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Some patients with metastatic prostate cancer carry a pathogenic germline variant (PV) in a gene, that is mainly associated with an increased risk of breast cancer in women. If they test positive for such a PV, prostate cancer patients are encouraged to disclose the genetic test result to relatives who are at risk in case the carrier status changes the relatives' medical care. Our study aimed to investigate how men who learned they carry a PV in BRCA1, BRCA2, PALB2, CHEK2 or ATM disclosed their carrier status to at-risk relatives and to assess the possible psychological burden for the carrier and their perception of the burden for relatives. In total, 23 men with metastatic prostate cancer carrying a PV completed the IRI questionnaire about family communication; 14 also participated in a semi-structured interview. Patients felt highly confident in discussing the genetic test result with relatives. The diagnosis of prostate cancer was experienced as a burden, whereas being informed about genetic testing results did in most cases not add to this burden. Two patients encountered negative experiences with family communication, as they considered the genetic test result to be more urgent than their relatives. This mixed-methods study shows that metastatic prostate cancer patients with a PV in genes mainly associated with increased risk of breast cancer feel well-equipped to communicate about this predisposition in their families. Carriers felt motivated to disclose their genetic test result to relatives. Most of them indicated that the disclosure was not experienced as a psychological burden. [ABSTRACT FROM AUTHOR]

In this retrospective observational study we focused on the failure of prostate specific membrane antigenradioligand therapy. Therefore we evaluated the correlation between PSMA uptake on positron emission tomography/computed tomography and PSMA protein expression on IHC on fresh biopsy leasion of mCRPC-patients. Secondly we PSMA uptake on PET/CT, protein expression of PSMA and Ki67 were associated with the therapeutic outcome of PSMA-RLT. Introduction: Prostate specific membrane antigen (PSMA) directed radioligand therapy (RLT) is a novel therapy for metastatic castration-resistant prostate cancer (mCRPC) patients. However, it is still poorly understood why approximately 40% of the patients does not respond to PSMA-RLT. The aims of this study were to evaluate the pretreatment PSMA expression on immunohistochemistry (IHC) and PSMA uptake on PET/CT imaging in mCRPC patients who underwent PSMA-RLT. We correlated these parameters and a cell proliferation marker (Ki67) to the therapeutic efficacy of PSMA-RLT. Patients and Methods: In this retrospective study, mCRPC patients who underwent PSMARLT were analyzed. Patients biopsies were scored for immunohistochemical Ki67 expression, PSMA staining intensity and percentage of cells with PSMA expression. Moreover, the PSMA tracer uptake of the tumor lesion(s) and healthy organs on PET/CT imaging was assessed. The primary outcome was to evaluate the association between histological PSMA protein expression of tumor in pre-PSMA-RLT biopsies and the PSMA uptake on PSMA PET/CT imaging of the biopsied lesion. Secondary outcomes were to assess the relationship between PSMA expression and Ki67 on IHC and the progression free survival (PFS) and overall survival (OS) following PSMA-RLT. Results: In total, 22 mCRPC patients were included in this study. Nineteen (86%) patients showed a high and homogenous PSMA expression of > 80% on IHC. Three (14%) patients had low PSMA expression on IHC. Although there was limited PSMA uptake on PET/CT imaging, these 3 patients had lower PSMA uptake on PET/CT imaging compared to the patients with high PSMA expression on IHC. Yet, no correlation was found between PSMA uptake on PET/CT imaging and PSMA expression on IHC (SUVmax: R 2 = 0.046 and SUVavg: R 2 = 0.036). The 3 patients had a shorter PFS compared to the patients with high PSMA expression on IHC (HR: 4.76, 95% CI: 1.14-19.99; P = .033). Patients with low Ki67 expression had a longer PFS and OS compared to patients with a high Ki67 expression (HR: 0.40, 95% CI: 0.15-1.06; P = .013) Conclusion: The PSMA uptake on PSMA-PET/CT generally followed the PSMA expression on IHC. However, heterogeneity may be missed on PSMA-PET/CT. Immunohistochemical PSMA and Ki67 expression in fresh tumor biopsies, may contribute to predict treatment efficacy of PSMA-RLT in mCRPC patients. This needs to be further explored in prospective cohorts. [ABSTRACT FROM AUTHOR]

Simple Summary: CAPRI-3 is an observational registry on metastatic prostate cancer that uses artificial intelligence (AI) for patient identification and data collection. The aim of this study is to demonstrate the reliability and efficiency of this method. Our deliberate effort to maximize the negative predictive value of our patient-identification algorithm to rule out unsuitable candidates without manual screening was successful and reached 94.8%. Completeness and accuracy of data extraction were 92.3% or higher but were lower (up to 10%) for date fields and inaccessible data (images/pdf). The AI-driven approach, including additional manual quality control, was much faster than full manual data collection (105 vs. 300 min per patient). In conclusion, the AI-driven approach of the CAPRI-3 registry is largely reliable and timesaving but manual quality control is needed for the less reliable and inaccessible data. Background: Manual data collection is still the gold standard for disease-specific patient registries. However, CAPRI-3 uses text mining (an artificial intelligence (AI) technology) for patient identification and data collection. The aim of this study is to demonstrate the reliability and efficiency of this AI-driven approach. Methods: CAPRI-3 is an observational retrospective multicenter cohort registry on metastatic prostate cancer. We tested the patient-identification algorithm and automated data extraction through manual validation of the same patients in two pilots in 2019 and 2022. Results: Pilot one identified 2030 patients and pilot two 9464 patients. The negative predictive value of the algorithm was maximized to prevent false exclusions and reached 94.8%. The completeness and accuracy of the automated data extraction were 92.3% or higher, except for date fields and inaccessible data (images/pdf) (10–88.9%). Additional manual quality control took over 3 h less time per patient than the original fully manual CAPRI registry (105 vs. 300 min). Conclusions: The CAPRI-3 patient-identification algorithm is a sound replacement for excluding ineligible candidates. The AI-driven data extraction is largely accurate and complete, but manual quality control is needed for less reliable and inaccessible data. Overall, the AI-driven approach of the CAPRI-3 registry is reliable and timesaving. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simple Summary: Platinum-based chemotherapy and PARP inhibitors are two types of treatment that can benefit prostate cancer patients with mutations in genes that are involved in the repair of damage in the DNA. However, patients who receive one type of treatment may not respond as well to the other treatment later on. The optimal sequencing of these agents is still unclear. In this study, we looked at how 28 prostate cancer patients responded to both treatments. We found that patients generally responded best to the initially given treatment, but still over 40% of patients responded to the second treatment. We also found that the efficacy of the second given treatment was higher in the order of platinum-based chemotherapy first and PARP inhibitor second, compared to the opposite order. Patients with metastatic castration-resistant prostate cancer (mCRPC) harbouring homologous recombination repair-related gene aberrations (HRRm) can derive meaningful benefits from both platinum-based chemotherapy (PlCh) and PARP inhibitors (PARPi). Cross-resistance between these agents is well-recognised in other tumour types but data on prostate cancer is lacking. In this retrospective pre-planned study, we assessed 28 HRRm mCRPC patients who received PlCh and PARPi. Progression-free survival (PFS) on initial therapy was longer than on subsequent therapy (median 5.3 vs. 3.4 months, p = 0.016). The median PFS of PlCh was influenced by the order of agents, with 3.6 months shorter PFS after PARPi than when administered first. The median PFS of PARPi was less influenced, with 0.9 months shorter PFS after PlCh than before. In the PARPi-first subgroup, six out of 16 evaluable patients (37.5%) had a >50% PSA decline to PlCh, and two of eight (25.0%) had a radiographic response to PlCh. In the PlCh-first subgroup, 6/10 (60.0%) had a >50% PSA decline, and 5/9 (55.6%) had a radiographic response to PARPi. These data show >40% of the cohort is sensitive to a subsequent HRR-targeting agent. PlCh appears to induce less cross-resistance than PARPi. Additional data on resistance mechanisms will be crucial in defining an optimal treatment sequence in HRRm mCRPC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate-specific membrane antigen-direct radioligand therapy is a novel treatment for patients with castration-resistant prostate cancer. Yet, given the mode of action of PSMA-RLT, it is postulated that in early disease prostate cancer settings, e.g. hormone-sensitive, can also benefit from this treatment. In this retrospective study, the safety and efficacy was investigated of two PSMA-RLT schemes: monotherapy with 177Lu-PSMA and 177Lu-PSMA in combination with 225Ac-PSMA in twenty patients with early stage metastatic prostate cancer. The treatment appeared safe with limited and mainly transient side effects, also on a longer term follow-up, with encouraging efficacy for twenty early-stage metastatic prostate cancer. Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) is a novel treatment for patients with castration-resistant prostate cancer (CRPC). Given the mode of action, patients in an earlier disease stage, such as hormone-sensitive prostate cancer (HSPC), are also likely to benefit from [177Lu]Lu-PSMA- (177Lu-PSMA) or [225Ac]Ac-PSMA-radioligand treatment (225Ac-PSMA). In this retrospective study, we analyzed the safety and efficacy of PSMA-RLT in early-stage and hormone-sensitive metastatic prostate cancer patients. Methods: A retrospective study was performed in patients who received 177Lu-PSMA and/or 225Ac-PSMA with early-stage metastatic prostate cancer. The primary outcome parameter evaluated in this study was the progression-free survival (PFS) after PSMA-RLT and toxicity according to the Common Terminology Criteria for Adverse Events. Secondary outcome parameters were prostate-specific antigen (PSA) response and the date of onset of CRPC state. Results: In total, 20 patients were included of which 18 patients received 177Lu-PSMA radioligand and two patients received tandem treatment with both 177Lu-PSMA and 225Ac-PSMA radioligands. Patients received a median of 2 treatment cycles (range 1–6) and a median activity of 6.2 GBq 177Lu-PSMA per cycle (interquartile range (IQR) 5.2–7.4 GBq). PSMA-RLT was overall well-tolerated. The most common grade 1–2 side effects were xerostomia (n = 6) and fatigue (n = 8), which were only temporarily reported. One patient that received 225Ac-PSMA developed grade 3–4 bone marrow toxicity. The median PFS was 12 months (95% confidence interval (CI), 4.09–19.9 months). Seventeen (85%) patients had a ≥50% PSA response following PSMA-RLT. One patient developed CRPC 9 months following PSMA-RLT. Conclusions: In this small cohort study, PSMA-RLT appeared safe and showed encouraging efficacy for (metastasized) early-stage and hormone-sensitive prostate cancer patients. Prospective studies are awaited and should include long-term follow-up. [ABSTRACT FROM AUTHOR]

Background: In international guidelines, germline genetic testing is recommended for patients with metastatic prostate cancer. Before undergoing germline genetic testing, these patients should receive pre-test counseling. In the standard genetic care pathway, pre-test counseling is provided by a healthcare professional of a genetics department. Because the number of patients with metastatic prostate cancer is large, the capacity in the genetics departments might be insufficient. Therefore, we aim to implement so-called mainstream genetic testing in the Netherlands for patients with metastatic prostate cancer. In a mainstream genetic testing pathway, non-genetic healthcare professionals discuss and order germline genetic testing. In our DISCOVER study, we will assess the experiences among patients and non-genetic healthcare professionals with this new pathway. Methods: A multicenter prospective observational cohort study will be conducted in 15 hospitals, in different regions of the Netherlands. We developed an online training module on genetics in prostate cancer and the counseling of patients. After completion of this module, non-genetic healthcare professionals will provide pre-test counseling and order germline genetic testing in metastatic prostate cancer patients. Both non-genetic healthcare professionals and patients receive three questionnaires. We will determine the experience with mainstream genetic testing, based on satisfaction and acceptability. Patients with a pathogenic germline variant will also be interviewed. We will determine the efficacy of the mainstreaming pathway, based on time investment for non-genetic healthcare professionals and the prevalence of pathogenic germline variants. Discussion: This study is intended to be one of the largest studies on mainstream genetic testing in prostate cancer. The results of this study can improve the mainstream genetic testing pathway in patients with prostate cancer. Trial registration: The study is registered in the WHO's International Clinical Trials Registry Platform (ICTRP) under number NL9617. [ABSTRACT FROM AUTHOR]

Simple Summary: An emerging group of advanced cancer patients are living long term on systemic treatment. However, studies examining the psychosocial impact of this prolonged cancer treatment trajectory are scarce. This scoping review summarizes findings on these psychosocial issues, as well as the terminology used to refer to these patients. Prominent psychosocial outcomes included uncertainty, anxiety, and fear of disease progression or death, hope, loss and worries about loved ones and changes in social life. These themes were not extensively investigated in research using validated psychological questionnaires. More quantitative research in this area should be conducted to further understand these psychological constructs. A large variety of terms used to refer to the patient group was observed, which calls for a uniform definition to better address this specific patient group in research and in practice. By identifying key themes and gaps in the literature, directions for future research and clinical practice can be provided. (1) Background: Studies examining the psychosocial impact of living long term on systemic treatment in advanced cancer patients are scarce. This scoping review aimed to answer the research question "What has been reported about psychosocial factors among patients living with advanced cancer receiving life-long systemic treatment?", by synthesizing psychosocial data, and evaluating the terminology used to address these patients; (2) Methods: This scoping review was conducted following the five stages of the framework of Arksey and O'Malley (2005); (3) Results: 141 articles published between 2000 and 2021 (69% after 2015) were included. A large variety of terms referring to the patient group was observed. Synthesizing qualitative studies identified ongoing uncertainty, anxiety and fear of disease progression or death, hope in treatment results and new treatment options, loss in several aspects of life, and worries about the impact of disease on loved ones and changes in social life to be prominent psychosocial themes. Of 82 quantitative studies included in the review, 76% examined quality of life, 46% fear of disease progression or death, 26% distress or depression, and 4% hope, while few studies reported on adaptation or cognitive aspects. No quantitative studies focused on uncertainty, loss, or social impact; (4) Conclusion and clinical implications: Prominent psychosocial themes reported in qualitative studies were not included in quantitative research using specific validated questionnaires. More robust studies using quantitative research designs should be conducted to further understand these psychological constructs. Furthermore, the diversity of terminology found in the literature calls for a uniform definition to better address this specific patient group in research and in practice. [ABSTRACT FROM AUTHOR]

Background: Real-world disease models spanning multiple treatment lines can provide insight into the (cost) effectiveness of treatment sequences in clinical practice. Objective: Our objective was to explore whether a disease model based solely on real-world data (RWD) could be used to estimate the effectiveness of treatments for patients with castration-resistant prostate cancer (CRPC) that could then be suitably used in a cost-effectiveness analysis. Methods: We developed a patient-level simulation model using patient-level data from the Dutch CAPRI registry as input parameters. Time to event (TTE) and overall survival (OS) were estimated with multivariate regression models, and type of event (i.e., next treatment or death) was estimated with multivariate logistic regression models. To test internal validity, TTE and OS from the simulation model were compared with the observed outcomes in the registry. Results: Although patient characteristics and survival outcomes of the simulated data were comparable to those in the observed data (median OS 20.6 vs. 19.8 months, respectively), the disease model was less accurate in estimating differences between treatments (median OS simulated vs. observed population: 18.6 vs. 17.9 [abiraterone acetate plus prednisone], 24.0 vs. 25.0 [enzalutamide], 20.2 vs. 18.7 [docetaxel], and 20.0 vs. 23.8 months [radium-223]). Conclusions: Overall, the disease model accurately approximated the observed data in the total CRPC population. However, the disease model was unable to predict differences in survival between treatments due to unobserved differences. Therefore, the model is not suitable for cost-effectiveness analysis of CRPC treatment. Using a combination of RWD and data from randomised controlled trials to estimate treatment effectiveness may improve the model. [ABSTRACT FROM AUTHOR]

Background: Molecular tumour boards (MTB) optimally match oncological therapies to patients with genetic aberrations. Prostate cancer (PCa) is underrepresented in these MTB discussions. This study describes the impact of routine genetic profiling and MTB referral on the outcome of PCa patients in a tertiary referral centre.Methods: All PCa patients that received next-generation sequencing results and/or were discussed at an MTB between Jan 1, 2017 and Jan 1, 2020 were included. Genetically matched therapies (GMT) in clinical trials or compassionate use were linked to actionable alterations. Response to these agents was retrospectively evaluated.Results: Out of the 277 genetically profiled PCa patients, 215 (78%) were discussed in at least one MTB meeting. A GMT was recommended to 102 patients (47%), of which 63 patients (62%) initiated the GMT. The most recommended therapies were PARP inhibitors (n = 74), programmed death-(ligand) 1 inhibitors (n = 21) and tyrosine kinase inhibitors (n = 19). Once started, 41.3% had a PFS of ≥6 months, 43.5% a PSA decline ≥50% and 38.5% an objective radiographic response.Conclusion: Recommendation for a GMT is achieved in almost half of the patients with advanced prostate cancer, with GMT initiation leading to durable responses in over 40% of patients. These data justify routine referral of selected PCa patients to MTB's. [ABSTRACT FROM AUTHOR]

Aims: To assess whether the exposure–response relation for abiraterone is different in pre‐chemotherapy patients compared to post‐chemotherapy patients with metastatic castration‐resistant prostate cancer (mCRPC). Methods: Data were collected from three clinical studies in mCRPC patients treated with abiraterone acetate. Cox regression analysis was used to determine the relation between abiraterone exposure and survival (progression‐free survival [PFS] and overall survival [OS]). An interaction term was used to test whether chemotherapy pretreatment was an effect modifier. To investigate the effect of the previously defined exposure threshold of 8.4 ng/mL on survival, Kaplan–Meier analysis was used. Results: In total, 98 mCRPC patients were included, of which 78 were pre‐chemotherapy and 20 were post‐chemotherapy patients. Chemotherapy pretreatment in mCRPC setting appears to be an effect modifier. In pre‐chemotherapy patients, no significant association between abiraterone exposure and survival was observed (HR 0.68 [95% CI 0.42–1.10], P =.12 and HR 0.85 [95% CI 0.46–1.60], P =.61, PFS and OS, respectively) and no longer survival was seen for patients with an abiraterone exposure above the predefined threshold. In contrast, a significant association was seen in post‐chemotherapy patients (HR 0.30 [95% CI 0.12–0.74], P =.01 and HR 0.38 [95% CI 0.18–0.82] P =.01, PFS and OS, respectively), with an increased survival when exposed above this threshold. Conclusion: Chemotherapy pretreatment in mCRPC setting modifies the abiraterone exposure–response relation. No relation between abiraterone exposure and survival was seen for pre‐chemotherapy patients. Therefore, potentially lower doses can be used in this setting to prevent overtreatment and reduce financial toxicity. [ABSTRACT FROM AUTHOR]

Patients with metastatic castration resistant prostate cancer (mCRPC) are at risk of developing symptomatic skeletal events (SSEs). We retrospectively investigated incidence of SSEs and the use of bone health agents (BHA) in a contemporary, treated bone metastatic CRPC population. Although patients with early BHA use had lower incidence rates of SSE and longer SSE-free survival, there was an undertreatment with BHAs in our population. Especially in patients with risk factors as pain and/or opioid use and prior SSE, timely initiation of BHAs is recommended. Background: Patients with metastatic castration resistant prostate cancer (mCRPC) are at risk of symptomatic skeletal events (SSE). Bone health agents (BHA, ie bisphosphonates and denosumab) and new life-prolonging drugs (LPDs) can delay SSEs. The aim of this study is to investigate the use of BHAs in relation to SSEs in treated real-world mCRPC population. Patients and Methods: We included patients from the CAPRI registry who were treated with at least one LPD and diagnosed with bone metastases prior to the start of first LPD (LPD1). Outcomes were SSEs (external beam radiation therapy (EBRT) to the bone, orthopedic surgery, pathologic fracture or spinal cord compression) and SSE-free survival (SSE-FS) since LPD1. Results: One-thousand nine hundred and twenty-three patients were included with a median follow-up from LPD1 of 16.7 months. Fifty-two percent (n = 996) started BHA prior or within 4 weeks after the start of LPD1 (early BHA). In total, 41% experienced at least one SSE. SSE incidence rate was 0.29 per patient year for patients without BHA and 0.27 for patients with early BHA. Median SSE-FS from LPD1 was 12.9 months. SSE-FS was longer in patients who started BHA early versus patients without BHA (13.2 vs. 11.0 months, P = .001). Conclusion: In a real-world population we observed an undertreatment with BHAs, although patients with early BHA use had lower incidence rates of SSEs and longer SSE-FS. This finding was irrespective of type of SSE and presence of risk factors. In addition to LPD treatment, timely initiation of BHAs is recommended in bone metastatic CRPC-patients with both pain and/or opioid use and prior SSE. [ABSTRACT FROM AUTHOR]

Homologous recombination repair deficiency (HRD) is observed in 10% of patients with castrate-resistant prostate cancer (PCa). Preliminary data suggest that HRD-PCa might be more responsive to immune checkpoint inhibitors (ICIs). In this study, we compare the tumor immune landscape and peripheral T cell receptor (TCR) repertoire of patients with and without HRD-PCa to gain further insight into the immunogenicity of HRD-PCa. Immunohistochemistry was performed on tumor tissue of 81 patients, including 15 patients with HRD-PCa. Peripheral TCR sequencing was performed in a partially overlapping cohort of 48 patients, including 16 patients with HRD-PCa. HRD patients more frequently had intratumoral CD3+, CD3+CD8-FoxP3- or Foxp3+ TILs above median compared to patients without DNA damage repair alterations (DDRwt; CD3+ and Foxp3+: 77% vs 35%, p = .013; CD3+CD8-FoxP3-: 80% vs 44%, p = .031). No significant difference in CD8+ TILs or PD-L1 expression was observed. In peripheral blood, HRD patients displayed a more diverse TCR repertoire compared to DDRwt patients (p = .014). Additionally, HRD patients shared TCR clusters with low generation probability, suggesting patient-overlapping T cell responses. A pooled analysis of clinical data from 227 patients with molecularly characterized PCa suggested increased efficacy of ICIs in HRD-PCa. In conclusion, patients with HRD-PCa display increased TIL density and an altered peripheral TCR repertoire. Further research into the efficacy of ICIs and the presence of shared neoantigens in HRD-PCa is warranted. [ABSTRACT FROM AUTHOR]

Background: Intensive end-of-life care (i.e., the overuse of treatments and hospital resources in the last months of life), is undesirable since it has a minimal clinical benefit with a substantial financial burden. The aim was to investigate the care in the last three months of life (end-of-life [EOL]) in castration-resistant prostate cancer (CRPC). Methods: Castration-resistant prostate cancer registry (CAPRI) is an investigator-initiated, observational multicenter cohort study in 20 hospitals retrospectively including patients diagnosed with CRPC between 2010 and 2016. High-intensity care was defined as the initiation of life-prolonging drugs (LPDs) in the last month, continuation of LPD in last 14 days, >1 admission, admission duration ≥14 days, and/or intensive care admission in last three months of life. Descriptive and binary logistic regression analyses were performed. Results: High-intensity care was experienced by 41% of 2429 patients in the EOL period. Multivariable analysis showed that age (odds ratio [OR] 0.98, 95% confidence interval [CI] 0.97–0.99), performance status (OR 0.57, 95% CI 0.33–0.97), time from CRPC to EOL (OR 0.98, 95% CI 0.97–0.98), referral to a medical oncologist (OR 1.99, 95% CI 1.55–2.55), prior LPD treatment (>1 line OR 1.72, 95% CI 1.31–2.28), and opioid use (OR 1.45, 95% CI 1.08–1.95) were significantly associated with high-intensity care. Conclusions: High-intensity care in EOL is not easily justifiable due to high economic cost and little effect on life span, but further research is awaited to give insight in the effect on patients' and their caregivers' quality of life. [ABSTRACT FROM AUTHOR]

Purpose: External Beam Radiotherapy (EBRT) techniques dramatically changed over the years. This may have affected the risk of radiation-induced second primary cancers (SPC), due to increased irradiated low dose volumes and scatter radiation. We investigated whether patterns of SPC after EBRT have changed over the years in prostate cancer (PCa) survivors. Materials and Methods: PCa survivors diagnosed between 1990-2014 were selected from the Netherlands Cancer Registry. Patients treated with EBRT were divided in three time periods, representing 2-dimensional Radiotherapy (RT), 3-dimensional conformal RT (3D-CRT), and the advanced RT (AdvRT) era. Standardized incidence ratios (SIR) and absolute excess risks (AER) were calculated to estimate relative and excess absolute SPC risks. Sub-hazard ratios (sHRs) were calculated to compare SPC rates between the EBRT and prostatectomy cohort. SPCs were categorized by subsite and anatomic region. Results: PCa survivors who received EBRT had an increased risk of developing a solid SPC (SIR=1.08; 1.05-1.11), especially in patients aged <70 years (SIR=1.13; 1.09-1.16). Pelvic SPC risks were increased (SIR=1.28; 1.23-1.34), with no obvious differences between the three EBRT eras. Non-pelvic SPC were only significantly increased in the AdvRT era (SIR=1.08; 1.02-1.14), in particular for the 1-5 year follow-up period. Comparing the EBRT cohort to the prostatectomy cohort, again an increased pelvic SPC risk was found for all EBRT periods (sHRs= 1.61, 1.47-1.76). Increased non-pelvic SPC risks were present for all RT eras and highest for the AdvRT period (sHRs=1.17, 1.06-1.29). Conclusion: SPC risk in patients with EBRT is increased and remained throughout the different EBRT eras. The risk of developing a SPC outside the pelvic area changed unfavorably in the AdvRT era. Prolonged follow-up is needed to confirm this observation. Whether this is associated with increased irradiated low-dose volumes and scatter, or other changes in clinical EBRT practice, is the subject of further research. [ABSTRACT FROM AUTHOR]

Background: The BULLSEYE trial is a multicenter, open-label, randomized controlled trial to test the hypothesis if 177Lu-PSMA is an effective treatment in oligometastatic hormone-sensitive prostate cancer (oHSPC) to prolong the progression-free survival (PFS) and postpone the need for androgen deprivation therapy (ADT). The original study protocol was published in 2020. Here, we report amendments that have been made to the study protocol since the commencement of the trial.Changes in Methods and Materials: Two important changes were made to the original protocol: (1) the study will now use 177Lu-PSMA-617 instead of 177Lu-PSMA-I&T and (2) responding patients with residual disease on 18F-PSMA PET after the first two cycles are eligible to receive additional two cycles of 7.4 GBq 177Lu-PSMA in weeks 12 and 18, summing up to a maximum of 4 cycles if indicated. Therefore, patients receiving 177Lu-PSMA-617 will also receive an interim 18F-PSMA PET scan in week 4 after cycle 2. The title of this study was modified to; "Lutetium-177-PSMA in Oligo-metastatic Hormone Sensitive Prostate Cancer" and is now partly supported by Advanced Accelerator Applications, a Novartis Company.Conclusions: We present an update of the original study protocol prior to the completion of the study. Treatment arm patients that were included and received 177Lu-PSMA-I&T under the previous protocol will be replaced.Trial Registration: ClinicalTrials.gov NCT04443062 . First posted: June 23, 2020. [ABSTRACT FROM AUTHOR]

Purpose: Radium-223 is a life-prolonging therapy for castration-resistant prostate cancer (CRPC) patients with symptomatic bone metastases. However, validated biomarkers for response monitoring are lacking. The study aim was to investigate whether early alkaline phosphatase (ALP) dynamics after the first radium-223 injection can act as surrogate marker for overall survival (OS). Methods: This retrospective multicenter study included consecutive CRPC patients treated with radium-223. Patients were divided into four subgroups based on baseline ALP level (normal/elevated) and early ALP response, defined as ≥10% ALP decrease after the first radium-223 injection. Primary endpoint was OS among the subgroups. Secondary endpoints included time to first skeletal-related event, time to ALP progression, and treatment completion rate. Results: A total of 180 patients were included for analysis. Median OS was 13.5 months (95% confidence interval 11.5–15.5). Patients with elevated baseline ALP without ALP response after the first injection had significantly worse OS when compared to all other patients (median OS 7.9 months versus 15.7 months, hazard ratio 2.56, 95% confidence interval 1.73–3.80, P < 0.001). Multivariate analysis demonstrated that elevated baseline ALP without ALP response after the first injection, the number of prior systemic therapies, baseline LDH level, and baseline ECOG performance status were prognostic factors of OS. Patients with elevated baseline ALP without ALP response after the first injection had significantly shorter times to ALP progression and first skeletal-related event, and more frequently discontinued radium-223 therapy when compared to other patients. Conclusion: Early treatment–induced changes in ALP after one radium-223 injection were associated with OS in metastatic CRPC patients. [ABSTRACT FROM AUTHOR]

Uptake of decision aids (DAs) in daily routine is low, resulting in limited knowledge about successful DA implementation at a large scale. We assessed implementation rates after multi-regional implementation of three different prostate cancer (PCa) treatment DAs and patient-perceived barriers and facilitators to use a DA. Thirty-three hospitals implemented one out of the three DAs in routine care. Implementation rates for each DA were calculated per hospital. After deciding about PCa treatment, patients (n = 1033) completed a survey on pre-formulated barriers and facilitators to use a DA. Overall DA implementation was 40%. For each DA alike, implementation within hospitals varied from incidental (< 10% of eligible patients receiving a DA) to high rates of implementation (> 80%). All three DAs were evaluated positively by patients, although concise and paper DAs yielded higher satisfaction scores compared with an elaborate online DA. Patients were most satisfied when they received the DA within a week after diagnosis. Pre-formulated barriers to DA usage were experienced by less than 10% of the patients, and most patients confirmed the facilitators. Many patients received a DA during treatment counseling, although a wide variation in uptake across hospitals was observed for each DA. Most patients were satisfied with the DA they received. Sustained implementation of DAs in clinical routine requires further encouragement and attention. [ABSTRACT FROM AUTHOR]

Background: Maintaining health-related quality of life (HRQoL) is highly desirable during systemic therapies for patients with castration-resistant prostate cancer (CRPC). Patient-reported outcome measures (PROs) were studied in our phase IIa trial on cellular-based immunotherapy with dendritic cells (DC). Methods: We treated 21 chemo-naive asymptomatic or minimally symptomatic patients with CRPC with maximally three cycles of DC vaccinations (ClinicalTrials.gov, NCT02692976). Here, we report the impact of DC vaccination on HRQoL. PROs were assessed using the EORTC-QLQ-C30, the EORTC-QLQ-PR25, Checklist Individual Strength (CIS20-R), and Beck Depression Inventory Primary Care questionnaires. Short-term and long-term vaccine-related effects on HRQoL were studied. Results: Questionnaires were collected at baseline (n=20), week 6 (n=19), week 12 (n=18), week 24 (n=13), week 50 (n=8) and week 100 (n=2). No clinically relevant differences in symptom-related outcome, functioning-related outcome, and Global Health Status were observed directly after the first cycle of DC vaccinations (week 6) and at follow-up (week 12) compared to baseline. HRQoL remained high throughout the vaccination cycle and six weeks afterward. In radiographic non-progressive patients, who continued DC vaccination, high HRQoL scores were observed up to one and two years after study enrolment. Conclusions: Patients with asymptomatic or minimally symptomatic CRPC show high HRQoL throughout DC-based immunotherapy. This is a clinically relevant finding in this older-aged patient population with advanced prostate cancer. [ABSTRACT FROM AUTHOR]

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Aim: Timing of radium-223 (Ra-223) in metastatic castration-resistant prostate cancer (mCRPC) remains challenging due to alternative options and short window of opportunity. Methods: Ra-223 treated patients in the CAPRI-registry were included. Outcomes were evaluated based on treatment line of Ra-223. Results: Out of 285 patients, 49% received Ra-223 in line ≥3. 51% completed six Ra-223 injections and 34% had a symptomatic skeletal event after first Ra-223 without differences between subgroups. After correction of known prognostic factors Ra-223 in line ≥3 (HR: 3.267; 95% CI: 1.689-6.317; p < 0.01) remained associated with worse OS. Conclusion: In the Netherlands, Ra-223 was mainly started as second or third mCRPC-treatment in 2014-2018. Later timing of Ra-223 did affect OS, but not treatment completion and occurrence of symptomatic skeletal events. [ABSTRACT FROM AUTHOR]

For the treatment choice of localized prostate cancer, effective patient decision aids have been developed. The implementation of decision aids in routine care, however, lags behind. Main known barriers are lack of confidence in the tool, lack of training on its use, lack of resources and lack of time. A new implementation strategy addresses these barriers. Using this implementation strategy, the implementation rate of a decision aid was measured in eight hospitals and questionnaires were filled out by 24 care providers and 255 patients. The average implementation rate was 60 per cent (range 31%–100%). Hardly any barriers remained for care providers. Patients who did not use the decision aid appeared to be more unwilling than unable to use the decision aid. By addressing known barriers, that is, informing care providers on the effectiveness of the decision aid, providing instructions on its use, embedding it in the existing workflow and making it available free of charge, a successful implementation of a prostate cancer decision aid was reached. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the study is to investigate the influence of patient characteristics, age and body mass index (BMI), on pharmacokinetics of enzalutamide, and to study the relationships between drug exposure and enzalutamide efficacy and toxicity, in mCRPC patients.Methods: Data were collected in a longitudinal cohort study (ANDROPS) and a prospective observational study (ILUMINATE), both in mCRPC patients treated with enzalutamide. To investigate the influence of age and BMI on exposure, enzalutamide and N-desmethylenzalutamide levels were compared by ANOVA. To investigate the relation of exposure versus time to progression (TTP), the sum plasma levels were divided into quartiles and compared by Kaplan-Meier analysis. To assess the relation of exposure with fatigue, plasma levels in patients experiencing fatigue vs. no fatigue were compared by and independent t test.Results: Data of 68 mCRPC patients were included for analysis. Plasma levels were not different for age or BMI. No difference in TTP between both studies was observed (383 days (95% CI 287-859), and 567 days (95% CI 351-NR), p = 0.36). Kaplan-Meier analysis of quartiles of sum levels showed no difference for TTP. Fatigue was reported by 22 patients, no difference in sum plasma levels was observed between patients with and without fatigue.Conclusions: We observed that age and BMI did not influence systemic exposure in patients treated with enzalutamide. No relation of exposure with efficacy or fatigue was observed. Further research using enzalutamide at a lower dose is needed to understand the relation of enzalutamide exposure and fatigue. [ABSTRACT FROM AUTHOR]

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Aims Metastatic castration-resistant prostate cancer (mCRPC) patients are generally older patients with several co-morbidities and are therefore at increased risk of complications due to drug-drug interactions (DDIs). We assessed the prevalence of potential DDIs in a cohort of mCRPC patients treated with enzalutamide. Methods We conducted a retrospective review of pharmacy records to retrieve individual drug histories of mCRPC patients who started enzalutamide therapy in a tertiary care setting. Potential DDIs were analysed using two international drug interaction compendia: Lexicomp® and Micromedex®, and the Dutch drug database. Two potential pharmacodynamic DDIs were analysed. Results A total of 105 records were evaluated for potential DDIs with enzalutamide. Of 205 different co-medications, 56 were flagged by at least one of the three compendia: Lexicomp, Micromedex and the Dutch drug database flagged for potential DDIs in 85%, 54% and 32%, respectively. Eighty-five per cent of DDIs were classified as major. The median number of co-medications per patient was 11 (range 1-26). The median (range) number of interactions per patient was 4 (0-10), 1 (0-5) and 0 (0-2) for Lexicomp, Micromedex and the Dutch drug database, respectively. In 23% and 45% of all patients, a potential DDI was found with PPIs and CNS depressants, respectively. Conclusions A high prevalence of potential DDIs was found. The inclusion and grading of potential DDIs was highly variable between the three drug interaction compendia. Physicians, nurses and pharmacists should be aware of this potential problem, which might require intensive monitoring or alternative treatment strategies to prevent suboptimal treatment of the co-morbidities in patients treated with enzalutamide. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy of enzalutamide (Enz) as fourth-or fifth-line treatment in men with metastasized castration-resistant prostate cancer (mCRPC), by analyzing a retrospective cohort of heavily pretreated patients. Methods: We evaluated toxicity, overall survival (OS), progression-free survival (PFS) and time to prostate-specific antigen (PSA) progression data from 47 CRPC patients treated with fourth- or fifth-line Enz. Results: All patients were treated with docetaxel and abiraterone acetate and 42 patients (89%) with cabazitaxel. The median age of the patients was 69 years (IQR, 63-73.5), 79% had bone metastases, 55% had lymph node metastases, and 17% had visceral metastases. The median duration of Enz treatment was 12.0 weeks (IQR, 8.3-20.4), and 11 patients (23%) responded to Enz (maximum PSA decline ≥50%). In general, Enz was well tolerated, with the most frequently reported adverse events being fatigue and nausea. The median OS was 40.1 weeks (95% CI, 25.4-61.4), the median PFS was 12.1 weeks (95% CI, 9.9-14.0) and the median time to PSA progression was 15.7 weeks (95% CI, 14.0-28.7). Conclusions: Analysis of this retrospective cohort suggests that Enz is well tolerated and that there is a 23% response rate in heavily pretreated CRPC patients, which is comparable with third-line treatment outcomes. [ABSTRACT FROM AUTHOR]

Two novel oral drugs that target androgen signaling have recently become available for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Abiraterone acetate inhibits the synthesis of the natural ligands of the androgen receptor, whereas enzalutamide directly inhibits the androgen receptor by several mechanisms. Abiraterone acetate and enzalutamide appear to be equally effective for patients with mCRPC pre- and postchemotherapy. Rational decision making for either one of these drugs is therefore potentially driven by individual patient characteristics. In this review, an overview of the pharmacokinetic characteristics is given for both drugs and potential and proven drug-drug interactions are presented. Additionally, the effect of patient-related factors on drug disposition are summarized and the limited data on the exposure-response relationships are described. The most important pharmacological feature of enzalutamide that needs to be recognized is its capacity to induce several key enzymes in drug metabolism. The potency to cause drug-drug interactions needs to be addressed in patients who are treated with multiple drugs simultaneously. Abiraterone has a much smaller drug-drug interaction potential; however, it is poorly absorbed, which is affected by food intake, and a large interpatient variability in drug exposure is observed. Dose reductions of abiraterone or, alternatively, the selection of enzalutamide, should be considered in patients with hepatic dysfunction. Understanding the pharmacological characteristics and challenges of both drugs could facilitate decision making for either one of the drugs. [ABSTRACT FROM AUTHOR]

Background: PCA3 and ERG are mRNA-based prostate cancer (PCa) specific biomarkers that can be detected in urine. However, urine is a complex substrate that can be separated in several fractions. In this study we compared the levels of PCa-specific biomarkers (PCA3 and ERG) and KLK3 as prostate-specific reference gene in three urine substrates-whole urine, urinary sediment (cell pellet) and exosomes-and evaluated the influence of performing a digital rectal examination (DRE) prior to urine sampling. Methods: First-voided urine samples were prospectively obtained before and after DRE from 29 men undergoing prostate biopsies. The urine was separated in whole urine, cell pellet and exosomes and the biomarker levels were measured with RT-qPCR. Results: PCa was identified in 52% (15/29) of men. In several samples the mRNA levels were below the analytical limit of detection (BDL). The biomarker levels were highest in whole urine and significantly higher after DRE in all substrates. In PCa patients higher levels of PCA3 and ERG were found in all urine substrates after DRE compared to non-PCa patients. Conclusions: This is the first study in which urinary PCa-specific biomarker levels were compared directly in three separate urine fractions. These results suggest that whole urine could be the urine substrate of choice for PCa-diagnostics based on analytical sensitivity, which is reflected directly in the high informative rate. Moreover, the significant positive effect of performing a DRE prior to urine sampling is confirmed. These findings could be of influence in the development of PCa-diagnostic urine tests. [ABSTRACT FROM AUTHOR]