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The introduction of immune checkpoint inhibitors has demonstrated significant improvements in survival for subsets of cancer patients. However, they carry significant and sometimes life-threatening toxicities. Prompt prediction and monitoring of immune toxicities have the potential to maximise the benefits of immune checkpoint therapy. Herein, we develop a digital nanopillar SERS platform that achieves real-time single cytokine counting and enables dynamic tracking of immune toxicities in cancer patients receiving immune checkpoint inhibitor treatment - broader applications are anticipated in other disease indications. By analysing four prospective cytokine biomarkers that initiate inflammatory responses, the digital nanopillar SERS assay achieves both highly specific and highly sensitive cytokine detection down to attomolar level. Significantly, we report the capability of the assay to longitudinally monitor 10 melanoma patients during immune inhibitor blockade treatment. Here, we show that elevated cytokine concentrations predict for higher risk of developing severe immune toxicities in our pilot cohort of patients. There is a clinical need to monitor immune-related toxicities of immune checkpoint blockade therapy. Here, the authors develop a digital SERS platform for multiplexed single cytokine counting to track immune-toxicities and demonstrate the ability to use pre-screening to identify patients at higher risk.

Cabozantinib is an oral inhibitor of tyrosine kinases including MET, VEGFR, and AXL. The randomised phase 3 METEOR trial compared the efficacy and safety of cabozantinib versus the mTOR inhibitor everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR tyrosine-kinase inhibitor treatment. Here, we report the final overall survival results from this study based on an unplanned second interim analysis. In this open-label, randomised phase 3 trial, we randomly assigned (1:1) patients aged 18 years and older with advanced or metastatic clear-cell renal cell carcinoma, measurable disease, and previous treatment with one or more VEGFR tyrosine-kinase inhibitors to receive 60 mg cabozantinib once a day or 10 mg everolimus once a day. Randomisation was done with an interactive voice and web response system. Stratification factors were Memorial Sloan Kettering Cancer Center risk group and the number of previous treatments with VEGFR tyrosine-kinase inhibitors. The primary endpoint was progression-free survival as assessed by an independent radiology review committee in the first 375 randomly assigned patients and has been previously reported. Secondary endpoints were overall survival and objective response in all randomly assigned patients assessed by intention-to-treat. Safety was assessed per protocol in all patients who received at least one dose of study drug. The study is closed for enrolment but treatment and follow-up of patients is ongoing for long-term safety evaluation. This trial is registered with ClinicalTrials.gov, number NCT01865747. Between Aug 8, 2013, and Nov 24, 2014, 658 patients were randomly assigned to receive cabozantinib (n=330) or everolimus (n=328). The median duration of follow-up for overall survival and safety was 18·7 months (IQR 16·1–21·1) in the cabozantinib group and 18·8 months (16·0–21·2) in the everolimus group. Median overall survival was 21·4 months (95% CI 18·7–not estimable) with cabozantinib and 16·5 months (14·7–18·8) with everolimus (hazard ratio [HR] 0·66 [95% CI 0·53–0·83]; p=0·00026). Cabozantinib treatment also resulted in improved progression-free survival (HR 0·51 [95% CI 0·41–0·62]; p<0·0001) and objective response (17% [13–22] with cabozantinib vs 3% [2–6] with everolimus; p<0·0001) per independent radiology review among all randomised patients. The most common grade 3 or 4 adverse events were hypertension (49 [15%] in the cabozantinib group vs 12 [4%] in the everolimus group), diarrhoea (43 [13%] vs 7 [2%]), fatigue (36 [11%] vs 24 [7%]), palmar-plantar erythrodysaesthesia syndrome (27 [8%] vs 3 [1%]), anaemia (19 [6%] vs 53 [17%]), hyperglycaemia (3 [1%] vs 16 [5%]), and hypomagnesaemia (16 [5%] vs none). Serious adverse events grade 3 or worse occurred in 130 (39%) patients in the cabozantinib group and in 129 (40%) in the everolimus group. One treatment-related death occurred in the cabozantinib group (death; not otherwise specified) and two occurred in the everolimus group (one aspergillus infection and one pneumonia aspiration). Treatment with cabozantinib increased overall survival, delayed disease progression, and improved the objective response compared with everolimus. Based on these results, cabozantinib should be considered as a new standard-of-care treatment option for previously treated patients with advanced renal cell carcinoma. Patients should be monitored for adverse events that might require dose modifications. Exelixis Inc.

Bone metastases are a major cause of morbidity in metastatic castration-resistant prostate cancer. Abiraterone acetate potently disrupts intracrine androgen receptor signalling pathways implicated in the progression of the disease, including bone metastases. We assessed data for pain control and skeletal-related events prospectively collected as part of the randomised, phase 3 COU-AA-301 trial of abiraterone acetate plus prednisone versus placebo plus prednisone in patients with metastatic castration-resistant prostate cancer after docetaxel chemotherapy. The COU-AA-301 trial enrolled patients with metastatic castration-resistant prostate cancer in whom one or two lines of chemotherapy (one docetaxel based) had been unsuccessful and who had Eastern Cooperative Oncology Group performance statuses of 2 or less. Pain intensity and interference of pain with daily activities were assessed with the Brief Pain Inventory-Short Form questionnaire at baseline, day 15 of cycle 1, and day 1 of each treatment cycle thereafter until discontinuation. We assessed, with prospectively defined response criteria that incorporated analgesic use, clinically meaningful changes in pain intensity and interference with daily living. We measured time to first occurrence of skeletal-related events, which we defined as pathological fracture, spinal cord compression, palliative radiation to bone, or bone surgery, and regularly assessed them throughout the study. Pain palliation was assessed in patients who had clinically significant baseline pain, whereas all other analyses were done in the overall intention-to-treat population. COU-AA-301 is registered with ClinicalTrials.gov, number NCT00638690. Median follow-up was 20·2 months (IQR 18·4–22·1). In patients with clinically significant pain at baseline, abiraterone acetate and prednisone resulted in significantly more palliation (157 of 349 [45·0%] patients vs 47 of 163 [28·8%]; p=0·0005) and faster palliation (median time to palliation 5·6 months [95% CI 3·7–9·2] vs 13·7 months [5·4–not estimable]; p=0·0018) of pain intensity than did prednisone only. Palliation of pain interference (134 of 223 [60·1%] vs 38 of 100 [38·0%], p=0·0002; median time to palliation of pain interference 1·0 months [95% CI 0·9–1·9] vs 3·7 months [2·7–not estimable], p=0·0004) and median duration of palliation of pain intensity (4·2 months [95% CI 3·0–4·9] vs 2·1 months [1·4–3·7]; p=0·0056) were significantly better with abiraterone acetate and prednisone than with prednisone only. In the overall population, median time to occurrence of first skeletal-related event was significantly longer with abiraterone acetate and prednisone than with prednisone only (25·0 months [95% CI 25·0–not estimable] vs 20·3 months [16·9–not estimable]; p=0·0001). In patients with metastatic castration-resistant prostate cancer previously treated with docetaxel, abiraterone acetate and prednisone offer significant benefits compared with prednisone alone in terms of pain relief, delayed pain progression, and prevention of skeletal-related events. Janssen Research & Development and Janssen Global Services.

Abiraterone acetate plus prednisone significantly improves radiographic progression-free survival in asymptomatic or mildly symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer compared with prednisone alone. We describe analyses of data for patient-reported pain and functional status in a preplanned interim analysis of a phase 3 trial. Between April 28, 2009, and June 23, 2010, patients with progressive, metastatic castration-resistant prostate cancer were enrolled into a multinational, double-blind, placebo-controlled trial. Patients were eligible if they were asymptomatic (score of 0 or 1 on item three of the Brief Pain Inventory Short Form [BPI-SF] questionnaire) or mildly symptomatic (score of 2 or 3) and had not previously received chemotherapy. Patients were randomly assigned (1:1) to receive oral abiraterone (1 g daily) plus prednisone (5 mg twice daily) or placebo plus prednisone in continuous 4-week cycles. Pain was assessed with the BPI-SF questionnaire, and health-related quality of life (HRQoL) with the Functional Assessment of Cancer Therapy—Prostate (FACT-P) questionnaire. We analysed data with prespecified criteria for clinically meaningful pain progression and deterioration in HRQoL. All patients who underwent randomisation were included in analyses. This study is registered with ClinicalTrials.gov, number NCT00887198. 1088 patients underwent randomisation: 546 were assigned to abiraterone plus prednisone and 542 to placebo plus prednisone. At the time of the second prespecified interim analysis, median follow-up was 22·2 months (IQR 20·2–24·8). Median time to progression of mean pain intensity was longer in patients assigned to abiraterone plus prednisone (26·7 months [95% CI 19·3–not estimable]) than in those assigned to placebo plus prednisone (18·4 months [14·9–not estimable]; hazard ratio [HR] 0·82, 95% CI 0·67–1·00; p=0·0490), as was median time to progression of pain interference with daily activities (10·3 months [95% CI 9·3–13·0] vs 7·4 months [6·4–8·6]; HR 0·79, 95% CI 0·67–0·93; p=0·005). Median time to progression of worst pain was also longer with abiraterone plus prednisone (26·7 months [95% CI 19·4–not estimable]) than with placebo plus prednisone (19·4 months [16·6–not estimable]), but the difference was not significant (HR 0·85, 95% CI 0·69–1·04; p=0·109). Median time to HRQoL deterioration was longer in patients assigned to abiraterone plus prednisone than in those assigned to placebo plus prednisone as assessed by the FACT-P total score (12·7 months [95% CI 11·1–14·0] vs 8·3 months [7·4–10·6]; HR 0·78, 95% CI 0·66–0·92; p=0·003) and by the score on its prostate-cancer-specific subscale (11·1 months [8·6–13·8] vs 5·8 months [5·5–8·3]; HR 0·70, 95% CI 0·60–0·83; p<0·0001). Abiraterone plus prednisone delays patient-reported pain progression and HRQoL deterioration in chemotherapy-naive patients with metastatic castration-resistant prostate cancer. These results provide further support for the efficacy of abiraterone in this population. Janssen Research & Development.

Among men with nonmetastatic prostate cancer who had a rapid PSA doubling time and were receiving androgen-deprivation therapy, the median metastasis-free survival was 40.5 months with apalutamide versus 16.2 months with placebo. Rash occurred in 24% of men receiving apalutamide.

In a phase 3 clinical trial involving previously treated patients with advanced renal-cell carcinoma, progression-free survival was significantly longer with the VEGF receptor inhibitor cabozantinib than with everolimus (7.4 months vs. 3.8 months). Renal-cell carcinoma is the most common form of kidney cancer, with more than 330,000 cases diagnosed and more than 140,000 deaths attributed to it worldwide every year. 1 Approximately one third of patients present with metastatic disease at diagnosis, 2 and in about one third of treated patients with localized disease, the disease will relapse. 3 – 5 Inactivation of the von Hippel–Lindau (VHL) tumor-suppressor protein characterizes clear-cell tumors, the predominant histologic subtype in patients with renal-cell carcinoma, and results in the up-regulation of vascular endothelial growth factor (VEGF) production. 6 , 7 Antiangiogenic drugs that target VEGF (bevacizumab) and its receptors (sunitinib, sorafenib, pazopanib, and . . .

In the final analysis of the phase 3 COU-AA-301 study, abiraterone acetate plus prednisone significantly prolonged overall survival compared with prednisone alone in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. Here, we present the final analysis of an early-access protocol trial that was initiated after completion of COU-AA-301 to enable worldwide preapproval access to abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. We did a multicentre, open-label, early-access protocol trial in 23 countries. We enrolled patients who had metastatic castration-resistant prostate cancer progressing after taxane chemotherapy. Participants received oral doses of abiraterone acetate (1000 mg daily) and prednisone (5 mg twice a day) in 28-day cycles until disease progression, development of sustained side-effects, or abiraterone acetate becoming available in the respective country. The primary outcome was the number of adverse events arising during study treatment and within 30 days of discontinuation. Efficacy measures (time to prostate-specific antigen [PSA] progression and time to clinical progression) were gathered to guide treatment decisions. We included in our analysis all patients who received at least one dose of abiraterone acetate. This study is registered with ClinicalTrials.gov, number NCT01217697. Between Nov 17, 2010, and Sept 30, 2013, 2314 patients were enrolled into the early-access protocol trial. Median follow-up was 5·7 months (IQR 3·5–10·6). 952 (41%) patients had a grade 3 or 4 treatment-related adverse event, and grade 3 or 4 serious adverse events were recorded in 585 (25%) people. Grade 3 and 4 adverse events of special interest were hepatotoxicity (188 [8%]), hypertension (99 [4%]), cardiac disorders (52 [2%]), osteoporosis (31 [1%]), hypokalaemia (28 [1%]), and fluid retention or oedema (23 [1%]). 172 (7%) patients discontinued the study because of adverse events (64 [3%] were drug-related), as assessed by the investigator, and 171 (7%) people died. The funder assessed causes of death, which were due to disease progression (85 [4%]), an unrelated adverse experience (72 [3%]), and unknown reasons (14 [1%]). Of the 86 deaths not attributable to disease progression, 18 (<1%) were caused by a drug-related adverse event, as assessed by the investigator. Median time to PSA progression was 8·5 months (95% CI 8·3–9·7) and median time to clinical progression was 12·7 months (11·8–13·8). No new safety signals or unexpected adverse events were found in this early-access protocol trial to assess abiraterone acetate for patients with metastatic castration-resistant prostate cancer who progressed after chemotherapy. Future work is needed to ascertain the most effective regimen of abiraterone acetate to optimise patients' outcomes. Janssen Research & Development.

In the SPARTAN trial, addition of apalutamide to androgen deprivation therapy, as compared with placebo plus androgen deprivation therapy, significantly improved metastasis-free survival in men with non-metastatic castration-resistant prostate cancer who were at high risk for development of metastases. We aimed to investigate the effects of apalutamide versus placebo added to androgen deprivation therapy on health-related quality of life (HRQOL). SPARTAN is a multicentre, international, randomised, phase 3 trial. Participants were aged 18 years or older, with non-metastatic castration-resistant prostate cancer, a prostate-specific antigen doubling time of 10 months or less, and a prostate-specific antigen concentration of 2 ng/mL or more in serum. Patients were randomly assigned (2:1) to 240 mg oral apalutamide per day plus androgen deprivation therapy, or matched oral placebo plus androgen deprivation therapy, using an interactive voice randomisation system. Permuted block randomisation was used according to the three baseline stratification factors: prostate-specific antigen doubling time (>6 months vs ≤6 months), use of bone-sparing drugs (yes vs no), and presence of local-regional nodal disease (N0 vs N1). Each treatment cycle was 28 days. The primary endpoint was metastasis-free survival. The trial was unblinded in July, 2017. In this prespecified exploratory analysis we assessed HRQOL using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-3L questionnaires, which we collected at baseline, day 1 of cycle 1 (before dose), day 1 of treatment cycles 1–6, day 1 of every two cycles from cycles 7 to 13, and day 1 of every four cycles thereafter. This study is registered with ClinicalTrials.gov, number NCT01946204. Between Oct 14, 2013, and Dec 15, 2016, we randomly assigned 1207 patients to receive apalutamide (n=806) or placebo (n=401). The clinical cutoff date, as for the primary analysis, was May 19, 2017. Median follow-up for overall survival was 20·3 months (IQR 14·8–26·6). FACT-P total and subscale scores were associated with a preservation of HRQOL from baseline to cycle 29 in the apalutamide group; there were similar results for EQ-5D-3L. At baseline, the mean for FACT-P total score in both the apalutamide and placebo groups were consistent with the FACT-P general population norm for US adult men. Group mean patient-reported outcome scores over time show that HRQOL was maintained from baseline after initiation of apalutamide treatment and was similar over time among patients receiving apalutamide versus placebo. Least-squares mean change from baseline shows that HRQOL deterioration was more apparent in the placebo group. In asymptomatic men with high-risk non-metastatic castration-resistant prostate cancer, HRQOL was maintained after initiation of apalutamide treatment. Considered with findings from SPARTAN, patients who received apalutamide had longer metastasis-free survival and longer time to symptomatic progression than did those who received placebo, while preserving HRQOL. Janssen Research & Development.

The accurate identification and stratified treatment of clinically significant early-stage prostate cancer have been ongoing concerns since the outcomes of large international prostate cancer screening trials were reported. The controversy surrounding clinical and cost benefits of prostate cancer screening has highlighted the lack of strategies for discriminating high-risk disease (that requires early treatment) from low-risk disease (that could be managed using watchful waiting or active surveillance). Advances in molecular subtyping and multiomics nanotechnology-based prostate cancer risk delineation can enable refinement of prostate cancer molecular taxonomy into clinically meaningful and treatable subtypes. Furthermore, the presence of intertumoural and intratumoural heterogeneity in prostate cancer warrants the development of novel nanodiagnostic technologies to identify clinically significant prostate cancer in a rapid, cost-effective and accurate manner. Circulating and urinary next-generation prostate cancer biomarkers for disease molecular subtyping and the newest complementary nanodiagnostic platforms for enhanced biomarker detection are promising tools for precision prostate cancer management. However, challenges in merging both aspects and clinical translation still need to be overcome.In this Review, the authors discuss biomarker-driven prostate cancer molecular subtyping and the development of nanodiagnostic strategies to refine biomarker detection. They also describe the challenges of merging both aspects for precision prostate cancer management.

Current biotechnological developments are driving a significant shift towards integrating proteomic analysis with landmark genomic, methylomic, and transcriptomic data to elucidate functional effects. For the majority of proteins, structure and function are closely intertwined. Post-translational protein modifications (e.g., phosphorylation) leading to aberrantly active structures can originate a wide variety of pathological conditions, including cancer. Analysis of protein structure variants is thus integral to the identification of clinically actionable targets and the design of novel disease diagnosis and therapy approaches. However, it is still challenging to interrogate subtle structural changes of proteins in a rapid and cost-effective manner with current tools. This review primarily compiles the latest biosensing techniques for protein structural analysis. In general, protein structure and function are intrinsically tangled, and protein phosphorylation is a key regulation of structural changes. Aberrantly function-active protein structures (due to constitutive phosphorylation) are frequently implicated in disease pathways.Advanced biosensing tools will allow better understanding of the protein molecular landscape in diseases and aid in diagnostics development for improved disease management.Importantly, there have been recent biotechnological advances in biosensors employed for the study and detection of protein structural changes associated with aberrant phosphorylation.