Treatment Of Metastatic Prostate Cancer Research Articles

Outcomes and toxicity of oral Fosfestrol in metastatic castration-resistant prostate cancer-a real-world experience.

Although there are multiple drugs approved for the treatment of metastatic castration-resistant prostate cancer (CRPC), the cost can be a limiting factor in using them in a resource-limited setting. Therefore, less expensive alternatives are the need of the hour. We have been using Fosfestrol which is a cheap and orally administered oestrogen analogue in metastatic CRPC. We carried out a retrospective study to analyse its efficacy and toxicity. A total of 65 patients received Fosfestrol during 2015-2020. The median age was 65 years (range 50-83 years). Thirty-four patients (53%) had other medical comorbidities. Skeletal-only metastasis was the commonest pattern of metastasis (n = 41, 64%) followed by skeletal with nodal metastasis (n = 15, 23%). The majority of the patients had undergone upfront surgical castration (n = 60, 93%). All the patients had adenocarcinoma and 38 patients (58%) had a high Gleason's score. Forty-one patients (63%) had a prostate-specific antigen (PSA) response (decrease of ≥50% in the PSA concentration from the pre-treatment baseline PSA value) and 54 patients (83%) had a symptomatic response. At the end of a median follow-up of 16 months, the median progression-free survival (PFS) was 8.3 months (CI 4.7-11.8) and the median overall survival (OS) was 27.5 months (CI 25.4-29.5). PSA response and prior treatment with abiraterone acetate were found to have a significant association with survival outcomes. Patients with PSA response had better median PFS and OS; while patients who have received prior abiraterone acetate therapy had worse survival outcomes. Twenty-nine patients (45%) received some form of subsequent treatment after stopping Fosfestrol. The most common oxicity observed was thrombosis (n = 9, 13%) followed by gynecomastia (n = 4, 6%). We conclude that oral Fosfestrol is a cheap and effective agent in the armamentarium against metastatic CRPC and warrants further studies in a clinical trial setting.

The Treatment of Metastatic Prostate Cancer Using Hormonal Therapy: A Narrative Review

The incidence of prostate cancer in men has increased significantly, making it one of the most prevalent malignancies in the male population. Over the past two decades, there has been a substantial shift in the approach to managing metastatic prostate cancer, with the approval of novel medications resulting from multiple pivotal phase III trials. These medications offer a range of therapeutic alternatives to patients, with varying modes of action. Despite the progress made in prostate cancer treatment, early metastases and drug resistance continue to pose significant challenges. In this narrative review, we examined the evidence regarding the effectiveness of hormone therapy in the treatment of metastatic prostate cancer, drawing on data from important clinical trials of hormonal therapy. In addition, we conducted a search of ClinicalTrials.gov to identify ongoing and upcoming trials related to metastatic and resistant prostate cancer. Finally, we present an overview of the pathophysiology of these residual effects and review relevant translational research and observational cohort studies.

AR antagonists develop drug resistance through TOMM20 autophagic degradation-promoted transformation to neuroendocrine prostate cancer

BackgroundProstate cancer(PCa) is the most commonly occurring male cancer in the USA. Abiraterone or Enzalutamide have been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC). However, the treatment-emergent neuroendocrine PCa (t-NEPC) may develop, resulting in drug resistance in about 10–17% CRPC patients. The detailed mechanisms remain unclear..MethodsThe expression correlation of TOMM20 and AR in PCa was determined by analyzing publicly available datasets, or by IHC staining in tumor specimens. The protein interaction of TOMM20 and AR was validated by co-immunoprecipitation or GST pull-down assay. The impact of TOMM20 depletion on drug sensitivity were elucidated by assays of cell proliferation, invasion, sphere formation, xenograft growth and intravenous metastasis. The intracellular ROS level was measured by flow cytometry, and the NEPC transdifferentiation and characteristics of cancer stem-like cells were validated by RNA-seq, RT-PCR and western blotting.ResultsThe protein level of TOMM20 is positively correlated with AR in PCa cells and specimens. TOMM20 protein physically interacts with AR. AR antagonists induced the protein degradation of TOMM20 through autophagy-lysosomal pathway, thereby elevating the intracellular ROS level and activating PI3K/AKT signaling pathway. When TOMM20 was depleted, PCa cells underwent EMT, acquired the characteristics of cancer stem-like cells, and developed resistance to AR antagonists. The stable depletion of TOMM20 promoted the transdifferentiation of PCa adenocarcinoma into NEPC and metastasis. Conversely, the rescue of TOMM20 re-sensitized the resistant PCa cells to AR antagonists.ConclusionsTOMM20 protein degradation induced by AR antagonists promoted the transdifferentiation of PCa to NEPC, thereby revealing a novel molecular mechanism by which AR antagonists develop drug resistance through mitochondrial outer membrane-mediated signaling pathway. These findings suggested that the decreasing or loss of TOMM20 expression in PCa tissues might become a useful predictor of PCa resistance to AR antagonists.

Darolutamide: A Review in Metastatic Hormone-Sensitive Prostate Cancer.

Darolutamide (NUBEQA®) is an oral androgen receptor inhibitor (ARi) that is approved for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy (ADT) and docetaxel. In a pivotal trial, darolutamide plus ADT and docetaxel was superior to placebo plus ADT and docetaxel in prolonging the primary endpoint of overall survival, with improvements also reported in most secondary endpoints. Treatment with darolutamide plus ADT and docetaxel was associated with a manageable tolerability profile. Furthermore, the adverse events reported with darolutamide plus ADT and docetaxel were generally consistent with the safety profiles previously reported for ADT and docetaxel. Darolutamide expands the availability of treatment options in mHSPC and may be useful as a treatment for high-volume disease (typically defined as ≥ 4 bone metastases with spread outside of the pelvis and vertebral column).

Controversies Involving the Systemic Treatment for Metastatic Prostatic Cancer

In the United States, 1987 estimates of cancer incidence by site indicate that prostatic cancer is equal to lung cancer as the first in incidence in adult males. Over 90,000 new cases are diagnosed and between 25-30,000 patients die of this disease each year. While early prostatic cancer is a surgically curable disease, the majority of patients present with widely metastatic cancer, where the main objective of treatment is palliation.

Current Trends in Chemotherapy in the Treatment of Metastatic Prostate Cancer.

Prostate cancer is the second most common cancer among men. Despite advances in diagnosis and management, prostate cancer led to more than 300,000 deaths globally in 2020. Chemotherapy is a cornerstone of therapy for advanced prostate cancer and can prolong survival of patients with both castration-sensitive and castration-resistant disease. Herein, we present a comprehensive review of the data supporting implementation of chemotherapy in the modern treatment of advanced prostate cancer, with special attention to the use of chemotherapy for aggressive variant prostate cancer (e.g., neuroendocrine prostate cancer) and the combination of chemotherapy with androgen signaling inhibitors. As the field of prostate cancer research continues to rapidly evolve yielding novel agents and treatment modalities, chemotherapy continues to play an essential role in prolonging the survival of patients with advanced and metastatic prostate cancer.

Multifunctional Nano-System for Multi-Mode Targeted Imaging and Enhanced Photothermal Therapy of Metastatic Prostate Cancer.

Prostate cancer (PCa) routinely employs magnetic resonance (MR) imaging, while metastatic PCa needs more complicated detection methods for precise localization. The inconvenience of using different methods to detect PCa and its metastases in patients and the limitations of single-mode imaging have brought great challenges to clinicians. Meanwhile, clinical treatments for metastatic PCa are still limited. Herein, we report a targeted theranostic platform of Au/Mn nanodots-luteinising hormone releasing hormone (AMNDs-LHRH) nano-system for multi-mode imaging guided photothermal therapy of PCa. The nano-system not only can simultaneously target Gonadotropin-Releasing Hormone Receptor (GnRH-R) positive PCa and its metastases for accurate preoperative CT/MR diagnosis, but also possesses fluorescence (FL) visualization navigated surgery, demonstrating its potential application in clinical cancer detection and surgery guidance. Meanwhile, the AMNDs-LHRH with promising targeting and photothermal conversion ability significantly improve the photothermal therapy effect of metastatic PCa. The AMNDs-LHRH nano-system guarantees the diagnostic accuracy and enhanced therapeutic effect, which provides a promising platform for clinical diagnosis and treatment of metastatic PCa. STATEMENT OF SIGNIFICANCE: : Accurate clinical diagnosis and treatment of prostate cancer and its metastases is challenging. A targeted theranostic platform of AMNDs-LHRH nano-system for multi-mode imaging (FL/CT/MR) guided photothermal therapy of metastatic prostate cancer has been reported. The nano-system not only can simultaneously target prostate cancer and its metastases for accurate preoperative CT/MR diagnosis, but also possesses fluorescence visualization navigated surgery, demonstrating its potential application in clinical cancer detection and surgery guidance. The nano-system with great targeting and photothermal conversion ability significantly improve the photothermal therapy effect of metastatic prostate cancer. Overall, the AMNDs-LHRH nano-system integrates tumor targeting, multi-mode imaging and enhanced therapeutic effect, which can provide an effective strategy for the clinical diagnosis and treatment of metastatic PCa.

Real-world Outcomes and Predictive Biomarkers for 177Lutetium Prostate-specific Membrane Antigen Ligand Treatment in Metastatic Castration-resistant Prostate Cancer: A European Association of Urology Young Academic Urologists Prostate Cancer Working Group Multi-institutional Observational Study

BackgroundThe European Association of Urology guidelines include the lutetium-177 (177Lu) PSMA-617 prostate-specific membrane antigen (PSMA) ligand as a therapy option for metastatic castration-resistant prostate cancer (mCRPC). A major challenge in clinical practice is to pursue a personalized treatment approach based on robust predictive biomarkers. ObjectiveTo assess the performance of 177Lu PSMA in real-world practice and to elaborate clinical biomarkers for evaluating treatment responses. Design, setting, and participantsWe conducted a retrospective observational study including 233 patients with mCRPC treated with 177Lu PSMA in eight high-volume European centers. Outcome measurements and statistical analysisBaseline characteristics and clinical parameters during and after 177Lu PSMA treatment were documented. Correlations to treatment response were analyzed using χ2 and log-rank tests, with differences between groups with and without disease progression calculated using a Mann-Whitney U test. Univariate and multivariate-adjusted hazard ratios (HRs) were measured using Cox proportional hazards models. Results and limitationsA prostate-specific antigen (PSA) decrease of ≥30% was observed in 41.7%, 63.5%, and 77.8% of patients after the first, second, and third treatment cycle, respectively. Restaging performed via PSMA positron emission tomography-computed tomography revealed that 33.7% of patients had an imaging-based response, including two patients with a complete response, while 13.4% had stable disease. The median time to progression was 5 mo and the median time until the start of a consecutive antineoplastic therapy was 8.5 mo. Of importance, a PSA decrease ≥30% after the first two cycles of 177Lu PSMA (1 cycle: p = 0.0003; 2 cycles: p = 0.004), absolute PSA after the first three cycles (1 cycle: p = 0.011; 2 cycles: p = 0.0005; 3 cycles: p = 0.002), and a PSA doubling time >6 mo (p = 0.009) were significantly correlated to treatment response. Furthermore, gamma-glutamyl transferase ≤31 U/L at the start of 177Lu PSMA therapy was correlated with 1.5 times higher risk of progression for patients without but not with visceral metastases (p = 0.046). Conclusions177Lu PSMA is an effective treatment option in mCRPC in the real-world setting. A PSA decrease ≥30% after the first two cycles is an early marker of response that can be easily implemented in clinical practice. Patient summary177Lu PSMA is a radioactive agent approved for treatment of advanced prostate cancer. We reviewed its use outside of clinical trials for patients treated at eight European centers. We found that 177Lu PSMA is an effective treatment option in real-world practice. A PSA (prostate-specific antigen) decrease of ≥30% after the first two therapy cycles is an early indicator of response to treatment and can be used in personalizing treatments for patients.

Improving treatment adherence in patients with cancer in low and middle-income countries, through digital health self-care interventions.

114 Background: The WHO notes that adherence to treatment for people living with chronic conditions, including cancer is of global concern. This poor adherence is brought about in low- and middle-income countries like Nigeria, by patient factors such as poor health literacy, overshadowing religious beliefs, and forgetfulness, as well as systemic factors like fragmented patient care due to physician burnout. The aim of this study was to evaluate the effectiveness of digital self-care interventions via CompleteHealth in improving treatment adherence in people living with cancer. Methods: This was a retrospective study done on 63 patients on treatment for metastatic castrate-resistant prostate cancer, enrolled on mDoc’s digital CompleteHealth platform between January to December 2022. Each patient was assigned a virtual health coach who provided self-care support, monitored their health metrics, encouraged regular physical activity, and maintained normal body weight. Synchronous and asynchronous digital nudges were provided via the multiple channels of the digital CompleteHealth platform such as the web app, SMS, and phone calls. The patients also had access to virtual fitness, nutrition, and emotional wellness coaches as required. Results: 56/63 patients (88%) completed their full course of 6 months of treatment. The adherence was at 78.4%, which represents the average percentage of members who refilled medication as at when due, allowing for 30 days or less between fillings. Allowing for 90 days in between fillings, adherence was at 90.5%. Conclusions: The use of digital health interventions via virtual health coaching for self-care support has been demonstrated through CompleteHealth to improve treatment adherence in patients living with cancer significantly. There is therefore a place to scale up the use of digital health coaching to further improve this statistic, as it is likely to impact treatment outcomes positively.

The STAMPEDE2 Trial: a Site Survey of Current Patterns of Care, Access to Imaging and Treatment of Metastatic Prostate Cancer

AimsThe forthcoming STAMPEDE2 trial has three comparisons in metastatic hormone-sensitive prostate cancer. We aim to determine clinical practices among STAMPEDE trial investigators for access to imaging and therapeutic choices and explore their interest in participation in STAMPEDE2. Materials and methodsThe survey was developed and distributed online to 120 UK STAMPEDE trial sites. Recipients were invited to complete the survey between 16 and 30 May 2022. The survey consisted of 30 questions in five sections on access to stereotactic ablative body radiotherapy (SABR), 177lutetium-prostate-specific membrane antigen-617 (177Lu-PSMA-617), choice of systemic therapies and use of positron emission tomography/computerised tomography and whole-body magnetic resonance imaging. ResultsFrom 58/120 (48%) sites, 64 respondents completed the survey: 55/64 (86%) respondents were interested to participate in SABR, 44/64 (69%) in 177Lu-PSMA-617 and 56/64 (87.5%) in niraparib with abiraterone comparisons; 45/64 (70%) respondents had access to bone, spine and lymph node metastases SABR delivery and 7/64 (11%) to 177Lu-PSMA-617. In addition to androgen deprivation therapy, 60/64 (94%) respondents used androgen receptor signalling inhibitors and 46/64 (72%) used docetaxel; 29/64 (45%) respondents would consider triplet therapy with androgen deprivation therapy, androgen receptor signalling inhibitors and docetaxel. Positron emission tomography/computerised tomography was available to 62/64 (97%) respondents and requested by 45/64 (70%) respondents for disease uncertainty on conventional imaging and 39/64 (61%) at disease relapse. Whole-body magnetic resonance imaging was available to 24/64 (38%) respondents and requested by 13/64 (20%) respondents in highly selected patients. In low-volume disease, 38/64 (59%) respondents requested scans at baseline and disease relapse. In high-volume disease, 29/64 (45%) respondents requested scans at baseline, best response (at prostate-specific antigen nadir) and disease relapse; 54/64 (84%) respondents requested computerised tomography and bone scan for best response assessment. ConclusionThere is noteworthy disparity in clinical practice across current study sites, however most have expressed an interest in participation in the forthcoming STAMPEDE2 trial.

Downregulation of EZH2 inhibits epithelial-mesenchymal transition in enzalutamide-resistant prostate cancer.

Androgen signaling inhibitors (ASI) have been approved for treatment of metastatic castration-resistant prostate cancer (mCRPC). However, the limited success of ASI in clinic justifies an urgent need to identify new targets and develop novel approaches for treatment. EZH2 significantly increases in prostate cancer (PCa). Little is understood, however, regarding the roles of EZH2 in Enzalutamide-resistant (EnzR) mCRPC. We firstly investigated the levels of EZH2 and the altered pathways in public database which was comprised with primary and metastatic PCa patient tumors. To elucidate the roles of EZH2 in mCRPC, we manipulated EZH2 in EnzR PCa cell lines to examine epithelial-mesenchymal transition (EMT). To dissect the underlying mechanisms, we measured the transcription levels of EMT-associated transcription factors (TFs). We found that EZH2 was highly expressed in mCRPC than that of primary PCa tumors and that EnzR PCa cells gained more EMT characteristics than those of enzalutamide-sensitive counterparts. Further, loss of EZH2-induced inhibition of EMT is independent of polycomb repressive complex 2 (PRC2). Mechanistically, downregulation of EZH2 inhibits transcription of EMT-associated TFs by repressing formation of H3K4me3 to the promotor regions of the TFs. We identified the novel roles of EZH2 in EnzR mCRPC. EnzR PCa gains more EMT properties than that of enzalutamide-sensitive PCa. Loss of EZH2-assocaited inhibition of EMT is PRC2 independent. Downregulation of EZH2 suppresses EMT by impairing formation of H3K4me3 at the promotor regions, thus repressing expression of EMT-associated TFs.

Clinical Pharmacokinetics and Pharmacodynamics of the Next Generation Androgen Receptor Inhibitor-Darolutamide.

Darolutamide is a next-generation androgen receptor signaling inhibitor (ARSI) currently approved for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC) and metastatic hormone sensitive prostate cancer (mHSPC). Studies suggest that darolutamide also has the potential to be used to treat other stages of prostate cancer (PC), suggesting that its indications will broaden in the near future. Since ARSIs show similar efficacy for the treatment of PC, pharmacokinetic properties of these drugs and patient characteristics could help physicians decide which drug to select. This review provides an overview of the pharmacokinetic and pharmacodynamic properties of darolutamide. One of the most important pharmacological advantages of darolutamide is its low brain distribution and therefore limited seizure potential and central nervous system adverse effects. In addition, darolutamide has little drug-drug interaction potential and is unlikely to alter the exposure of other cytochrome P450 or P-glycoprotein substrates. Nevertheless, it may significantly increase the exposure of breast cancer resistant protein (BCRP) substrates. The limited solubility and bioavailability of darolutamide increases when taken together with food, regardless of the fat content. Darolutamide is excessively metabolized by oxidation and glucuronidation and excreted in the urine and feces. For this reason, dose reduction is required in patients with moderate and severe renal or severe hepatic impairment. Although no exposure-response relationship was observed with darolutamide, less advanced stages of PC showed better PSA response on treatment. Overall, darolutamide has some advantageous pharmacological properties that may lead to its preferred use, when broader registered, in selected patients across different disease stages.

Cost-effectiveness analysis of 7 treatments in metastatic hormone-sensitive prostate cancer: a public-payer perspective.

Recently, several new treatment regimens have been approved for treating metastatic hormone-sensitive prostate cancer, building on androgen deprivation therapy alone. These include docetaxel androgen deprivation therapy, abiraterone acetate-prednisone androgen deprivation therapy, apalutamide androgen deprivation therapy, enzalutamide androgen deprivation therapy, darolutamide-docetaxel androgen deprivation therapy, and abiraterone-prednisone androgen deprivation therapy with docetaxel. There are no validated predictive biomarkers for choosing a specific regimen. The goal of this study was to conduct a health economic outcome evaluation to determine the optimal treatment from the US public sector (Veterans Affairs). We developed a partitioned survival model in which metastatic hormone-sensitive prostate cancer patients transitioned between 3 health states (progression free, progressive disease to castrate resistance state, and death) at monthly intervals based on Weibull survival model estimated from published Kaplan-Meier curves using a Bayesian network meta-analysis of 7 clinical trials (7208 patients). The effectiveness outcome in our model was quality-adjusted life-years (QALYs). Cost input parameters included initial and subsequent treatment costs and costs for terminal care and for managing grade 3 or higher drug-related adverse events and were obtained from the Federal Supply Schedule and published literature. Average 10-year costs ranged from $34 349 (androgen deprivation therapy) to $658 928 (darolutamide-docetaxel androgen deprivation therapy) and mean QALYs ranged from 3.25 (androgen deprivation therapy) to 4.57 (enzalutamide androgen deprivation therapy). Treatment strategies docetaxel androgen deprivation therapy, enzalutamide androgen deprivation therapy docetaxel, apalutamide androgen deprivation therapy, and darolutamide-docetaxel androgen deprivation therapy were eliminated because of dominance (ie, they were more costly and less effective than other strategies). Of the remaining strategies, abiraterone acetate-prednisone androgen deprivation therapy was the most cost-effective strategy at a willingness-to-pay threshold of $100 000/QALY (incremental cost-effectiveness ratios = $21 247/QALY). Our simulation model found abiraterone acetate-prednisone androgen deprivation therapy to be an optimal first-line treatment for metastatic hormone-sensitive prostate cancer from a public (Veterans Affairs) payer perspective.

Far from the truth: Real-world treatment patterns among newly diagnosed metastatic prostate cancer in the era of treatment intensification.

Real-world uptake of treatment intensification (TI) with novel hormonal agents (NHA) or chemotherapy as treatment of metastatic prostate cancer remains low outside of trial settings. We aim to report the prescription patterns and treatment outcomes of de novo metastatic hormone-sensitive prostate cancer (mHSPC) in a tertiary institution. This is a retrospective cohort study using real-world data from a prospectively maintained prostate cancer registry. We selected patients newly diagnosed with mHSPC from January 2016 to December 2020. Clinicopathological parameters were recorded to determine their impact on prescription patterns. In total, 585 patients with metastatic prostate cancer were identified. Prescription of NHA increased from 10.5% (2016) to 50.4% (2020), but that of chemotherapy declined. Factors associated with TI were (1) baseline health status: Charlson Comorbidity Index 0-2, ECOG 0-1, age ≤ 65, (2) disease burden: PSA (>400, CHAARTED high volume disease, p = 0.004), development of systemic complications and (3) physician factor: primary physician being uro-oncologist and medical oncologist versus general urologist. Patients with TI had a longer mean time to castration-resistant prostate cancer (45.0 vs. 32.5 months, HR 0.567, 95% CI: 0.441-0.730, p < 0.001) and overall survival (55.3 vs. 46.8 months, HR 0.612, 95% CI, 0.447-0.837, p = 0.001). This study demonstrated the trend of treatment prescription of mHSPC and factors contributing to the use of TI. TI improved mean time to CRPC and OS.

COMPARITIVE STUDY OF DENDRITIC CELL VACCINE PREPARATION WITH PRESENCE AND ABSENCE OF MALPIGHIA EMARGINATA FRUIT EXTRACT USING TUMOR RNA TRANSFECTION METHOD: A PROMISING APPROACH FOR PROSTATE CANCER

Acerola (Malpighia emarginata DC) is the richest natural source of ascorbic acid and also contains a plethora of phytonutrients such as flavonoids, anthocyanins, carotenoids, and phenolics. By using the fruits of Malpighia emarginata, are used for the treatment of cancer by inducing effective anti-tumor immunity through dendritic cells. Dendritic cells (DC) are the heterogeneous population of antigen-presenting cells that invade tumors. They play an important role in the priming and maintenance of local immunity, and their major function is diminished by some factors encountered in the local environment. For the success of cancer immunotherapy, adequate tumor-specific antigens play a very important role in inducing a tumor-specific immune response by effective delivery of these antigens. In this proposal, by using these strategies, mature and immature dendritic cells were obtained in-vitro by adding specific cytokines to monocyte cell culture containing Malpighia emarginata fruit extract in the presence of prostate-specific antigen (PSA), and their results were compared to those obtained without the presence of Malpighia emarginata fruit extract. In the prostate tumor lineage, the RNA is extracted into the cell by electroporation, and the transfection success was measured by immunocytochemistry of the PSA expression level in dendritic cells. For the comparative study of in-vitro RNA transcription, this method allows small tumors to be used for dendritic cell vaccine preparation through the activation of DC by in the presence and absence of Malpighia emarginata fruit extract and it is a promising approach for the treatment of metastatic prostate cancer.

Daily physical activity monitoring in older adults with metastatic prostate cancer on active treatment: Feasibility and associations with toxicity

IntroductionPhysical activity may be associated with cancer treatment toxicity, but generalizability to geriatric oncology is unclear. As many older adults have low levels of physical activity and technology use, this area needs further exploration. We evaluated the feasibility of daily step count monitoring and the association between step counts and treatment-emergent symptoms. Materials and MethodsAdults aged 65+ starting treatment (chemotherapy, enzalutamide/abiraterone, or radium-223) for metastatic prostate cancer were enrolled in a prospective cohort study. Participants reported step counts (measured via smartphone) and symptoms (Edmonton Symptom Assessment Scale) daily for one treatment cycle (i.e., 3–4 weeks). Embedded semi-structured interviews were performed upon completion of the study. The feasibility of daily monitoring was evaluated with descriptive statistics and thematic analysis. The predictive validity of a decline in daily steps (compared to pre-treatment baseline) for the emergence of symptoms was examined using sensitivity and positive predictive value (PPV). Associations between a 15% decline in steps and the emergence of moderate (4–6/10) to severe (7–10/10) symptoms and pain in the next 24 h were assessed using logistic regression. ResultsOf 90 participants, 47 engaged in step count monitoring (median age = 75, range = 65–88; 52.2% participation rate). Daily physical activity monitoring was found to be feasible (94% retention rate; 90.5% median response rate) with multiple patient-reported benefits including increased self-awareness and motivation to engage in physical activity. During the first treatment cycle, instances of a 15% decline in steps were common (n = 37, 78.7%), as was the emergence of moderate to severe symptoms overall (n = 40, 85.1%) and pain (n = 26, 55.3%). The predictive validity of a 15% decline in steps on the emergence of moderate to severe symptoms was good (sensitivity = 81.8%, 95% confidence interval [CI] = 68.7–95.0; PPV = 73.0%, 95% CI = 58.7–87.3), although the PPV for pain was poor (sensitivity = 77.8%, 95% CI = 58.6–97.0; PPV = 37.8%, 95% CI = 22.2–53.5). In the regression models, changes in daily physical activity were not associated with symptoms or pain. DiscussionChanges in physical activity had modest ability to predict moderate to severe symptoms overall. Although participation was suboptimal, daily activity monitoring in older adults with cancer appears feasible and may have other uses such as improving physical activity levels. Further studies are warranted.

Local Therapeutics for the Treatment of Oligo Metastatic Prostate Cancer.

Metastatic prostate cancer remains universally lethal. Although de-novo metastatic prostate cancer was historically managed with systemic therapy alone, local therapies are increasingly utilized in the early treatment of the disease, particularly in patients with oligometastatic prostate cancer (OMPC). OMPC represents an intermediate stage between clinically localized and widespread metastatic disease. Diseases classified within this stage present an opportunity for localized targeting of the disease prior to progression to widespread metastases. The purpose of this review is to discuss the contemporary and emerging local therapies for the treatment of OMPC. To date, there are three utilized forms of local therapy for OMPC: cryoablation, radiation therapy, and cytoreductive prostatectomy. Cryoablation can be utilized for the total ablation of the prostate and has shown promising results in patients with OMPC either in combination with ADT or with ADT and systemic chemotherapy. Radiation therapy along with ADT has demonstrated improvement in progression-free survival. The STAMPEDE Arm G, PEACE-1, and the HORRAD clinical trials have investigated radiation therapy for mPCa compared to standard of care versus systemic therapy with varying results. Cytoreductive radical prostatectomy (CRP) in conjunction with ADT has also been proposed in the management of OPMC with promising results from case-control and retrospective studies. Currently there are larger controlled trials investigating CRP for OPMC including the SIMCAP, LoMP, TRoMbone, SWOG 1802, IP2-ATLANTA, g-RAMPP, and FUSCC-OMPCa trials. Given the novel nature of local treatments for OPMC, treatment selection is still controversial and requires long-term follow-up and randomized clinical trials to aid patient and clinician decision making.

In brief: A new prostate cancer indication for darolutamide (Nubeqa).

The androgen receptor inhibitor darolutamide (Nubeqa – Bayer) has been approved by the FDA for use in combination with docetaxel for treatment of metastatic hormone-sensitive prostate cancer (mHSPC).

The Tyr Phenomenon: A Hypocalcemic Response in High-Volume Treatment Responders to 177Lu-Prostate-Specific Membrane Antigen Therapy.

177Lu-prostate-specific membrane antigen (PSMA) is an effective treatment for metastatic castration-resistant prostate cancer. Rarer treatment-related adverse events have not yet been described. Methods: We present case reviews of 2 men with a marked hypocalcemic osteosclerotic response to 177Lu-PSMA-I&T therapy. A clinical dataset of 177Lu-PSMA-I&T therapy was evaluated to estimate the incidence and clinical association with hypocalcemia. Results: Forty-one of the 127 men (32%) had a serum calcium drop, and 6 (5%) developed clinical hypocalcemia during 177Lu-PSMA therapy. The baseline total tumor volume was significantly higher in those who developed hypocalcemia (median, 3,249 cm3 [interquartile range, 1,856-3,852] vs. 465 [interquartile range 135-1,172]; P = 0.002). The mean prostate-specific antigen response in those with hypocalcemia was 78% (SD, 24%). Conclusion: Hypocalcemia may occur in response to 177Lu-PSMA-I&T, particularly with both high-volume bone metastases and a significant prostate-specific antigen response, and may be severe, requiring corticosteroids. Further evaluation of 177Lu-PSMA-induced hypocalcemia is required to better understand mechanisms, optimal treatments, and repercussions from any subsequent osteosclerotic response.

[Precision oncology options in urological cancers].

Advancements in the molecular genetic understanding of urological tumors have enabled the identification of numerous new therapeutic targets. Based on routinely applicable tumor sequencing, individual treatment decisions have been introduced in the context of precision oncology. This work provides an overview of the latest targeted tumor therapies in the treatment of prostate cancer, urothelial carcinoma, and renal cell carcinoma. Current studies on the administration of FGFR-inhibitors ("fibroblast growth factor receptor") in metastatic urothelial carcinoma show ahigh tumor response in patients with selected FGFR alterations. PARP-inhibitors ("Poly-[ADP-Ribose-]Polymerase") are routinely used in the treatment of metastatic prostate cancer. Patients with aBRCA mutation ("BReast CAncer gene") show high radiological response rates. Moreover, we discuss the latest results of the combination of PARP inhibitors with novel androgen receptor pathway inhibitors. In metastatic prostate cancer, there are numerous ongoing studies evaluating the promising drug targets PI3K/AKT/mTOR ("Phosphatidylinositol-3-Kinase")/AKT/mTOR ("mammalian target of rapamycine") and VEGF signaling pathways ("vascular endothelial growth factor"). AHIF-2a inhibitor ("hypoxia inducible factor") offers apromising new therapeutic option for metastatic renal cell carcinoma. Overall, molecular diagnostics to determine the right therapy for the right patient subgroup at the right time is important for uro-oncological precision medicine.