Explore the vast range of titles available.

In a trial, the median metastasis-free survival among men with nonmetastatic, castration-resistant prostate cancer and a short PSA doubling time was 36.6 months with enzalutamide and 14.7 months with placebo. Falls and heart problems were more common with enzalutamide.

Among men with high-risk, nonmetastatic, castration-resistant prostate cancer, the addition of enzalutamide to androgen-deprivation therapy improved overall survival by nearly a year as compared with ADT alone: median survival was 67 months with enzalutamide plus ADT and 56 months with ADT alone.

In a recent phase 3 randomized trial of 700 patients with advanced urothelial cancer (JAVELIN Bladder 100; NCT02603432 ), avelumab/best supportive care (BSC) significantly prolonged overall survival relative to BSC alone as maintenance therapy after first-line chemotherapy. Exploratory biomarker analyses were performed to identify biological pathways that might affect survival benefit. Tumor molecular profiling by immunohistochemistry, whole-exome sequencing and whole-transcriptome sequencing revealed that avelumab survival benefit was positively associated with PD-L1 expression by tumor cells, tumor mutational burden, APOBEC mutation signatures, expression of genes underlying innate and adaptive immune activity and the number of alleles encoding high-affinity variants of activating Fcγ receptors. Pathways connected to tissue growth and angiogenesis might have been associated with reduced survival benefit. Individual biomarkers did not comprehensively identify patients who could benefit from therapy; however, multi-parameter models incorporating genomic alteration, immune responses and tumor growth showed promising predictive utility. These results characterize the complex biologic pathways underlying survival benefit from immune checkpoint inhibition in advanced urothelial cancer and suggest that multiple biomarkers might be needed to identify patients who would benefit from treatment. Biomarker analysis of the phase 3 JAVELIN Bladder 100 trial leads to the development of a multi-parameter model comprising tumor and immune features that might identify patients with advanced urothelial cancer who will benefit from avelumab maintenance therapy.

Abiraterone acetate improved overall survival in metastatic castration-resistant prostate cancer at a preplanned interim analysis of the COU-AA-301 double-blind, placebo-controlled phase 3 study. Here, we present the final analysis of the study before crossover from placebo to abiraterone acetate (after 775 of the prespecified 797 death events). Between May 8, 2008, and July 28, 2009, this study enrolled 1195 patients at 147 sites in 13 countries. Patients were eligible if they had metastatic castration-resistant prostate cancer progressing after docetaxel. Patients were stratified according to baseline Eastern Cooperative Oncology Group (ECOG) performance status, worst pain over the past 24 h on the Brief Pain Inventory-Short Form, number of previous chemotherapy regimens, and type of progression. Patients were randomly assigned (ratio 2:1) to receive either abiraterone acetate (1000 mg, once daily and orally) plus prednisone (5 mg, orally twice daily) or placebo plus prednisone with a permuted block method via an interactive web response system. The primary endpoint was overall survival, analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00638690. Of the 1195 eligible patients, 797 were randomly assigned to receive abiraterone acetate plus prednisone (abiraterone group) and 398 to receive placebo plus prednisone (placebo group). At median follow-up of 20·2 months (IQR 18·4–22·1), median overall survival for the abiraterone group was longer than in the placebo group (15·8 months [95% CI 14·8–17·0] vs 11·2 months [10·4–13·1]; hazard ratio [HR] 0·74, 95% CI 0·64–0·86; p<0·0001). Median time to PSA progression (8·5 months, 95% CI 8·3–11·1, in the abiraterone group vs 6·6 months, 5·6–8·3, in the placebo group; HR 0·63, 0·52–0·78; p<0·0001), median radiologic progression-free survival (5·6 months, 5·6–6·5, vs 3·6 months, 2·9–5·5; HR 0·66, 0·58–0·76; p<0·0001), and proportion of patients who had a PSA response (235 [29·5%] of 797 patients vs 22 [5·5%] of 398; p<0·0001) were all improved in the abiraterone group compared with the placebo group. The most common grade 3–4 adverse events were fatigue (72 [9%] of 791 patients in the abiraterone group vs 41 [10%] of 394 in the placebo group), anaemia (62 [8%] vs 32 [8%]), back pain (56 [7%] vs 40 [10%]), and bone pain (51 [6%] vs 31 [8%]). This final analysis confirms that abiraterone acetate significantly prolongs overall survival in patients with metastatic castration-resistant prostate cancer who have progressed after docetaxel treatment. No new safety signals were identified with increased follow-up. Janssen Research & Development.

Androgen receptor (AR) signaling is a key pathway in prostate cancer, and patients are initially treated with androgen deprivation therapy. Patients who have stopped responding to androgen deprivation therapy are considered to have castration-resistant prostate cancer (CRPC), which is still dependent on AR signaling. Enzalutamide, an orally available AR inhibitor, was initially approved by the US FDA for the treatment of patients with metastatic CRPC who have previously received docetaxel. The indication was subsequently extended to include all patients with metastatic CRPC, and most recently to include patients with nonmetastatic CRPC. This review summarizes the body of evidence supporting enzalutamide efficacy and safety in CRPC.

The PI3K/AKT and androgen-receptor pathways are dysregulated in metastatic castration-resistant prostate cancers (mCRPCs); tumours with functional PTEN-loss status have hyperactivated AKT signalling. Dual pathway inhibition with AKT inhibitor ipatasertib plus abiraterone might have greater benefit than abiraterone alone. We aimed to compare ipatasertib plus abiraterone with placebo plus abiraterone in patients with previously untreated mCRPC with or without tumour PTEN loss. We did a randomised, double-blind, phase 3 trial at 200 sites across 26 countries or regions. Patients aged 18 years or older with previously untreated asymptomatic or mildly symptomatic mCRPC who had progressive disease and Eastern Collaborative Oncology Group performance status of 0 or 1 were randomly assigned (1:1; permuted block method) to receive ipatasertib (400 mg once daily orally) plus abiraterone (1000 mg once daily orally) and prednisolone (5 mg twice a day orally) or placebo plus abiraterone and prednisolone (with the same dosing schedule). Patients received study treatment until disease progression, intolerable toxicity, withdrawal from the study, or study completion. Stratification factors were previous taxane-based therapy for hormone-sensitive prostate cancer, type of progression, presence of visceral metastasis, and tumour PTEN-loss status by immunohistochemistry. Patients, investigators, and the study sponsor were masked to the treatment allocation. The coprimary endpoints were investigator-assessed radiographical progression-free survival in the PTEN-loss-by-immunohistochemistry population and in the intention-to-treat population. This study is ongoing and is registered with ClinicalTrials.gov, NCT03072238. Between June 30, 2017, and Jan 17, 2019, 1611 patients were screened for eligibility and 1101 (68%) were enrolled; 554 (50%) were assigned to the placebo–abiraterone group and 547 (50%) to the ipatasertib–abiraterone group. At data cutoff (March 16, 2020), median follow-up duration was 19 months (range 0–33). In the 521 (47%) patients who had tumours with PTEN loss by immunohistochemistry (261 in the placebo–abiraterone group and 260 in the ipatasertib–abiraterone group), median radiographical progression-free survival was 16·5 months (95% CI 13·9–17·0) in the placebo–abiraterone group and 18·5 months (16·3–22·1) in the ipatasertib–abiraterone group (hazard ratio [HR] 0·77 [95% CI 0·61–0·98]; p=0·034; significant at α=0·04). In the intention-to-treat population, median progression-free survival was 16·6 months (95% CI 15·6–19·1) in the placebo–abiraterone group and 19·2 months (16·5–22·3) in the ipatasertib–abiraterone group (HR 0·84 [95% CI 0·71–0·99]; p=0·043; not significant at α=0·01). Grade 3 or higher adverse events occurred in 213 (39%) of 546 patients in the placebo–abiraterone group and in 386 (70%) of 551 patients in the ipatasertib–abiraterone group; adverse events leading to discontinuation of placebo or ipatasertib occurred in 28 (5%) in the placebo–abiraterone group and 116 (21%) in the ipatasertib–abiraterone group. Deaths due to adverse events deemed related to treatment occurred in two patients (<1%; acute myocardial infarction [n=1] and lower respiratory tract infection [n=1]) in the placebo–abiraterone group and in two patients (<1%; hyperglycaemia [n=1] and chemical pneumonitis [n=1]) in the ipastasertb–abiraterone group. Ipatasertib plus abiraterone significantly improved radiographical progression-free survival compared with placebo plus abiraterone among patients with mCRPC with PTEN-loss tumours, but there was no significant difference between the groups in the intention-to-treat population. Adverse events were consistent with the known safety profiles of each agent. These data suggest that combined AKT and androgen-receptor signalling pathway inhibition with ipatasertib and abiraterone is a potential treatment for men with PTEN-loss mCRPC, a population with a poor prognosis. F Hoffmann-La Roche and Genentech.

In the AFFIRM trial of patients with metastatic castration-resistant prostate cancer after progression with docetaxel treatment, enzalutamide significantly increased overall survival compared with placebo. Here we present the prospectively defined analyses of some secondary endpoints, including occurrence of skeletal-related events, measures of pain control, and patient-reported health-related quality of life (HRQoL). In this phase 3, double-blind trial, patients were randomly assigned (2:1) to receive enzalutamide 160 mg/day or placebo orally, stratified by ECOG baseline performance status (0 or 1 vs 2) and mean pain score (Brief Pain Inventory-Short Form [BPI-SF] question 3 worst pain, score ≤3 vs ≥4). Secondary endpoints were time to first skeletal-related event (radiation therapy or surgery to bone, clinically apparent pathological bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain); change from baseline to week 13 in pain severity and interference; pain palliation and progression at week 13; time to pain progression; overall improvement in HRQoL; improvements in HRQoL domains; and time to HRQoL deterioration. Analysis was done on the intention-to-treat population for each endpoint. AFFIRM is registered with ClinicalTrials.gov, number NCT00974311. Median time to first skeletal-related event in the enzalutamide (n=800) and placebo (n=399) groups was 16·7 months (95% CI 14·6 to 19·1) and 13·3 months (95% CI 9·9 to not yet reached), respectively (hazard ratio [HR] 0·69 [95% CI 0·57–0·84]; p=0·0001). Pain progression at week 13 occurred in 174 (28%) of 625 evaluable patients in the enzalutamide group versus 101 (39%) of 259 patients in the placebo group (difference −11·2%, 95% CI −18·1 to −4·3; p=0·0018). Median time to pain progression was not yet reached in the enzalutamide group (95% CI not yet reached to not yet reached) versus 13·8 (13·8 to not yet reached) months in the placebo group (HR 0·56 [95% CI 0·41 to 0·78]; p=0·0004). Mean treatment effects for pain severity (mean change from baseline in the enzalutamide group −0·15, 95% CI −0·28 to −0·02, vs placebo 0·50, 0·29 to 0·70; difference −0·65, 95% CI −0·89 to −0·41; p<0·0001) and interference (−0·01, −0·18 to 0·16, vs 0·74, 0·47 to 1·00; respectively, difference −0·74, 95% −1·06 to −0·43; p<0·0001) were significantly better with enzalutamide than with placebo. 22 (45%) of 49 evaluable patients in the enzalutamide group reported pain palliation at week 13 versus one (7%) of 15 in the placebo group (difference 38·2%, 95% CI 19·4–57·0; p=0·0079). Overall improvement in HRQoL was reported in more patients receiving enzalutamide (275 [42%] of 652) than in those receiving placebo (36 [15%] of 248; p<0·0001). Patients in the enzalutamide group had longer median time to HRQoL deterioration than did those in the placebo group (9·0 months, 95% CI 8·3–11·1, vs 3·7 months, 95% CI 3·0–4·2; HR 0·45, 95% CI 0·37–0·55; p<0·0001). Our results show that, in addition to improving overall survival, enzalutamide improves wellbeing and everyday functioning of patients with metastatic castration-resistant prostate cancer. Astellas Pharma and Medivation.

Enzalutamide significantly increased overall survival and radiographic progression-free survival compared with placebo in the PREVAIL trial of asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer. We report the effect of enzalutamide on health-related quality of life (HRQoL), pain, and skeletal-related events observed during this trial. In this phase 3, double-blind trial, patients were randomly assigned (1:1) to receive enzalutamide 160 mg/day (n=872) or placebo (n=845) orally. HRQoL was assessed at baseline and during treatment using the Functional Assessment of Cancer Therapy–Prostate (FACT-P) and EQ-5D questionnaires. Pain status was assessed at screening, baseline, week 13, and week 25 with the Brief Pain Inventory Short Form (BPI-SF). The primary analysis of HRQoL data used a mixed-effects model to test the difference between least square means change from baseline at week 61. We assessed change from baseline, percentage improvement, and time to deterioration in HRQoL and pain, the proportion of patients with a skeletal-related event, and time to first skeletal-related event. Analysis was done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01212991. Median treatment duration was 16·6 months (IQR 10·1–21·1) in the enzalutamide group and 4·6 months (2·8–9·7) in the placebo group. The mixed-effects model analyses showed significant treatment differences in change from baseline to week 61 with enzalutamide compared with placebo for most FACT-P endpoints and EQ-5D visual analogue scale. Median time to deterioration in FACT-P total score was 11·3 months (95% CI 11·1–13·9) in the enzalutamide group and 5·6 months (5·5–5·6) in the placebo groups (hazard ratio [HR] 0·62 [95% CI 0·54–0·72]; p<0·0001). A significantly greater proportion of patients in the enzalutamide group than in the placebo group reported clinically meaningful improvements in FACT-P total score (327 [40%] of 826 vs 181 [23%] of 790), in EQ-5D utility index (224 [28%] of 812 vs 99 [16%] of 623), and visual analogue scale (218 [27%] of 803 vs 106 of [18%] 603; all p<0·0001). Median time to progression in BPI-SF pain at its worst was 5·7 months (95% CI 5·6–5·7) in the enzalutamide group and 5·6 months (5·4–5·6) in the placebo group (HR 0·62 [95% CI 0·53–0·74]; p<0·0001). Progression of pain at its worst was less common in the enzalutamide group than in the placebo group at week 13 (220 [29%] of 769 vs 257 [42%] of 610; p<0·0001), but not at week 25 (225 [32%] of 705 vs 135 [38%] of 360; p=0·068). 278 (32%) of 872 patients in the enzalutamide group and 309 (37%) of 845 patients in the placebo group had experienced a skeletal-related event by data cutoff. Median time to first skeletal-related events in the enzalutamide group was 31·1 months (95% CI 29·5–not reached) and 31·3 months (95% CI 23·9–not reached) in the placebo group (HR 0·72 [95% CI 0·61–0·84]; p<0·0001). In addition to improving overall survival relative to placebo, enzalutamide significantly improves patient-related outcomes and delays occurrence of first skeletal-related event in chemotherapy-naive men with metastatic castration-resistant prostate cancer. Astellas Pharma and Medivation.

Despite standard curative-intent treatment with neoadjuvant cisplatin-based chemotherapy, followed by radical surgery in eligible patients, muscle-invasive urothelial carcinoma has a high recurrence rate and no level 1 evidence for adjuvant therapy. We aimed to evaluate atezolizumab as adjuvant therapy in patients with high-risk muscle-invasive urothelial carcinoma. In the IMvigor010 study, a multicentre, open-label, randomised, phase 3 trial done in 192 hospitals, academic centres, and community oncology practices across 24 countries or regions, patients aged 18 years and older with histologically confirmed muscle-invasive urothelial carcinoma and an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 were enrolled within 14 weeks after radical cystectomy or nephroureterectomy with lymph node dissection. Patients had ypT2–4a or ypN+ tumours following neoadjuvant chemotherapy or pT3–4a or pN+ tumours if no neoadjuvant chemotherapy was received. Patients not treated with neoadjuvant chemotherapy must have been ineligible for or declined cisplatin-based adjuvant chemotherapy. No post-surgical radiotherapy or previous adjuvant chemotherapy was allowed. Patients were randomly assigned (1:1) using a permuted block (block size of four) method and interactive voice-web response system to receive 1200 mg atezolizumab given intravenously every 3 weeks for 16 cycles or up to 1 year, whichever occurred first, or to observation. Randomisation was stratified by previous neoadjuvant chemotherapy use, number of lymph nodes resected, pathological nodal status, tumour stage, and PD-L1 expression on tumour-infiltrating immune cells. The primary endpoint was disease-free survival in the intention-to-treat population. Safety was assessed in patients who either received at least one dose of atezolizumab or had at least one post-baseline safety assessment. This trial is registered with ClinicalTrials.gov, NCT02450331, and is ongoing but not recruiting patients. Between Oct 5, 2015, and July 30, 2018, we enrolled 809 patients, of whom 406 were assigned to the atezolizumab group and 403 were assigned to the observation group. Median follow-up was 21·9 months (IQR 13·2–29·8). Median disease-free survival was 19·4 months (95% CI 15·9–24·8) with atezolizumab and 16·6 months (11·2–24·8) with observation (stratified hazard ratio 0·89 [95% CI 0·74–1·08]; p=0·24). The most common grade 3 or 4 adverse events were urinary tract infection (31 [8%] of 390 patients in the atezolizumab group vs 20 [5%] of 397 patients in the observation group), pyelonephritis (12 [3%]) vs 14 [4%]), and anaemia (eight [2%] vs seven [2%]). Serious adverse events occurred in 122 (31%) patients who received atezolizumab and 71 (18%) who underwent observation. 63 (16%) patients who received atezolizumab had a treatment-related grade 3 or 4 adverse event. One treatment-related death, due to acute respiratory distress syndrome, occurred in the atezolizumab group. To our knowledge, IMvigor010 is the largest, first-completed phase 3 adjuvant study to evaluate the role of a checkpoint inhibitor in muscle-invasive urothelial carcinoma. The trial did not meet its primary endpoint of improved disease-free survival in the atezolizumab group over observation. Atezolizumab was generally tolerable, with no new safety signals; however, higher frequencies of adverse events leading to discontinuation were reported than in metastatic urothelial carcinoma studies. These data do not support the use of adjuvant checkpoint inhibitor therapy in the setting evaluated in IMvigor010 at this time. F Hoffmann-La Roche/Genentech.

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.