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The majority of patients with metastatic castration-resistant prostate cancer (mCRPC) will have disease progression of a uniformly fatal disease. mCRPC is driven by both activated androgen receptors and elevated intratumoural androgens; however, the current standard of care is therapy that targets a single androgen signalling mechanism. We aimed to investigate the combination treatment using apalutamide plus abiraterone acetate, each of which suppresses the androgen signalling axis in a different way, versus standard care in mCRPC. ACIS was a randomised, placebo-controlled, double-blind, phase 3 study done at 167 hospitals in 17 countries in the USA, Canada, Mexico, Europe, the Asia-Pacific region, Africa, and South America. We included chemotherapy-naive men (aged ≥18 years) with mCRPC who had not been previously treated with androgen biosynthesis signalling inhibitors and were receiving ongoing androgen deprivation therapy, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a Brief Pain Inventory-Short Form question 3 (ie, worst pain in the past 24 h) score of 3 or lower. Patients were randomly assigned (1:1) via a centralised interactive web response system with a permuted block randomisation scheme (block size 4) to oral apalutamide 240 mg once daily plus oral abiraterone acetate 1000 mg once daily and oral prednisone 5 mg twice daily (apalutamide plus abiraterone–prednisone group) or placebo plus abiraterone acetate and prednisone (abiraterone–prednisone group), in 28-day treatment cycles. Randomisation was stratified by presence or absence of visceral metastases, ECOG performance status, and geographical region. Patients, the investigators, study team, and the sponsor were masked to group assignments. An independent data-monitoring committee continually monitored data to ensure ongoing patient safety, and reviewed efficacy data. The primary endpoint was radiographic progression-free survival assessed in the intention-to-treat population. Safety was reported for all patients who received at least one dose of study drug. This study is completed and no longer recruiting and is registered with ClinicalTrials.gov, number NCT02257736. 982 men were enrolled and randomly assigned from Dec 10, 2014 to Aug 30, 2016 (492 to apalutamide plus abiraterone–prednisone; 490 to abiraterone–prednisone). At the primary analysis (median follow-up 25·7 months [IQR 23·0–28·9]), median radiographic progression-free survival was 22·6 months (95% CI 19·4–27·4) in the apalutamide plus abiraterone–prednisone group versus 16·6 months (13·9–19·3) in the abiraterone–prednisone group (hazard ratio [HR] 0·69, 95% CI 0·58–0·83; p<0·0001). At the updated analysis (final analysis for overall survival; median follow-up 54·8 months [IQR 51·5–58·4]), median radiographic progression-free survival was 24·0 months (95% CI 19·7–27·5) versus 16·6 months (13·9–19·3; HR 0·70, 95% CI 0·60–0·83; p<0·0001). The most common grade 3–4 treatment-emergent adverse event was hypertension (82 [17%] of 490 patients receiving apalutamide plus abiraterone–prednisone and 49 [10%] of 489 receiving abiraterone–prednisone). Serious treatment-emergent adverse events occurred in 195 (40%) patients receiving apalutamide plus abiraterone–prednisone and 181 (37%) patients receiving abiraterone–prednisone. Drug-related treatment-emergent adverse events with fatal outcomes occurred in three (1%) patients in the apalutamide plus abiraterone–prednisone group (2 pulmonary embolism, 1 cardiac failure) and five (1%) patients in the abiraterone–prednisone group (1 cardiac failure and 1 cardiac arrest, 1 mesenteric arterial occlusion, 1 seizure, and 1 sudden death). Despite the use of an active and established therapy as the comparator, apalutamide plus abiraterone–prednisone improved radiographic progression-free survival. Additional studies to identify subgroups of patients who might benefit the most from combination therapy are needed to further refine the treatment of mCRPC. Janssen Research & Development.

PurposeMen with localized or locally advanced prostate cancer (LPC/LAPC) are at risk of progression after radiotherapy (RT) or radical prostatectomy (RP). Using real-world data, we evaluated patient characteristics, treatment patterns, and outcomes in LPC/LAPC.MethodsOptum claims and electronic health records (EHR) data from January 2010 to December 2021 were queried for men with LPC/LAPC who received primary RT, RP, or androgen deprivation therapy alone within 180 days after diagnosis. Survival outcomes were analyzed using descriptive statistics and Kaplan–Meier curves. Real-world overall survival (rwOS) was compared in patients with and without evidence of disease (i.e., disease recurrence, metastasis, diagnosis of castration-resistant PC) at defined time points.Results61,772 and 62,361 men in claims and EHR cohorts met the inclusion criteria. Median follow-up was 719 and 901 days, respectively. Most men received primary RT (51.0% claims, 35.0% EHR) or RP (39.4% claims, 53.8% EHR). Survival was greatest among men treated with RP, followed by RT. Adjusted for age and comorbidity, rwOS was shorter among men with evidence of disease within 1, 3, 4, and 5 years after primary treatment than those without at the same time points.ConclusionReal-world claims and EHR data show that survival among men with LPC/LAPC differs by primary treatment and time point of disease recurrence thereafter. Poor outcomes in men with LPC/LAPC who progress early indicate an unmet medical need for more effective primary treatment. If validated for surrogacy, no evidence of disease at specific time points could represent an intermediate efficacy endpoint in future trials.

Background Apalutamide plus androgen-deprivation therapy (ADT) improved outcomes in metastatic castration-sensitive prostate cancer (mCSPC) and non-metastatic castration-resistant PC (nmCRPC) in the Phase 3 randomised TITAN and SPARTAN studies, respectively, and maintained health-related quality of life (HRQoL). Apalutamide treatment effect by patient age requires assessment. Methods Post-hoc analysis assessed patients receiving 240 mg/day apalutamide (525 TITAN and 806 SPARTAN) or placebo (527 TITAN and 401 SPARTAN) with ongoing ADT, stratified by age groups. Prostate-specific antigen declines, radiographic progression-free survival, metastasis-free survival, overall survival (OS), HRQoL and safety were assessed using descriptive statistics, Kaplan-Meier method, Cox proportional-hazards model and mixed-effects model for repeated measures. Results Hazard ratios (95% confidence intervals) generally favoured apalutamide plus ADT versus ADT alone across all endpoints regardless of age; e.g., OS values were 0.57 (0.40–0.80), 0.70 (0.54–0.91) and 0.74 (0.40–1.39) (TITAN) and 0.39 (0.19–0.78), 0.89 (0.69–1.16) and 0.81 (0.58–1.15) (SPARTAN) in patients aged <65, 65–79 and ≥80 years. Regardless of age, apalutamide also maintained HRQoL and was tolerated well with a potential trend in rates of adverse events increasing with age. Limitations include post-hoc nature and variability in sample size of age groups. Conclusions Apalutamide plus ADT was an effective and well-tolerated option maintaining HRQoL in patients with mCSPC and nmCRPC regardless of age. Clinical trial registration TITAN (NCT02489318); SPARTAN (NCT01946204).

BackgroundThe phase III SPARTAN study demonstrated that apalutamide significantly improves metastasis-free survival and overall survival vs. placebo in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). However, patients receiving apalutamide experienced falls more frequently vs. those receiving placebo (15.6% vs. 9.0%).Methods806 patients with nmCRPC randomized to apalutamide in SPARTAN and treated with apalutamide in addition to ongoing androgen deprivation therapy (ADT) were included in this post-hoc analysis investigating clinical variables associated with a subsequent fall. Time to a fall was assessed with Cox proportional-hazards models adjusted for baseline characteristics and time-varying factors. Statistical inference was based on final multivariable models.ResultsFalls were reported for 125/803 (15.6%) patients treated with apalutamide and ADT. Most falls were grade 1 or 2 and did not require hospitalization. Median time from randomization to first fall was 9.2 months (range 0.1–25.3 months). In the final multivariable model of both baseline and after-baseline covariates, baseline patient characteristics (older age, poor Eastern Cooperative Oncology Group performance status, history of neuropathy, and α-blocker use before study treatment) remained significantly associated with fall; after-baseline clinical characteristics significantly associated with time to fall were development of neuropathy, arthralgia, and weight loss before fall.ConclusionsThis analysis identified risk factors for fall among nmCRPC patients treated with apalutamide. Clinical management can minimize these identified risks while enhancing patient outcomes. Preventive interventions should be considered when the identified baseline conditions and post-treatment neuropathy, arthralgia, or weight decrease are present, to reduce risk of fall.Trial registrationClinicalTrials.gov: NCT01946204

The bone marrow of patients with myelodysplastic syndromes (MDS) shows excessive intramedullary apoptosis, particularly in S-phase cells. In the light of previous reports that showed a link between experimental overexpression of the E2F1 transcription factor and apoptosis in the S phase, we compared the status of E2F1 protein in bone marrow mononuclear cells of MDS patients with that of healthy donors. Nearly 67% of MDS marrow samples showed higher expression of E2F1 transcription factor than in healthy donors. The retinoblastoma gene product, Rb, is a major negative regulator of E2F1 activity; however, Rb protein levels were found to be normal in MDS marrow samples. Amplification of genomic DNA by the polymerase chain reaction (PCR) showed no E2F1 gene amplification or mutation in the Rb-binding region of E2F1 in MDS patients, nor was transcriptional up-regulation noted when E2F1 messenger RNA (mRNA) levels were estimated with real-time reverse transcriptase-PCR. Furthermore, the overexpression of E2F1 was paralleled by its increased transcriptional activity, as reflected by the increased mRNA levels for one of its target genes, dihydrofolate reductase. Importantly, in a subset of the studied MDS patients for whom a simultaneous measurement of apoptosis in S-phase cells was possible, the E2F1 protein levels showed a significant positive correlation with this phenomenon. Previously, increased E2F1 activity in human disease had been found primarily as a consequence of Rb derailment. Hence, the observation in MDS of increased E2F1 activity in the presence of normal Rb levels is novel and unique, and E2F1 activity in association with apoptosis in S-phase cells may thus have significant therapeutic implications.

Impaired erythropoiesis and refractory anemia are clinical hallmarks of the myelodysplastic syndromes (MDS). As the disease evolves, a steady decline in hemoglobin in these disorders invariably results in dependence on packed red blood cell (PRBC) transfusion. Such chronic transfusion dependence has been associated with iron overload causing cardio-hepatic toxicity and alloimmunization, and can result in reduced survival in these patients. The use of hematopoietic growth factors, particularly erythropoiesis-stimulating agents (ESAs), has been reported to reduce the need for PRBC transfusion, raise hemoglobin and improve quality of life, at least in patients responding to such a therapy. Importantly, the clinical benefits of ESA are well balanced, with an apparently favorable safety profile in MDS, thus providing an eminent therapeutic option to delay or avoid transfusion dependence in these patients. The present report provides a detailed comparative profile of long-term PRBC transfusions and the balance of clinical benefits versus risks associated with ESA therapy for MDS.

The field of cytogenetics has already entered the molecular era and a rapid expansion of its contribution is seen in genomic disease management. Among the evolving advanced molecular techniques, with an impeccable balance of high specificity, sensitivity and assay rapidity, fluorescence in situ hybridization has made its home in routine clinical laboratory. Today, its clinical application is vivid in every phase of disease management of a number of malignancies. The rapid growth in the knowledge of specific associations between distinct chromosomal abnormalities and different types of cancers will necessitate simultaneous detection of multiple abnormalities using multicolor/multiplex fluorescence in situ hybridization tests more often in the near future. Also, as the human genome sequence is ascertained, genome-wide screening with microarray technology will gain eminence in the clinical scenario, yield better solutions and bring the concept of personalized medicine in cancer closer to reality than ever before.