Drug Interactions between Androgen Receptor Axis-Targeted Therapies and Antithrombotic Therapies in Prostate Cancer: Delphi Consensus.

Background/Objectives: Abiraterone acetate, apalutamide, darolutamide, and enzalutamide, which make up the androgen receptor axis-targeted therapies (ARATs) drug class, are commonly used in the management of prostate cancer. Many patients on ARATs also receive oral antithrombotic therapy (i.e., anticoagulants or antiplatelets). The concomitant use of ARATs and antithrombotic therapies creates the potential for clinically relevant drug-drug interactions, but the literature regarding the actual consequences of these interactions, and guidance for co-prescribing, is limited. We assembled a multidisciplinary panel of experts and provided them with clinical information derived from a comprehensive literature review regarding the drug-drug interactions between ARATs and antithrombotic therapies. Methods: A three-stage modified electronic Delphi process was used to gather and consolidate opinions from the panel. Each stage consisted of up to three rounds of voting to achieve consensus on which ARAT/antithrombotic therapy drug pairs warrant attention, the possible clinical consequences of drug-drug interactions, and suggested actions for management. Results: The panel achieved consensus to avoid 11 ARAT/antithrombotic therapy drug pairs and modify therapy for eight pairs. Assessments relied heavily on pharmacokinetic data and extrapolation from drug-drug interaction studies of similarly metabolized drugs. Conclusions: This e-Delphi process highlights the need for further research into the clinical impact of ARAT/antithrombotic drug interactions. Nonetheless, the suggested actions aim to provide clinicians with a practical framework for therapeutic decision making.

Targeting PLOD2 suppresses invasion and metastatic potential in radiorecurrent prostate cancer.

Background: Metastatic relapse of prostate cancer after radiotherapy is a significant cause of prostate cancer-related morbidity and mortality. PLOD2 is a mediator of invasion and metastasis that we identified as being upregulated in our highly aggressive radiorecurrent prostate cancer cell line. Methods: Patient dataset analysis was conducted using a variety of prostate cancer cohorts. Prostate cancer cell lines were treated with siRNA, or the drug PX-478 prior to in vitro invasion, migration, or in vivo chick embryo (CAM) extravasation assay. Protein levels were detected by western blot. For RNA analysis, RNA sequencing was conducted on PLOD2 knockdown cells and validated by qRT-PCR. Results: PLOD2 is a negative prognostic factor associated with biochemical relapse, driving invasion, migration, and extravasation in radiorecurrent prostate cancer. Mechanistically, HIF1α upregulation drives PLOD2 expression in our radiorecurrent prostate cancer cells, which is effectively inhibited by HIF1α inhibitor PX-478 to reduce invasion, migration, and extravasation. Finally, the long non-coding RNA LNCSRLR acts as a promoter of invasion downstream of PLOD2. Conclusions: Together, our results demonstrate for the first time the role of PLOD2 in radiorecurrent prostate cancer invasiveness, and point towards its potential as a therapeutic target to reduce metastasis and improve survival outcomes in prostate cancer patients.

Correlates and predictors of sarcopenia among men with metastatic castrate-resistant prostate cancer.

INTRODUCTION: Sarcopenia is a predictor of clinical outcomes in men with metastatic castrate-resistant prostate cancer (mCRPC); however, correlates and predictors of sarcopenia are poorly understood in this population. The aim of this study was to examine correlates and predictors of sarcopenia in men with mCRPC prior to treatment. METHODS: A secondary analysis of an observational study was performed. Participants were receiving care for mCRPC at the Princess Margaret Cancer Centre. Sarcopenia was assessed prior to treatment and was defined as the combination of low grip strength (<35.5 kg), low gait speed (<0.8 m/s), and computed tomography-derived low muscle mass or density. Participants' sociodemographic and clinical characteristics, comorbidity information, and clinically relevant blood markers were collected prior to treatment and were used to identify correlates and predictors of sarcopenia through Spearman correlations and multivariable logistic regression, respectively. RESULTS: In total, 110 men had complete data on sarcopenia measures and were included in the analysis. Sarcopenia was identified in 30 (27.3%) participants. Pre-treatment sarcopenia was moderately correlated with dependence in one or more instrumental activities of daily living (IADLs) (r=0.412), Vulnerable Elders Survey-13 (r=0.404), and a lower hemoglobin (r=0.407 per 10 g/L decrease). In adjusted logistic regression, dependence in one or more IADLs (odds ratio [OR] 4.37, 95% confidence interval [CI] 1.37-13.86, p=0.012), and a 10 g/L decrease in hemoglobin (OR 1.70, 95% CI 1.13-2.57, p=0.012) were significantly associated with sarcopenia. CONCLUSIONS: In settings where assessment of sarcopenia is not feasible, evaluation of IADLs and hemoglobin may be used to identify high-risk patients that can benefit from supportive care strategies aiming to improve muscle mass and function.

Pembrolizumab plus Abiraterone Acetate and Prednisone in Patients with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Results from KEYNOTE-365 Cohort D.

BACKGROUND AND OBJECTIVE: Abiraterone acetate (abiraterone) plus prednisone is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Our aim was to evaluate the efficacy and safety of pembrolizumab plus abiraterone in mCRPC. METHODS: In cohort D of the phase 1b/2 KEYNOTE-365 study (NCT02861573), patients were chemotherapy-naïve, had disease progression ≤6 mo before screening, and had either not received prior next-generation hormonal agents for mCRPC or had received prior enzalutamide for mCRPC and had disease progression or became intolerant to enzalutamide. Patients received pembrolizumab 200 mg intravenously every 3 wk plus abiraterone 1000 mg orally once daily and prednisone 5 mg orally twice daily. The primary endpoints were safety, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review (BICR). Secondary endpoints included radiographic progression-free survival (rPFS) according to Prostate Cancer Clinical Trials Working Group 3-modified RECIST v1.1 by BICR and overall survival (OS). KEY FINDINGS AND LIMITATIONS: For the 103 patients who were treated, median follow-up was 28 mo (interquartile range 26-31). The confirmed PSA response rate was 56% (58/103 patients). The ORR for patients with RECIST v1.1-measurable disease was 16% (6/37 patients). Median rPFS was 15 mo (95% confidence interval 9.2-22) and median OS was 30 mo (95% confidence interval 23-not reached); the estimated 24-mo OS rate was 58%. In total, 91% of patients experienced treatment-related adverse events, and 39% experienced grade 3-5 events. Grade 3/4 elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) was observed in 12% and 6.8% of patients, respectively. One patient died due to treatment-related myasthenic syndrome. Study limitations include the single-arm design. CONCLUSIONS: Pembrolizumab plus abiraterone and prednisone demonstrated antitumor activity and acceptable safety in patients with chemotherapy-naïve mCRPC. Higher incidence of grade 3/4 elevated ALT/AST occurred than was reported for the individual agents. PATIENT SUMMARY: For patients with metastatic castratation-resistant prostate cancer, the drug combination of pembrolizumab plus abiraterone and prednisone showed antitumor activity and acceptable safety.

Tolerability of Olaparib Combined with Abiraterone in Patients with Metastatic Castration-resistant Prostate Cancer: Further Results from the Phase 3 PROpel Trial.

BACKGROUND: The PROpel study (NCT03732820) demonstrated a statistically significant progression-free survival benefit with olaparib plus abiraterone versus placebo plus abiraterone in the first-line metastatic castration-resistant prostate cancer (mCRPC) setting, irrespective of homologous recombination repair mutation status. OBJECTIVE: We report additional safety analyses from PROpel to increase clinical understanding of the adverse-event (AE) profiles of olaparib plus abiraterone versus placebo plus abiraterone. DESIGN, SETTING, AND PARTICIPANTS: A randomised (1:1), double-blind, placebo-controlled trial was conducted at 126 centres in 17 countries (October 2018-January 2020). Patients had mCRPC and no prior systemic mCRPC treatment. INTERVENTION: Olaparib (300 mg bid) or placebo with abiraterone (1000 mg od) plus prednisone/prednisolone (5 mg bid). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The data cut-off date was July 30, 2021. Safety was assessed by AE reporting (Common Terminology Criteria for Adverse Events v4.03) and analysed descriptively. RESULTS AND LIMITATIONS: The most common AEs (all grades) for olaparib plus abiraterone versus placebo plus abiraterone were anaemia (46.0% vs 16.4%), nausea (28.1% vs 12.6%), and fatigue (27.9% vs 18.9%). Grade ≥3 anaemia occurred in 15.1% versus 3.3% of patients in the olaparib plus abiraterone versus placebo plus abiraterone arm. The incidences of the most common AEs for olaparib plus abiraterone peaked early, within 2 mo, and were managed typically by dose modifications or standard medical practice. Overall, 13.8% versus 7.8% of patients discontinued treatment with olaparib plus abiraterone versus placebo plus abiraterone because of an AE; 3.8% versus 0.8% of patients discontinued because of anaemia. More venous thromboembolism events were observed in the olaparib plus abiraterone arm (any grade, 7.3%; grade ≥3, 6.8%) than in the placebo plus abiraterone arm (any grade, 3.3%; grade ≥3, 2.0%), most commonly pulmonary embolism (6.5% vs 1.8% for olaparib plus abiraterone vs placebo plus abiraterone). CONCLUSIONS: Olaparib plus abiraterone has a manageable and predictable safety profile. PATIENT SUMMARY: The PROpel trial showed that in patients who had not received any previous treatment for metastatic castration-resistant prostate cancer, olaparib combined with abiraterone was more effective in delaying progression of the disease than abiraterone alone. Most side effects caused by combining olaparib with abiraterone could be managed with supportive care methods, by pausing olaparib administration for a short period of time and/or by reducing the dose of olaparib.

Mainstream Model of Genetic Testing for Prostate Cancer at a Large Tertiary Cancer Centre.

BACKGROUND: An estimated 20% to 30% of men with advanced prostate cancer carry a mutation in DNA damage repair genes, of which half are estimated to be germline. Eligibility criteria for germline genetic testing expanded significantly for Ontario patients in May 2021 and many centers adopted a "mainstream" model, defined as oncologist-initiated genetic testing. METHODS: We conducted a retrospective chart review to report on the first-year mainstream experience of a large tertiary oncologic center, the Sunnybrook Odette Cancer Centre. All patients who underwent mainstream at the discretion of their treating physician were included. A subset underwent somatic profiling as part of clinical trial screening. Descriptive statistics were used to report baseline clinicopathologic characteristics and treatments received. RESULTS: Between May 1, 2021, and May 30, 2022, 174 patients with prostate cancer underwent mainstream germline genetic testing with a 19-gene panel. Median age was 75 (IQR 68-80), and 82% of patients were diagnosed with either de novo metastatic or high-risk localized prostate adenocarcinoma. Fourteen patients (8%; 95% CI 4%-12%) were found to have a deleterious germline mutation, including pathogenic or likely pathogenic variants in BRCA1/2, ATM, CHEK2, PMS2, RAD51C, HOXB13, and BRIP1. Forty-nine patients (28%; 95% CI 21%-35%) were found to have a variant of uncertain significance. Thirty-four patients also had next-generation sequencing (NGS) of their somatic tissue. Among this subset, 8 of 34 (23%) had an alteration in homologous recombination repair (HRR) genes. Of the 14 patients with a germline mutation, none had a prior personal history of malignancy and 6 (43%) did not have any first- or second-degree relatives with history of prostate, pancreatic, breast, or ovarian cancer. CONCLUSION: We report on the real-world characteristics of prostate cancer patients who underwent mainstream germline genetic testing. Personal history and family history of cancer cannot reliably stratify patients for the presence of pathogenic germline variants.

TOward a comPrehensive supportive Care intervention for Older men with metastatic Prostate cancer (TOPCOP3): A pilot randomized controlled trial and process evaluation.

INTRODUCTION: Current management of metastatic prostate cancer (mPC) includes androgen receptor axis-targeted therapy (ARATs), which is associated with substantial toxicity in older adults. Geriatric assessment and management and remote symptom monitoring have been shown to reduce toxicity and improve quality of life in patients undergoing chemotherapy, but their efficacy in patients being treated with ARATs has not been explored. The purpose of this study is to examine whether these interventions, alone or in combination, can improve treatment tolerability and quality of life (QOL) for older adults with metastatic prostate cancer on ARATs. MATERIALS AND METHODS: TOPCOP3 is a multi-centre, factorial pilot clinical trial coupled with an embedded process evaluation. The study includes four treatment arms: geriatric assessment and management (GA + M); remote symptom monitoring (RSM); geriatric assessment and management plus remote symptom monitoring; and usual care and will be followed for six months. The aim is to recruit 168 patients between two cancer centres in Toronto, Canada. Eligible participants will be randomized equally via REDCap. Participants in all arms will complete a comprehensive baseline assessment upon enrollment following the Geriatric Core dataset, as well as follow-up assessments at 1.5, 3, 4.5, and 6 months. The co-primary outcomes will be grade 3-5 toxicity and QOL. Toxicities will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. QOL will be measured by patient self-reporting using the EuroQol 5 dimensions of health questionnaire. Secondary outcomes include fatigue, insomnia, and depression. Finally, four process evaluation outcomes will also be observed, namely feasibility, fidelity, and acceptability, along with implementation barriers and facilitators. DISCUSSION: Data will be collected to observe the effects of GA + M and RSM on QOL and toxicities experienced by older adults receiving ARATs for metastatic prostate cancer. Data will also be collected to help the design and conduct of a definitive multicentre phase III randomized controlled trial. This study will extend supportive care interventions for older adults with cancer into new areas and inform the design of larger trials. TRIAL REGISTRATION: The trial is registered at clinicaltrials.gov (registration number: NCT05582772).

177Lu-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer: A Review of the Evidence and Implications for Canadian Clinical Practice.

Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer and a therapeutic target. Lutetium-177 (177Lu)-PSMA-617 is the first radioligand therapy to be approved in Canada for use in patients with metastatic castration-resistant prostate cancer (mCRPC). As this treatment represents a new therapeutic class, guidance regarding how to integrate it into clinical practice is needed. This article aims to review the evidence from prospective phase 2 and 3 clinical trials and meta-analyses of observational studies on the use of 177Lu-PSMA-617 in prostate cancer and discuss how Canadian clinicians might best apply these data in practice. The selection of appropriate patients, the practicalities of treatment administration, including necessary facilities for treatment procedures, the assessment of treatment response, and the management of adverse events are considered. Survival benefits were observed in clinical trials of 177Lu-PSMA-617 in patients with progressive, PSMA-positive mCRPC who were pretreated with androgen receptor pathway inhibitors and taxanes, as well as in taxane-naïve patients. However, the results of ongoing trials are awaited to clarify questions regarding the optimal sequencing of 177Lu-PSMA-617 with other therapies, as well as the implications of predictive biomarkers, personalized dosimetry, and combinations with other therapies.

Understanding the incidence, duration, and severity of symptoms through daily symptom monitoring among frail and non-frail older patients receiving metastatic prostate cancer treatments.

INTRODUCTION: Older adults with metastatic prostate cancer (mPC) experience high symptom burden associated with treatment. Frailty may exacerbate treatment toxicity. The aim of this study was to explore short-term treatment toxicity in patients with metastatic prostate cancer. MATERIALS AND METHODS: Older adults with metastatic prostate cancer starting chemotherapy, androgen-receptor-axis targeted therapies, or radium-223 participated in a prospective, multicentre, observational study. Participants self-reported symptoms daily using the Edmonton Symptom Assessment System for one treatment cycle via internet or telephone. The most common moderate-to-severe symptoms (score≥4), their duration, and the proportion of participants who experienced improvements in symptom severity (score<4) after reporting moderate-to-severe symptoms at baseline were determined using descriptive statistics. Once-weekly symptom questionnaires were administered and analyzed using linear mixed effect models. Symptom incidence, duration, and frailty associations were assessed using t-tests and chi-square tests. RESULTS: Ninety participants completed the study (mean age=77 years [standard deviation=6.1], 42% frail [Vulnerable Elders Survey≥3]). The most common moderate-to-severe symptoms across cohorts were fatigue (46.8%), insomnia (42.9%), poor wellbeing (41.2%), pain (37.5%), and decreased appetite (37.1%). Poor wellbeing had a higher incidence in frail participants (62.5% in frail vs. 31.4% in non-frail, p=0.039). Symptom duration varied across cohorts and between frail and non-frail participants. Among participants who reported moderate-to-severe symptoms at baseline, no more than 15% improved in any symptom. There were statistically significant improvements in weekly symptoms for fatigue, decreased appetite, and insomnia in the chemotherapy cohort only. DISCUSSION: Limitations include a short follow-up duration, lack of a control group, and few radium-223 participants. Regular symptom monitoring can help clinicians understand temporal patterns and durations of symptoms and inform supportive care approaches.

Extended Safety and Tolerability of Darolutamide for Nonmetastatic Castration-Resistant Prostate Cancer and Adverse Event Time Course in ARAMIS.

BACKGROUND: Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) are usually asymptomatic and seek treatments that improve survival but have a low risk of adverse events. Darolutamide, a structurally distinct androgen receptor inhibitor (ARi), significantly reduced the risk of metastasis and death versus placebo in ARAMIS. We assessed the extended safety and tolerability of darolutamide and the time-course profile of treatment-emergent adverse events (TEAEs) related to ARis and androgen-suppressive treatment. PATIENTS AND METHODS: Patients with nmCRPC were randomized 2:1 to darolutamide (n = 955) or placebo (n = 554). After trial unblinding, patients could receive open-label darolutamide. Tolerability and TEAEs were assessed every 16 weeks. Time interval-specific new and cumulative event rates were determined during the first 24 months of the double-blind period. RESULTS: Darolutamide remained well tolerated during the double-blind and open-label periods, with 98.8% of patients receiving the full planned dose. The incidence of TEAEs of interest in the darolutamide group was low and ≤2% different from that in the placebo group, except for fatigue. When incidences were adjusted for exposure time, there were minimal differences between the darolutamide double-blind and double-blind plus open-label periods. The rate of initial onset and cumulative incidence of grade 3/4 TEAEs and serious TEAEs were similar for darolutamide and placebo groups over 24 months. CONCLUSION: Extended treatment with darolutamide was well tolerated and no new safety signals were observed. Most ARi-associated and androgen-suppressive treatment-related TEAEs occurred at low incidences with darolutamide, were similar to placebo, and showed minimal increase over time with continued treatment. TRIAL NUMBER: ClinicalTrials.gov identifier NCT02200614.

Prostate Cancer Liver Metastasis: An Ominous Metastatic Site in Need of Distinct Management Strategies.

Prostate cancer liver metastasis (PCLM), seen in upwards of 25% of metastatic castration-resistant PC (mCRPC) patients, is the most lethal site of mCRPC with a median overall survival of 10-14 months. Despite its ominous prognosis and anticipated rise in incidence due to longer survival with contemporary therapy, PCLM is understudied. This review aims to summarize the existing literature regarding the risk factors associated with the development of PCLM, and to identify areas warranting further research. A literature search was conducted through Ovid MEDLINE from 2000 to March 2023. Relevant subject headings and text words were used to capture the following concepts: "Prostatic Neoplasms", "Liver Neoplasms", and "Neoplasm Metastasis". Citation searching identified additional manuscripts. Forty-one studies were retained for detailed analysis. The clinical risk factors for visceral/liver metastasis included <70 years, ≥T3 tumor, N1 nodal stage, de novo metastasis, PSA >20 ng/mL, and a Gleason score >8. Additional risk factors comprised elevated serum AST, LDH or ALP, decreased Hb, genetic markers like RB1 and PTEN loss, PIK3CB and MYC amplification, as well as numerous PC treatments either acting directly or indirectly through inducing liver injury. Further research regarding predictive factors, early detection strategies, and targeted therapies for PCLM are critical for improving patient outcomes.

Pembrolizumab and Enzalutamide in Patients with Abiraterone Acetate-Pretreated Metastatic Castration-Resistant Prostate Cancer: Cohort C of the Phase 1b/2 KEYNOTE-365 Study.

BACKGROUND: Limited responses have been observed in patients treated with enzalutamide after disease progression on abiraterone for metastatic castration-resistant prostate cancer (mCRPC), but androgen receptor signaling impacts T-cell function. OBJECTIVE: To evaluate the efficacy and safety of pembrolizumab plus enzalutamide in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: Patients in cohort C of the phase 1b/2 KEYNOTE-365 study, who received ≥4 wk of treatment with abiraterone acetate in the prechemotherapy mCRPC state and experienced treatment failure or became drug-intolerant, were included. INTERVENTION: Pembrolizumab 200 mg intravenously every 3 wk plus enzalutamide 160 mg orally once daily. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoints were safety, the confirmed prostate-specific antigen (PSA) response rate, and the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1 on blinded independent central review (BICR). Secondary endpoints included radiographic progression-free survival (rPFS) on BICR and overall survival (OS). RESULTS AND LIMITATIONS: A total of 102 patients received pembrolizumab plus enzalutamide. Median follow-up was 51 mo (interquartile range 37-56). The confirmed PSA response rate was 24% (95% confidence interval [CI] 16-33%). The confirmed ORR was 11% (95% CI 2.9-25%; 4/38 patients; two complete responses). Median rPFS was 6.0 mo (95% CI 4.1-6.3). Median OS was 20 mo (95% CI 17-24). Treatment-related adverse events (TRAEs) occurred in 94 patients (92%); grade 3-5 TRAEs occurred in 44 patients (43%). The incidence of treatment-related rash was higher with combination therapy than expected from the safety profile of each drug. One patient (1.0%) died of a TRAE (cause unknown). Study limitations include the single-arm design. CONCLUSIONS: Pembrolizumab plus enzalutamide had limited antitumor activity in patients who received prior abiraterone treatment without previous chemotherapy for mCRPC, with a safety profile consistent with the individual profiles of each agent. PATIENT SUMMARY: Pembrolizumab plus enzalutamide showed limited antitumor activity and manageable safety in patients with metastatic castration-resistant prostate cancer. The KEYNOTE-365 trial is registered on ClinicalTrials.gov as NCT02861573.

Prevalence and Prognostic Implications of PSA Flares during Radium-223 Treatment among Men with Metastatic Castration Resistant Prostate Cancer.

Radium-223 (Ra233) prolongs the survival of men with symptomatic bone-predominant metastatic castration-resistant prostate cancer (mCRPC). However, prostate-specific antigen (PSA) response patterns are not closely associated with Ra223 therapy outcomes. Herein, we sought to analyze the impact of Ra223-induced PSA flares on patient outcome. Using a retrospective cohort study of Ra223 treatment in four Ontario/Canada cancer centres, we identified 134 patients grouped into sub-cohorts according to distinct PSA response patterns: (i) initial PSA flare followed by eventual PSA decline; (ii) PSA response (≥30% PSA decrease within 12 weeks of treatment); and (iii) PSA non-response. We analyzed patient characteristics and outcome measures, including overall survival (OS), using the Kaplan-Meier method and log-rank testing. PSA flares were observed in 27 (20.2%), PSA responses in 11 (8.2%), and PSA non-responses in 96 (71.6%) patients. Amongst PSA flare patients, 12 presented with post-flare PSA decreases below baseline and 15 with PSA decreases below the flare peak but above baseline. Although only six flare patients achieved ≥30% PSA decreases below baseline, the median OS of all flare patients (16.8 months, 95% CI 14.9-18.7) was comparable to that of PSA responders and non-responders (p = 0.349). In summary, around 20% of mCRPC patients experience Ra223-induced PSA flares, whose outcome is similar to that of men with or without PSA responses. Further studies are needed regarding suitable biochemical surrogate markers of response to Ra223.

Predicting Patterns of Distant Metastasis in Breast Cancer Patients following Local Regional Therapy Using Machine Learning.

Up to 30% of breast cancer (BC) patients will develop distant metastases (DM), for which there is no cure. Here, statistical and machine learning (ML) models were developed to estimate the risk of site-specific DM following local-regional therapy. This retrospective study cohort included 175 patients diagnosed with invasive BC who later developed DM. Clinicopathological information was collected for analysis. Outcome variables were the first site of metastasis (brain, bone or visceral) and the time interval (months) to developing DM. Multivariate statistical analysis and ML-based multivariable gradient boosting machines identified factors associated with these outcomes. Machine learning models predicted the site of DM, demonstrating an area under the curve of 0.74, 0.75, and 0.73 for brain, bone and visceral sites, respectively. Overall, most patients (57%) developed bone metastases, with increased odds associated with estrogen receptor (ER) positivity. Human epidermal growth factor receptor-2 (HER2) positivity and non-anthracycline chemotherapy regimens were associated with a decreased risk of bone DM, while brain metastasis was associated with ER-negativity. Furthermore, non-anthracycline chemotherapy alone was a significant predictor of visceral metastasis. Here, clinicopathologic and treatment variables used in ML prediction models predict the first site of metastasis in BC. Further validation may guide focused patient-specific surveillance practices.

Implementing geriatric assessment and management for older Canadians with cancer: Adherence to and satisfaction with the intervention, results of the 5C study.

INTRODUCTION: Geriatric assessment and management (GAM) is recommended by professional organizations and recently several randomized controlled trials (RCTs) demonstrated benefits in multiple health outcomes. GAM typically leads to one or more recommendations for the older adult on how to optimize their health. However, little is known about how well recommendations are adhered to. Understanding these issues is vital to designing GAM trials and clinical programs. Therefore, the aim of this study was to examine the number of GAM recommendations made and adherence to and satisfaction with the intervention in a multicentre RCT of GAM for older adults with cancer. MATERIALS AND METHODS: The 5C study was a two-group parallel RCT conducted in eight hospitals across Canada. Each centre kept a detailed recruitment and retention log. The intervention teams documented adherence to their recommendations. Medical records were also reviewed to assess which recommendations were adhered to. Twenty-three semi-structured interviews were conducted with 12 members of the intervention teams and 11 oncology team members to assess implementation of the study and the intervention. RESULTS: Of the 350 participants who were enrolled, 173 were randomized to the intervention arm. Median number of recommendations was seven. Mean adherence to recommendations based on the GAM was 69%, but it varied by type of recommendation, ranging from 98% for laboratory tests to 28% for psychosocial/psychiatry oncology referrals. There was no difference in the number of recommendations or non-adherence to recommendations by sex, level of frailty, or functional status. Oncologists and intervention team members were satisfied with the study implementation and intervention delivery. DISCUSSION: Adherence to recommendations was variable. Adherence to laboratory investigations and further imaging were generally high but much lower for recommendations regarding psychosocial support. Further collaborative work with older adults with cancer is needed to understand how to optimize the intervention to be consistent with patient goals, priorities, and values to ensure maximal impact on health outcomes.

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

INTRODUCTION: Physical 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 METHODS: Adults 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. RESULTS: Of 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. DISCUSSION: Changes 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.

The impact of sarcopenia on clinical outcomes in men with metastatic castrate-resistant prostate cancer.

INTRODUCTION: Sarcopenia is common in men with metastatic castrate-resistant prostate cancer (mCRPC) and has been largely assessed opportunistically through computed-tomography (CT) scans, excluding measures of muscle function. Therefore, the impact of a comprehensive assessment of sarcopenia on clinical outcomes in men with mCRPC is poorly understood. The objectives of this study were to comprehensively assess sarcopenia through CT scans and measures of muscle function and examine its impact on severe treatment toxicity, time to first emergency room (ER) visit, disease progression, and overall mortality in men initiating chemotherapy or androgen receptor-targeted axis (ARAT) therapy for mCRPC. METHODS: This was a secondary analysis of a prospective observational study of men with mCRPC at the Princess Margaret Cancer Centre between July 2015-May 2021. Participants were classified as sarcopenic if they had CT-based low muscle mass or low muscle density, a grip strength and gait speed score of <35.5kg and <0.8m/s, respectively, prior to treatment initiation. The impact of sarcopenia on severe treatment toxicity was assessed using multivariable logistic regression. Multivariable Cox regression models were used to determine the impact of sarcopenia on risk of visiting the ER, prostate-specific antigen progression, radiographic progression, and overall mortality. RESULTS: A total of 110 men (mean age: 74.6) were included in the analysis. At baseline, 30 (27.3%) were classified as sarcopenic. Sarcopenia was a significant predictor of severe toxicity (aOR = 6.26, 95%CI = 1.17-33.58, P = 0.032) and ER visits (aHR = 4.41, 95%CI = 1.26-15.43, p = 0.020) in men initiating ARAT but not in men initiating chemotherapy. Sarcopenia was also a predictor of radiographic progression (aHR = 2.39, 95%CI = 1.06-5.36, p = 0.035) and overall mortality (aHR = 2.44, 95%CI = 1.17-5.08, p = 0.018) regardless of treatment type. CONCLUSIONS: Baseline sarcopenia predicts radiographic progression and overall mortality in men with mCRPC regardless of the type of treatment and may also predict severe treatment toxicity and ER visits in men initiating ARAT.

Impact of treatment on elder-relevant physical function and quality of life outcomes in older adults with metastatic castration-resistant prostate cancer.

INTRODUCTION: Understanding physical function (PF) and quality of life (QoL) treatment effects are important in treatment decision-making for older adults with cancer. However, data are limited for older men with metastatic castration-resistant prostate cancer (mCRPC). We evaluated the effects of treatment on PF and QoL in older men with mCRPC. MATERIALS AND METHODS: Men aged 65+ with mCRPC were enrolled in this multicenter prospective observational study. PF measures included instrumental activities of daily living, grip strength, chair stands, and gait speed. QoL measures included fatigue, pain, mood, and Functional Assessment of Cancer Therapy (FACT)-General total and sub-scale scores. Outcomes were collected at baseline, three, and six months. Linear mixed effects regression models were used to examine PF and QoL differences over time across various treatment cohorts. RESULTS: We enrolled 198 men starting chemotherapy (n = 71), abiraterone (n = 37), enzalutamide (n = 67), or radium-223 (n = 23). At baseline, men starting chemotherapy had worse measures of PF, QoL, pain, and mood than the other groups. Over time, all PF measures remained stable, pain improved, but functional wellbeing (FWB) and mood worsened significantly for all cohorts. However, change over time in all outcomes was not appreciably different between treatment cohorts. Worst-case sensitivity analyses identified attrition (ranging from 22 to 42% by six months) as a major limitation of our study, particularly for the radium-223 cohort. DISCUSSION: FWB and mood were most prone to deterioration over time, whereas pain improved with treatment. Although patients initiating chemotherapy had worse baseline PF and QoL, chemotherapy was not associated with significantly greater worsening over time compared to other common therapies for mCRPC. These findings may assist in treatment discussions with patients. However, given the modest sample size, attrition, and timeframe of follow-up, the impact of treatment on PF and QoL outcomes in this setting requires further study, particularly for radium-223.