Background and ObjectivePain management in patients with prostate cancer receiving enzalutamide is challenging owing to its high potential for drug-drug interactions. Morphine is generally preferred because of its favorable metabolic profile, but the effect of enzalutamide on the pharmacokinetics of morphine is unclear. The objective of this study was to assess whether a drug-drug interaction exists between enzalutamide and morphine in patients with prostate cancer.MethodsIn a multicenter two-arm parallel study, 24 men with prostate cancer received morphine with enzalutamide (n = 12) and without enzalutamide (n = 12). Plasma concentrations of morphine and its active metabolite morphine-6-glucuronide were measured. Pharmacokinetic parameters were calculated using a non-compartmental analysis. Geometric mean ratios (GMR) of the area under the plasma concentration-time curves were calculated. No clinically relevant interaction was defined if 90% of the confidence interval (CI) of the GMR of morphine was within the range of 0.5-2.0.ResultsMorphine exposure was similar between both groups, with the 90% CI falling within the range of 0.5-2.0 (GMR 1.01; 90% CI 0.77-1.31). The exposure of morphine-6-glucuronide was increased with enzalutamide (GMR 1.77; 90% CI 1.43-2.17).ConclusionsThe exposure of morphine was unaffected by enzalutamide, while morphine-6-glucuronide exposure was increased. Because of the inconclusive potency of morphine-6-glucuronide and its uncertain ability to cross the blood-brain barrier, the increase is likely of modest clinical significance. Therefore, morphine and enzalutamide can be safely combined when starting at a low dose and titrated based on efficacy and tolerability.Clinical Trial RegistrationNCT05339672.

BACKGROUND: International guidelines suggest prophylactic anticoagulation for patients with cancer at high risk of venous thromboembolism (VTE). Here, we evaluated whether tumor whole-genome sequencing data may improve the selection of high-risk patients. METHODS: In a pan-cancer cohort of 3087 patients, associations of candidate clinical predictors, the germline extended 297-single nucleotide polymorphism polygenic risk score, tumor mutational characteristics, and somatic tumor mutations with VTE were estimated by calculating hazard ratios (HRs). RESULTS: During 12-month follow-up, 237 (7.7%) developed VTE. The germline extended 297-single nucleotide polymorphism score was associated with VTE (HR per point increase, 2.11 [95% CI, 1.45-3.06]), as well as the total number of somatic structural variants (HR per 1000 increase, 1.21 [95% CI, 1.07-1.37]) and 129 somatic mutations (unadjusted P<0.05), including POLR2E (HR, 3.34 [95% CI, 1.68-6.97]), PALM (HR, 3.73 [95% CI, 1.74-7.99]), TBX22 (T-box Transcription Factor 22; HR, 2.47 [95% CI, 1.40-4.35]), and ELANE (HR, 3.22 [95% CI, 1.51-6.87]). To further explore the potential of tumor whole-genome sequencing, prediction models were constructed including selected clinical predictors only (model 1), clinical predictors and germline variants (model 2), and the combination of clinical predictors, germline variants, and 14 top discriminating somatic mutations (model 3). The optimism corrected concordance index was 0.66 (95% CI, 0.62-0.69) for model 1, 0.67 (95% CI, 0.62-0.72) for model 2, and 0.77 (95% CI, 0.72-0.81) for model 3. This was significantly higher than that of the currently endorsed clinical Khorana VTE risk score (concordance index, 0.55 [95% CI, 0.51-0.59]; P<0.005). CONCLUSIONS: These data indicate that tumor whole-genome sequencing may improve VTE prediction by clinical risk scores. Validation studies to confirm these findings are needed.

Relationship between on-treatment detection of circulating tumor DNA patient outcomes

On-treatment ctDNA fraction, PSA responses and baseline genomic and clinical features

Oncoprint showing the copy number alterations, structural variants and mutations per patient at baseline

PSA protein calibration curve (A): Serial dilutions of PSA protein spotted on PVDF membrane, stained and visualized in FITC. (B): Calibration graph of PSA (pg/μm2) versus the normalized mean intensity of the spots (R2 = 0.97).

Frequency of recurrent somatic alterations compared to published cohorts

Evidence for ctDNA estimates per patient per timepoint

Changes in PSA levels between baseline and 4 weeks on-treatment in the different ctDNA kinetics groups

CASSIOPE was a real-world study of cabozantinib use as a second-line or later-line therapy for advanced renal cell carcinoma after prior VEGF-targeted therapy. Of 679 patients prospectively enrolled in Europe, second-line or later-line cabozantinib use was shown to be effective and manageable in a real-world setting and had a safety profile consistent with previous studies. Background: There is a lack of published data on real-world cabozantinib use in patients with advanced renal cell carcinoma after prior vascular endothelial growth factor (VEGF)-targeted therapy. Methods: CASSIOPE was a real- world, prospective, multicenter, non-interventional postauthorization safety study of cabozantinib in adult patients with advanced renal cell carcinoma in Europe following prior VEGF-targeted treatment (NCT03419572). Endpoints included cabozantinib utilization (dose modifications due to adverse events [AEs; primary endpoint], dose, dose modifications, and treatment duration), safety, effectiveness (progression-free survival [PFS], overall survival [OS], best overall response [BOR]), and healthcare resource utilization. Findings: Full analysis set (FAS)/safety population comprised 679 patients; 433 of these initiated cabozantinib at 60 mg/day (recommended dose) (primary safety population). Median age (FAS) was 67 (range, 29-93) years; most were male (73 0%), had clear-cell histology (85 7%), metastatic disease at cabozantinib initiation (97 8%), and prior nephrectomy (80 3%). In the primary safety population, 77 1% experienced dose modification owing to an AE. In the safety population, the median daily dose was 40 0 (range, 7 8-60 0) mg/day and the median treatment duration was 7 8 (< 0 1-15 2) months. Treatment-emergent and treatment-related AEs were experienced by 95 9% and 90 4% of patients, respectively. Median PFS (FAS) assessed by the local investigator using any method was 8 3 months, and 1-year OS rate was 74%. Approximately one-third of all patients had a BOR of partial response and 6 had a complete response. Interpretation: Second- or later-line cabozantinib was effective and manageable in a real-world setting and had a safety profile consistent with previous studies.

Per patient ctDNA fractions and PSA levels at baseline and after 4 weeks of treatment

Purpose of Research The ASSUSTENT application and the ASSIST brochure have been developed to support medication intake and symptom monitoring. This study aimed to evaluate patient experiences and the factors that are a barrier to or facilitate the use of these tools. Additionally, the effect of their use on Health-Related Quality of Life (HRQoL) and satisfaction with information about medication was also assessed. Methods An exploratory study with a mixed method design was performed. Patients starting or already using sunitinib were asked to use the application or the brochure for 6 months. They completed questionnaires about their experiences with the intervention, that is, the Satisfaction with Information about Medication scale (SIMS) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) at baseline (T0), three months (T1), and 6 months (T2) following inclusion. Patients were also asked to participate in a semi-structured interview at T2. The main study endpoint was the feasibility of the use of the application and the brochure. Results Of the 22 (65%) patients who signed the informed consent, 19 (86%) completed T0, 15 (68%) T1, and 12 (54%) T2. Twelve agreed to be interviewed. Both the application and brochure were considered user friendly and useful to manage symptoms and prepare for consultations. Patients were generally satisfied with the information about medication. The mean global HRQoL increased from 69 (T0) to 84 (T2). Conclusion As supplements to usual care, both the application and the brochure met the needs of cancer patients using sunitinib. Their use led to an increased self-efficacy in managing symptoms. The availability of the brochure adds to patient-centered care and equal access to care, and increases self-efficacy.

The current options and recent developments in the field of systemic therapy for advanced urothelial cancer (UC) patients urge the need for selection criteria to identify the most optimal therapeutic option for individual patients. The molecular makeup of tumors, including molecular subtype, tumor microenvironment composition, and gene mutations, fusions, and amplifications, has previously been correlated with a response to immune checkpoint inhibitors, erdafitinib, or enfortumab vedotin (EV) monotherapy, and may withhold potential candidate biomarkers. In this study, we aimed to stratify metastatic UC (mUC) patients based on molecular biomarkers that might be associated with a response to EV, a fibroblast growth factor receptor inhibitor, or anti-PD-(L)1, by using whole-genome DNA-sequencing and paired RNA-sequencing data of fresh-frozen metastatic tumor biopsies of 155 mUC patients. We observed that NECTIN4 amplification, FGFR2/3 mutations, and the RNA expression-based T-cell-to-stroma enrichment (TSE) score were mutually exclusive, and may therefore reflect biologically distinct tumors and sensitivity to treatments. This finding was validated in two independent bladder cohorts: the IMvigor210 study and The Cancer Genome Atlas. Stratification of patients into subgroups based on these molecular features is possible. Our data challenge the concept of a one-treatment-fits-all paradigm and support the rationale for prospective clinical trials with biomarker-guided treatment selection of mUC patients.

PSA is the most common biomarker used in the screening and monitoring of prostate cancer. However, changes in PSA do not always reflect disease dynamics in every patient, and antihormonal agents may modulate its levels without significant antitumor effects. Changes in circulating tumor cells (CTC) have been described as a more objective measure of treatment response. Differences between PSA and CTC may be explained by heterogeneity in tumor cells producing PSA. To explore this, we measured the PSA secretion from a single CTC to gain insights into the PSA secretion heterogeneity between tumor cells. CTCs were enriched using EpCAM-based immunomagnetic enrichment in diagnostic leukapheresis of 18 patients with metastatic castration-naïve prostate cancer (mCNPC) not pretreated with any therapy, including androgen deprivation therapy. Calcein+ CD45- cells were sorted by flow cytometry and deposited as single cells on a nanowell array to measure the PSA secretion after 24 hours. In nine of 18 patients, PSA secretion was detectable and observed from both prostate-specific membrane antigen-positive and prostate-specific membrane antigen-negative CTCs. In these patients, 29% to 100% (mean, 52; median, 47) of CTCs secreted PSA, with average PSA secretion levels ranging from 4 to 11.68 pg/cell (mean, 6.38 ± 2.29; median, 6.05). Notably, a strong heterogeneity in PSA secretion was observed within each patient. Our study demonstrates that CTC in mCNPC, even before therapy, produces varying amounts of PSA and often no PSA. These findings may explain the shortcomings of PSA as a biomarker for therapy response. SIGNIFICANCE:This study reveals heterogeneity in PSA secretion among individual CTCs from patients with mCNPC prior to any therapeutic intervention, thereby highlighting the limitations of PSA as a biomarker.

Prostate-specific antigen (PSA) is the most common biomarker used in the screening and monitoring of prostate cancer. However, changes in PSA do not always reflect disease dynamics in every patient, and antihormonal agents may modulate its levels without significant anti-tumor effects. Changes in Circulating Tumor Cells (CTC) have been described as a more objective measure of treatment response. Differences between PSA and CTC may be explained by heterogeneity in tumor cells producing PSA. To explore this, we measured the PSA secretion from a single CTC to gain insights into the PSA secretion heterogeneity between tumor cells. CTC were enriched using EpCAM-based immunomagnetic enrichment in Diagnostic Leukapheresis (DLA) of 18 metastatic castration naïve prostate cancer (mCNPC) patients, not pretreated with any therapy including androgen deprivation therapy. Calcein+ CD45- cells were sorted by flow cytometry and deposited as single cells on a nanowell array to measure the PSA secretion after 24 hours. In 9 out of 18 patients, PSA secretion was detectable and observed from both PSMA+ and PSMA- CTC. In these patients, 29-100% (mean 52, median 47) of CTC secreted PSA, with average PSA secretion levels ranging from 4 to 11.68 pg/cell (mean 6.38 ± 2.29, median 6.05). Notably, a strong heterogeneity in PSA secretion was observed within each patient. Our study demonstrates that CTC in mCNPC, even before therapy, produces varying amounts of PSA and often no PSA. These findings may explain the shortcomings of PSA as a biomarker for therapy response.

Baseline circulating tumor DNA fraction according to detection status at 4 weeks

BACKGROUND AND OBJECTIVE:Whether cabazitaxel or an androgen receptor pathway inhibitor (ARPI) is the optimal treatment option for poor-prognosis metastatic castration-resistant prostate cancer (mCRPC), progressing on docetaxel, remains unclear. There are limited prospective data supporting a preference for one of these treatments and few candidate biomarkers to inform individual patient management. This study aims to compare the clinical efficacy of cabazitaxel versus ARPIs in patients with poor-prognosis mCRPC who have progressed on docetaxel, and to evaluate the prognostic and predictive utility of circulating tumor DNA (ctDNA) in this treatment-refractory population. METHODS:A multicenter, open-label, phase 2b trial randomized poor-prognosis mCRPC patients to an ARPI (1000 mg abiraterone plus prednisone or 160 mg enzalutamide daily) or cabazitaxel (25 mg/m2 every 3 wk plus prednisone daily). The primary endpoint was the clinical benefit rate (CBR) at 12 wk. The secondary endpoints included radiographic progression-free survival (rPFS), overall survival (OS), and PSA50 response. Genomic analyses on plasma utilized targeted cell-free DNA sequencing at baseline, 12 wk, and progression. KEY FINDINGS AND LIMITATIONS:In total, 106 patients were randomized. The CBR at 12 wk was 62.3% (66/106), with no difference between treatments (p = 0.54). Between groups, rPFS and OS (median follow-up of 30.9 mo) were not different. PSA50 was higher in the ARPI arm (47.2%) than in the cabazitaxel arm (26.9%; p = 0.04). Prior ARPI exposure (in 37.7%) predicted inferior outcomes on ARPIs but not on cabazitaxel. Adverse events of grade ≥3 were more frequent with cabazitaxel (65.4% vs 30.2%). A high baseline ctDNA fraction correlated with reduced rPFS and OS; plasma AR copy number status was not associated with outcomes, but PTEN alterations were linked with shorter OS (hazard ratio: 1.9, multivariable p = 0.02). CONCLUSIONS AND CLINICAL IMPLICATIONS:No significant differences in CBR or time-to-event endpoints were observed between cabazitaxel and ARPIs. However, prior ARPI exposure, a higher baseline ctDNA fraction, and PTEN alterations were strongly prognostic.

Representativeness of study participants

Cell-free circulating tumor DNA (ctDNA) has emerged as a promising biomarker for response evaluation in metastatic castration-resistant prostate cancer (mCRPC). The current study evaluated the modified fast aneuploidy screening test-sequencing system (mFast-SeqS), a quick, tumor-agnostic and affordable ctDNA assay that requires a small input of DNA, to generate a genome-wide aneuploidy (GWA) score in mCRPC patients, and correlated this to matched metastatic tumor biopsies. In this prospective multicenter study, GWA scores were evaluated from blood samples of 196 mCRPC patients prior to treatment (baseline) with taxanes (docetaxel and cabazitaxel) and androgen receptor signaling inhibitors (ARSI; abiraterone and enzalutamide), and from 74 mCRPC patients at an early timepoint during treatment (early timepoint; median 21 days). Z-scores per chromosome arm were tested for their association with tumor tissue genomic alterations. We found that a high tumor load in blood (GWA(high)) at baseline was associated with poor response to ARSI [HR: 2.63 (95% CI: 1.86-3.72) P < 0.001] but not to taxanes. Interestingly, GWA(high) score at the early timepoint was associated with poor response to both ARSIs [HR: 6.73 (95% CI: 2.60-17.42) P < 0.001] and taxanes [2.79 (95% CI: 1.34-5.78) P = 0.006]. A significant interaction in Cox proportional hazards analyses was seen when combining GWA status and type of treatment (at baseline P = 0.008; early timepoint P = 0.018). In summary, detection of ctDNA in blood by mFast-SeqS is cheap, fast and feasible, and could be used at different timepoints as a potential predictor for outcome to ARSI and taxane treatment in mCRPC.

Aims Treatment with enzalutamide in prostate cancer is challenging due to its high potential for drug-drug interactions, particularly in the typically older population of patients with frequent comorbidities treated with multiple drugs, such as anticoagulants. While low molecular weight-heparin can be safely combined with enzalutamide, the safety of combining enzalutamide with more convenient oral anticoagulants remains uncertain. The objective of this study was to assess whether a drug-drug interaction exists between enzalutamide and edoxaban.Methods A prospective, multicentre, two-arm parallel study was performed in men with prostate cancer who are treated with edoxaban, with and without enzalutamide. Plasma concentrations of edoxaban were measured at steady state. Pharmacokinetic (PK) parameters were calculated using non-compartmental analysis. Geometric mean ratios (GMR) of the area under the plasma concentration time curve over one dosing interval (AUC0-24h) were calculated. No clinically relevant interaction was defined if 90% of the confidence interval (CI) of the GMR was within the range of 0.8-1.25.Results Sixteen patients with prostate cancer using edoxaban (eight patients with enzalutamide and eight patients without enzalutamide) were enrolled. The exposure of edoxaban was similar between patients treated with or without enzalutamide, however the 90% CI fell outside of the 0.8-1.25 range (AUC0-24h GMR 1.03; 90% CI 0.78-1.35).Conclusions The average exposure of edoxaban was not affected by enzalutamide. However, bioequivalence could not be established due to the broader than anticipated CI. Despite this, the larger variability in edoxaban exposure is not expected to be clinically relevant, supporting the safe co-administration of both drugs.