how to best select candidates for these novel combinations. Furthermore, the growing adoption of PET imaging with increasingly sensitive and prostate tissue-specific tracers replacing conventional staging technologies has led to the identification of a subset of low-volume mCSPC with nodal metastases which would otherwise not be considered abnormal by RECIST criteria. We describe our PSA-adapted approach to treatment in this unique population with non-measurable low-volume mCSPC which has not been specifically investigated in any phase III clinical trials. We also discuss ongoing clinical trials evaluating treatment de-escalation strategies. Finally, we review how local treatment modalities directed at the prostate or distant sites of disease in oligometastatic CSPC may benefit patients, and how we incorporate metastasis-directed therapy in the management of mCSPC.

The Omission of Upfront Treatment Intensification Does Not Adversely Affect Oncological Outcomes in a Subset of Castration-Highly Sensitive Metastatic Prostate Cancer.

BACKGROUND/AIM: In patients with metastatic castration-sensitive prostate cancer (mCSPC), upfront treatment intensification with the addition of new hormonal agents and/or docetaxel to androgen deprivation therapy (ADT) is recommended. However, this modality is potentially excessive in a subset of these patients. This study aimed to identify patients who may be eligible to omit upfront treatment intensification. PATIENTS AND METHODS: Patients with mCSPC who underwent ADT were enrolled. The association between undetectable prostate-specific antigen (PSA) (<0.2 ng/ml) after ADT initiation and overall or castration-resistance-free survival was evaluated. RESULTS: Ninety-seven out of the 242 enrolled patients had low-risk and/or low-volume cancer and were further analyzed. Of these, 45 (46.4%) patients achieved undetectable PSA. The median follow-up period after ADT initiation was 70 months. The median overall survival among patients with undetectable PSA was quite long, reaching 226 months and significantly longer than that among patients with detectable PSA [71 months, hazard ratio (HR)=0.27, 95% confidence interval (CI)=0.15-0.49, p<0.001]. Time to development of castration-resistance was also long and significantly longer in the undetectable PSA group than that in the detectable PSA group (median: 124 vs. 17 months, HR=0.20, 95% CI=0.12-0.34, p<0.001). CONCLUSION: Patients with low-risk and/or low-volume mCSPC showed long-term survival when undetectable PSA was achieved during conventional ADT. In these patients, skipping upfront treatment intensification does not seem to negatively impact survival.

Systemic therapy landscape of advanced prostate cancer.

Prostate cancer is the most commonly diagnosed cancer in American men and 2nd leading cause of cancer-related deaths in the United States. Androgen deprivation therapy (ADT) is the backbone of treatment for advanced prostate cancer. Over the past several decades a number of new therapeutics, such as novel androgen receptor pathway inhibitors, targeted agents and radionuclide therapies, have been introduced for the treatment of prostate cancers. These agents have been demonstrated to improve clinical outcomes of prostate cancer patients in randomized clinical trials. In addition, new therapeutic strategies, such as early intensification of ADT, novel treatment combinations, and treatment sequencing, are expected to improve outcomes further. In this clinical review, we discuss the changing treatment landscape for advanced prostate cancer with a focus on new therapeutics.

Cost-effectiveness analysis of rezvilutamide versus bicalutamide in the treatment of metastatic hormone-sensitive prostate cancer.

OBJECTIVES: The economic implications of combining rezvilutamide with androgen deprivation therapy (ADT) remain uncertain, despite the observed survival advantages compared with bicalutamide plus ADT. Therefore, this study evaluates the cost-effectiveness of rezvilutamide plus ADT as the first-line treatment of metastatic hormone-sensitive prostate cancer (mHSPC) from the perspective of the Chinese healthcare system. DESIGN: A partitioned survival model was developed to assess the cost-effectiveness of rezvilutamide combined with ADT. Clinical data were obtained from the CHART trial. Costs and utility values were obtained from local estimate and published literature. Only direct medical costs were included in the model. INTERVENTIONS: Rezvilutamide was administered at 240 mg daily or bicalutamide at 50 mg daily until progression. OUTCOME MEASURES: The main outputs of the model included costs and quality-adjusted life years (QALYs), which were used to determine the incremental cost-effectiveness ratio (ICER). One-way and probabilistic sensitivity analysis (PSA) were used to explore model uncertainties. RESULTS: The rezvilutamide group showed an expected gain of 2.28 QALYs and an incremental cost of US$60 758.82 compared with the bicalutamide group. The ICER for rezvilutamide group versus bicalutamide group was US$26 656.94 per QALY. The variables with the greatest impact on the model results were the utility for progression-free survival state and the price of rezvilutamide. PSA revealed that rezvilutamide group had 100% probability of being cost-effective at a willingness-to-pay threshold of US$35707.5 per QALY. CONCLUSION: Rezvilutamide in combination with ADT is more cost-effective compared with bicalutamide plus ADT as the first-line treatment of mHSPC from the perspective of the Chinese healthcare system.

Targeting a STING agonist to perivascular macrophages in prostate tumors delays resistance to androgen deprivation therapy.

BACKGROUND: Androgen deprivation therapy (ADT) is a front-line treatment for prostate cancer. In some men, their tumors can become refractory leading to the development of castration-resistant prostate cancer (CRPC). This causes tumors to regrow and metastasize, despite ongoing treatment, and impacts negatively on patient survival. ADT is known to stimulate the accumulation of immunosuppressive cells like protumoral tumor-associated macrophages (TAMs), myeloid-derived suppressor cells and regulatory T cells in prostate tumors, as well as hypofunctional T cells. Protumoral TAMs have been shown to accumulate around tumor blood vessels during chemotherapy and radiotherapy in other forms of cancer, where they drive tumor relapse. Our aim was to see whether such perivascular (PV) TAMs also accumulate in ADT-treated prostate tumors prior to CRPC, and, if so, whether selectively inducing them to express a potent immunostimulant, interferon beta (IFNß), would stimulate antitumor immunity and delay CRPC. METHODS: We used multiplex immunofluorescence to assess the effects of ADT on the distribution and activation status of TAMs, CD8+T cells, CD4+T cells and NK cells in mouse and/or human prostate tumors. We then used antibody-coated, lipid nanoparticles (LNPs) to selectively target a STING agonist, 2'3'-cGAMP (cGAMP), to PV TAMs in mouse prostate tumors during ADT. RESULTS: TAMs accumulated at high density around blood vessels in response to ADT and expressed markers of a protumoral phenotype including folate receptor-beta (FR-ß), MRC1 (CD206), CD169 and VISTA. Additionally, higher numbers of inactive (PD-1-) CD8+T cells and reduced numbers of active (CD69+) NK cells were present in these PV tumor areas. LNPs coated with an antibody to FR-ß selectively delivered cGAMP to PV TAMs in ADT-treated tumors, where they activated STING and upregulated the expression of IFNß. This resulted in a marked increase in the density of active CD8+T cells (along with CD4+T cells and NK cells) in PV tumor areas, and significantly delayed the onset of CRPC. Antibody depletion of CD8+T cells during LNP administration demonstrated the essential role of these cells in delay in CRPC induced by LNPs. CONCLUSION: Together, our data indicate that targeting a STING agonist to PV TAMs could be used to extend the treatment window for ADT in prostate cancer.

Treatment escalation and de-escalation of de-novo metastatic castration-sensitive prostate cancer.

Androgen receptor signaling inhibitors combined with androgen deprivation therapy have become the standard of care for metastatic castration-sensitive prostate cancer (mCSPC), regardless of tumor volume or risk. However, survival of approximately one-third of these patients has not improved, necessitating further treatment escalation. On the other hand, for patients with oligometastatic mCSPC, there is an emerging role for local radiation therapy. Although data remain scarce, it is expected that treatment of both primary tumor as well as metastasis-directed therapy may improve survival outcomes. In these patients, systemic therapy may be de-escalated to intermittent therapy. However, precise risk stratification is necessary for risk-based treatment escalation or de-escalation. In addition to risk stratification based on clinical parameters, research has been conducted to incorporate genomic and/or transcriptomic data into risk stratification. In future, an integrated risk model is expected to precisely stratify patients and guide treatment strategies. Here, we first review the transition of the standard treatment for mCSPC over the last decade and further discuss the newest concept of escalating or de-escalating treatment using a multi-modal approach based on the currently available literature.

Seminal Papers in Urology: Darolutamide and survival in metastatic, hormone-sensitive prostate cancer.

The ARASENS trial recruited 1306 men with metastatic hormone sensitive prostate cancer. It investigated the effect of androgen deprivation therapy (ADT) and systemic therapy docetaxel in combination with a third novel drug - daralutamide, compared with placebo on overall survival. Triple therapy with ADT, docetaxel and darolutamide resulted in improved overall survival rates as compared with ADT, docetaxel and placebo (HR 0.68; 95% CI, 0.57-0.80; p < 0.001). The side effect profile for both treatments was similar. This randomised, double blinded, placebo controlled study, was assessed to have a low risk of bias using the Cochrane Risk of Bias 2 tool.

Bone Pain and Survival Among Patients With Metastatic, Hormone-Sensitive Prostate Cancer: A Secondary Analysis of the SWOG-1216 Trial.

Importance: The presence of bone pain is significantly associated with worse overall survival (OS) in patients with castration-resistant prostate cancer. However, there are few data regarding bone pain and survival outcomes in the context of metastatic, hormone-sensitive prostate cancer (MHSPC). Objective: To compare survival outcomes among patients with MHSPC by presence or absence of baseline bone pain at diagnosis. Design, Setting, and Participants: This post hoc secondary analysis, conducted from September 1 to December 31, 2023, used patient-level data from SWOG-1216, a phase 3, prospective randomized clinical trial that enrolled patients with newly diagnosed MHSPC from 248 academic and community centers across the US from March 1, 2013, to July 15, 2017. All patients in the intention-to-treat population who had available bone pain status were eligible and included in this secondary analysis. Interventions: In the SWOG-1216 trial, patients were randomized (1:1) to receive either androgen deprivation therapy (ADT) with orteronel, 300 mg orally twice daily (experimental group), or ADT with bicalutamide, 50 mg orally daily (control group), until disease progression, unacceptable toxic effects, or patient withdrawal. Main Outcomes and Measures: Overall survival was the primary end point; progression-free survival (PFS) and prostate-specific antigen (PSA) response were secondary end points. Cox proportional hazards regression models were used for both univariable and multivariable analyses adjusting for age, treatment type, Gleason score, disease volume, Zubrod performance status, and PSA level. Results: Of the 1279 male study participants, 301 (23.5%) had baseline bone pain at MHSPC diagnosis and 896 (70.1%) did not. Bone pain status was unavailable in 82 patients (6.4%). The median age of the 1197 patients eligible and included in this secondary analysis was 67.6 years (IQR, 61.8-73.6 years). Compared with patients who did not experience bone pain, those with baseline bone pain were younger (median age, 66.0 [IQR, 60.1-73.4] years vs 68.2 [IQR, 62.4-73.7] years; P = .02) and had a higher incidence of high-volume disease (212 [70.4%] vs 373 [41.6%]; P < .001). After adjustment, bone pain was associated with shorter PFS and OS. At a median follow-up of 4.0 years (IQR, 2.5-5.4 years), patients with bone pain had median PFS of 1.3 years (95% CI, 1.1-1.7 years) vs 3.7 years (95% CI, 3.3-4.2 years) in patients without initial bone pain (adjusted hazard ratio [AHR], 1.46; 95% CI, 1.22-1.74; P < .001) and OS of 3.9 years (95% CI, 3.3-4.8 years) vs not reached (NR) (95% CI, 6.6 years to NR) in patients without initial bone pain (AHR, 1.66; 95% CI, 1.34-2.05; P < .001). Conclusions and Relevance: In this post hoc secondary analysis of the SWOG-1216 randomized clinical trial, patients with baseline bone pain at MHSPC diagnosis had worse survival outcomes than those without bone pain. These data suggest prioritizing these patients for enrollment in clinical trials, may aid patient counseling, and indicate that the inclusion of bone pain in prognostic models of MHSPC may be warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT01809691.

Circulating Lipid Profiles Associated With Resistance to Androgen Deprivation Therapy in Localized Prostate Cancer.

PURPOSE: Intense androgen deprivation therapy (ADT) with androgen receptor pathway inhibitors (ARPIs) before radical prostatectomy (RP) produced favorable pathologic responses in approximately 20% of patients. The molecular reason for the low rate of response remains unclear. Lipid metabolism is known to influence androgen receptor signaling and ARPI efficacy. The aim of the study was to identify circulating lipid profiles associated with ADT/ARPI resistance in localized prostate cancer. MATERIALS AND METHODS: Two independent experimental approaches were used. Experiment 1: Post hoc analysis of the association between plasma lipidomic profiles and ADT/ARPI response was performed on patients (n = 104) from two phase II trials of neoadjuvant ADT/ARPI. Response to ADT/ARPI was defined by pathologic response. Experiment 2: Patient-derived tumor explants from RP (n = 105) were cultured in enzalutamide for 48 hours. Explant response to enzalutamide was evaluated against pre-RP plasma lipidomic profiles (n = 105) and prostate tissue lipidomic profiles (n = 36). Response was defined by Ki67 (cell proliferation marker) fold difference between enzalutamide and vehicle-treated explants. In both experiments, associations between lipid profiles and ADT/ARPI response were analyzed by latent class analysis. RESULTS: Pretreatment plasma lipid profiles classified each experimental cohort into two groups with differences in ADT/ARPI response rates. The response rates of the groups were 9.6% versus 29% in experiment 1 (chi-squared test P = .012) and 49% versus 70% in experiment 2 (chi-squared test P = .037). In both experiments, the group with a higher incidence of ADT/ARPI resistance had higher plasma levels of sphingomyelin, glycosylceramides, free fatty acids, acylcarnitines, cholesterol esters, and alkyl/alkenyl-phosphatidylcholine and lower plasma levels of triacylglycerols, diacylglycerols, and phosphoethanolamine (t-test P < .05). CONCLUSION: Pretreatment circulating lipid profiles are associated with ADT/ARPI resistance in localized cancer in both human cohorts and explant models.

Real-world evidence of 18F-fluciclovine Positron emission tomography/computed tomography performance for recurrent prostate cancer in the Veterans Affairs Health System.

BACKGROUND: There are no population-level studies assessing 18F-fluciclovine (fluciclovine) utilization of Positron emission tomography/computed tomography (PET/CT) for biochemically recurrent prostate cancer (PC). We assessed fluciclovine PET/CT in the Veterans Affairs Health Care System. METHODS: Of 1153 men with claims suggesting receipt of fluciclovine PET/CT, we randomly reviewed charts of 300 who indeed underwent fluciclovine PET/CT. The primary outcome was fluciclovine PET/CT result (positive or negative). Comparison among groups stratified by androgen deprivation therapy (ADT) (yes vs. no) and prostate-specific antigen (PSA) (≤1 vs. >1 ng/mL) at imaging were performed. Logistic regression tested associations between PSA, ADT receipt, and race with fluciclovine PET/CT positive imaging. RESULTS: Fluciclovine PET/CT positivity rate was 33% for patients with PSA 0-0.5 ng/mL, 21% for >0.5-1.0, 54% for >1.0-2.0, and 66% for >2.0 (p < 0.01). A 59% positivity rate ocurred in patients treated with concurrent ADT versus 37% in those not on ADT (p < 0.01). White were more likely to have a positive scan versus Black patients (55% vs. 38%; p = 0.02). Patients whose primary treatment was radical prostatectomy had a lower positivity rate (33%) versus those treated with radiotherapy (55%) (p < 0.001). On multivariable logistic regression, PSA > 1 ng/mL (all men odds ratio [OR]: 4.06, 95% confidence interval [CI]: 2.07-7.96; men on ADT only OR: 4.42, 95% CI: 1.73-11.26) and use of ADT (OR: 3.94, 95% CI: 1.32-11.75), and White (all men OR: 2.22, 95% CI: 1.20-4.17) predicted positive fluciclovine PET/CT. CONCLUSION: This real-world study assessing 18F-fluciclovine PET/CT performance in an equal access health care system confirms higher detection rates than traditional imaging methods, but positivity is highly influenced by PSA at time of imaging. Additionally, patients currently receiving ADT have at least four times higher likelihood of a positive scan, showing that scan positivity isn't negatively affected by ADT status in this study. Finally, White men were more likely to have a positive scan, the reasons for which should be explored in future studies.

Efficacy and safety of androgen receptor inhibitors for treatment of advanced prostate cancer: A systematic review and network meta-analysis.

AIMS: Androgen receptor inhibitors (ARIs) have become an effective treatment for advanced prostate cancer (PC). However, it is unknown which ARI is the most helpful and safe for men with advanced PC. Our aim is to help physicians make clinical decisions and provide medication guidelines for patients with advanced PC to avoid potential risks when using ARIs for treatment. METHODS: We systematically searched the following databases: PubMed, Embase and Cochrane Library, with a literature publication deadline of February 2023. The primary efficacy outcomes were 18-month overall survival (OS), treatment-emergent adverse events (TEAEs), hypertension and fatigue. The network meta-analysis (NMA) was performed by Stata 15.1, and Revman 5.3 was used to assess the included studies' risk of bias. RESULTS: The analysis included 26 trials with 26 263 people. The surface under the cumulative ranking curve (SUCRA) concluded that enzalutamide (86.8%) showed the best effect in prolonging the OS of patients. Flutamide led to the highest risk of TEAEs (29.9%) and AEs leading to discontinuation (12.8%). Apalutamide (13.4%) led to the highest risk of grade ≥3 TEAEs. Enzalutamide had the highest risk of hypertension (0.2%), grade ≥3 hypertension (4.5%) and fatigue (5.2%). CONCLUSIONS: This NMA indicates there is no one ARI to reach both the most effective and safe therapy aims for treating advanced PC and that there is a compromise between the efficacy and safety of ARIs in the treatment of advanced PC. Physicians should weigh the risks to safety against the anticipated benefits when prescribing these drugs to patients with PC.

Epitranscriptomic mechanisms of androgen signalling and prostate cancer.

Prostate cancer (PCa) is the second most common cancer diagnosed in men. While radical prostatectomy and radiotherapy are often successful in treating localised disease, post-treatment recurrence is common. As the androgen receptor (AR) and androgen hormones play an essential role in prostate carcinogenesis and progression, androgen deprivation therapy (ADT) is often used to deprive PCa cells of the pro-proliferative effect of androgens. ADTs act by either blocking androgen biosynthesis (e.g. abiraterone) or blocking AR function (e.g. bicalutamide, enzalutamide, apalutamide, darolutamide). ADT is often effective in initially suppressing PCa growth and progression, yet emergence of castrate-resistant PCa and progression to neuroendocrine-like PCa following ADT are major clinical challenges. For this reason, there is an urgent need to identify novel approaches to modulate androgen signalling to impede PCa progression whilst also preventing or delaying therapy resistance. The mechanistic convergence of androgen and epitranscriptomic signalling offers a potential novel approach to treat PCa. The epitranscriptome involves covalent modifications of mRNA, notably, in the context of this review, the N(6)-methyladenosine (m6A) modification. m6A is involved in the regulation of mRNA splicing, stability, and translation, and has recently been shown to play a role in PCa and androgen signalling. The m6A modification is dynamically regulated by the METTL3-containing methyltransferase complex, and the FTO and ALKBH5 RNA demethylases. Given the need for novel approaches to treat PCa, there is significant interest in new therapies that target m6A that modulate AR expression and androgen signalling. This review critically summarises the potential benefit of such epitranscriptomic therapies for PCa patients.

Bone health and body composition in prostate cancer: Meet-URO and AIOM consensus about prevention and management strategies.

BACKGROUND: Prostate cancer (PCa) treatments are associated with a detrimental impact on bone health (BH) and body composition. However, the evidence on these issues is limited and contradictory. This consensus, based on the Delphi method, provides further guidance on BH management in PCa. MATERIALS AND METHODS: In May 2023, a survey made up of 37 questions and 74 statements was developed by a group of oncologists and endocrinologists with expertise in PCa and BH. In June 2023, 67 selected Italian experts, belonging to the Italian scientific societies Italian Association of Medical Oncology and Italian Network for Research in Urologic-Oncology (Meet-URO), were invited by e-mail to complete it, rating their strength of agreement with each statement on a 5-point scale. An agreement ≥75% defined the statement as accepted. RESULTS: In non-metastatic hormone-sensitive PCa, the panel agreed that androgen deprivation therapy (ADT) alone implies sufficient fracture risk to warrant antifracture therapy with bone-targeting agents (BTAs) for cancer treatment-induced bone loss (CTIBL) prevention (79%). Therefore, no consensus was reached (48%) for the treatment with BTAs of patients receiving short-term ADT (<6 months). All patients receiving active treatment for metastatic hormone-sensitive PCa (75%), non-metastatic castration-resistant PCa (89%) and metastatic castration-resistant PCa (mCRPC) without bone metastases (84%) should be treated with BTAs at the doses and schedule for CTIBL prevention. All mCRPC patients with bone metastasis should be treated with BTAs to reduce skeletal-related events (94%). In all settings, the panel analyzed the type and timing of treatments and examinations to carry out for BH monitoring. The panel agreed on the higher risk of sarcopenic obesity of these patients and its correlation with bone fragility. CONCLUSIONS: This consensus highlights areas lacking major agreement, like non-metastatic hormone-sensitive prostate cancer patients undergoing short-term ADT. Evaluation of these issues in prospective clinical trials and identification of early biomarkers of bone loss are particularly urgent.

Development of a Novel Patient-Reported Outcome Measure to Assess Symptoms and Impacts of Androgen Deprivation Therapy for Advanced Prostate Cancer.

INTRODUCTION: This qualitative research study was conducted to develop a novel, comprehensive, patient-reported outcome measure (PRO), the "Symptoms and Impacts of Androgen Deprivation Therapy (ADT) for Prostate Cancer" (SIADT-PC), assessing hormonal therapy-related symptoms and their impacts on men with advanced prostate cancer. METHODS: Concept elicitation (CE) interviews were conducted among adult men with prostate cancer to evaluate their experiences with ADT. Based on key symptom and impact concepts mentioned, an initial PRO measure was developed. The draft measure was further assessed in cognitive debriefing (CD) interviews with men with prostate cancer, in which participants reviewed items, response options, and recall periods. Initial item-based psychometric analyses were conducted using interview data. The draft questionnaire was revised on the basis of participant feedback, quantitative psychometric results, and consultation with clinical experts. RESULTS: A total of 21 participants were interviewed (CE concept elicitation, n = 12; CD cognitive debriefing, n = 17; n = 8 completed both). Mean participant age (SD) was 59.7 (8.7) years and 76.2% were white. The de novo SIADT-PC measure consists of 27 items: 11 symptoms (e.g., fatigue, hot flashes, and erectile dysfunction), 2 long-term symptoms (e.g., weight gain), 10 impacts (e.g., impacts on physical activities and relationships), and 4 related to mode of administration (i.e., injection-site reactions). Items were assessed with a 5-point verbal rating scale, with answer choices that capture frequency or severity. CONCLUSIONS: Once fully validated, this de novo measure may be used in clinical studies and clinical practice to assess hormone therapy-related symptoms and impacts, enabling physicians to identify timely and appropriate interventions.

PROX1 drives neuroendocrine plasticity and liver metastases in prostate cancer.

With the widespread use of anti-androgen therapy, such as abiraterone and enzalutamide, the incidence of neuroendocrine prostate cancer (NEPC) is increasing. NEPC is a lethal form of prostate cancer (PCa), with a median overall survival of less than one year after diagnosis. In addition to the common bone metastases seen in PCa, NEPC exhibits characteristics of visceral metastases, notably liver metastasis, which serves as an indicator of a poor prognosis clinically. Key factors driving the neuroendocrine plasticity of PCa have been identified, yet the underlying mechanism behind liver metastasis remains unclear. In this study, we identified PROX1 as a driver of neuroendocrine plasticity in PCa, responsible for promoting liver metastases. Mechanistically, anti-androgen therapy alleviates transcriptional inhibition of PROX1. Subsequently, elevated PROX1 levels drive both neuroendocrine plasticity and liver-specific transcriptional reprogramming, promoting liver metastases. Moreover, liver metastases in PCa induced by PROX1 depend on reprogrammed lipid metabolism, a disruption that effectively reduces the formation of liver metastases.