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A randomized trial involving patients with metastatic prostate cancer whose disease progressed after receipt of docetaxel and hormonal therapy showed that cabazitaxel was superior to an androgen-signaling–targeted agent in extending imaging-based progression-free survival, overall survival, and PSA response.

Standard treatment for high-risk non-muscle-invasive bladder cancer is transurethral resection of bladder tumour followed by intravesical BCG immunotherapy. However, despite high initial responses rates, up to 50% of patients have recurrence or become BCG-unresponsive. PD-1 pathway activation is implicated in BCG resistance. In the KEYNOTE-057 study, we evaluated pembrolizumab, a PD-1 inhibitor, in BCG-unresponsive non-muscle-invasive bladder cancer. We did this open-label, single-arm, multicentre, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. In cohort A of the trial, adults aged 18 years or older with histologically confirmed BCG-unresponsive carcinoma in situ of the bladder, with or without papillary tumours, with an Eastern Cooperative Oncology Group performance status of 0–2, and who were ineligible for or declined radical cystectomy were enrolled. All enrolled patients were assigned to receive pembrolizumab 200 mg intravenously every 3 weeks for up to 24 months or until centrally confirmed disease persistence, recurrence, or progression; unacceptable toxic effects; or withdrawal of consent. The primary endpoint was clinical complete response rate (absence of high-risk non-muscle-invasive bladder cancer or progressive disease), assessed by cystoscopy and urine cytology approximately 3 months after the first dose of study drug. Patient follow-ups were done every 3 months for the first 2 years and every 6 months thereafter for up to 5 years. Efficacy was assessed in all patients who received at least one dose of the study drug and met BCG-unresponsive criteria. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing. Between Dec 9, 2015, and April 1, 2018, we screened 334 patients for inclusion. 186 patients did not meet inclusion criteria, and 47 patients were assigned to cohort B (patients with BCG-unresponsive high grade Ta or any grade T1 papillary disease without carcinoma in situ; results will be reported separately). 101 eligible patients were enrolled and assigned to receive pembrolizumab. All 101 patients received at least one dose of the study drug and were included in the safety analysis. Five patients had disease that did not meet the US Food and Drug Administration definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore not included in the efficacy analysis (n=96). Median follow-up was 36·4 months (IQR 32·0–40·7). 39 (41%; 95% CI 30·7–51·1) of 96 patients with BCG-unresponsive carcinoma in situ of the bladder with or without papillary tumours had a complete response at 3 months. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients; the most common were arthralgia (in two [2%] patients) and hyponatraemia (in three [3%] patients). Serious treatment-related adverse events occurred in eight (8%) patients. There were no deaths that were considered treatment related. Pembrolizumab monotherapy was tolerable and showed promising antitumour activity in patients with BCG-unresponsive non-muscle-invasive bladder cancer who declined or were ineligible for radical cystectomy and should be considered a a clinically active non-surgical treatment option in this difficult-to-treat population. Merck Sharp & Dohme.

The RANGE study (NCT02426125) evaluated ramucirumab (an anti-VEGFR2 monoclonal antibody) in patients with platinum-refractory advanced urothelial carcinoma (UC). Here, we use programmed cell death-ligand 1 (PD-L1) immunohistochemistry (IHC) and transcriptome analysis to evaluate the association of immune and angiogenesis pathways, and molecular subtypes, with overall survival (OS) in UC. Higher PD-L1 IHC and immune pathway scores, but not angiogenesis scores, are associated with greater ramucirumab OS benefit. Additionally, Basal subtypes, which have higher PD-L1 IHC and immune/angiogenesis pathway scores, show greater ramucirumab OS benefit compared to Luminal subtypes, which have relatively lower scores. Multivariable analysis suggests patients from East Asia as having lower immune/angiogenesis signature scores, which correlates with decreased ramucirumab OS benefit. Our data highlight the utility of multiple biomarkers including PD-L1, molecular subtype, and immune phenotype in identifying patients with UC who might derive the greatest benefit from treatment with ramucirumab. Identification of biomarkers to stratify patients who might benefit from treatment is needed to optimize targeted therapies. Here, based on an analysis of the RANGE trial (NCT02426125), the authors report potentially predictive biomarkers for survival benefit in patients with platinum-refractory advanced urothelial carcinoma treated with the anti-VEGFR2 monoclonal antibody ramucirumab.

Background and purpose: Chemotherapy-induced neutropenia and neutrophil-to-lymphocyte ratio (NLR) are potentially useful prognostic markers in patients with metastatic castration-resistant prostate cancer (mCRPC). This post hoc analysis investigated whether these markers can be utilized for dose considerations and evaluated the prognostic impact of leukocyte subtypes. Patients and methods: PROSELICA assessed the non-inferiority of cabazitaxel 20 mg/m2 (C20; n = 598) versus 25 mg/m2 (C25; n = 602) for overall survival (OS) in patients with mCRPC previously treated with docetaxel. The association of grade ⩾ 3 neutropenia, NLR, baseline neutrophilia and lymphopenia with OS, progression-free survival (PFS), and prostate-specific antigen response rate (PSArr) was investigated by an unplanned uni- and multivariate analyses. Results: PROSELICA confirmed the negative prognostic value of increased baseline NLR [⩾3, hazard ratio (HR) 1.40; p < 0.0001], but did not identify a subgroup of patients benefiting more from C20 or C25. In this post hoc analysis, patients who developed grade ⩾3 neutropenia (n = 673) had a significantly improved OS [∆OS = 2.7 months, HR = 0.78 (95% CI 0.68–0.89)] with the greatest advantage observed in patients with baseline neutrophilia [n = 85; 5.3 months, 0.60 (0.42–0.84)]. After adjustment for the Halabi criteria, neutropenia grade ⩾ 3 was the only biomarker that remained significantly associated with OS [ (HR 0.86 (0.75–0.98)], PFS [HR 0.78 (0.68–0.88)], and PSArr [odds ratio (OR) 1.82 (1.37–2.41)] while neutrophilia showed the strongest association with OS [1.53 (1.29–1.81)]. Conclusions: Grade ⩾ 3 neutropenia was the only leukocyte-based biomarker associated with all key outcome parameters in mCRPC patients receiving cabazitaxel and might be able to overcome the negative prognostic effect of baseline neutrophilia. NCT number: NCT01308580

In a randomized trial involving 542 patients with relapsed urothelial cancer, treatment with pembrolizumab resulted in overall survival of more than 10 months, as compared with 7 months with chemotherapy. Urothelial cancer is highly lethal in the metastatic state. 1 Platinum-based combination chemotherapy remains the standard first-line treatment for metastatic disease. Carboplatin-based combinations are associated with a median overall survival of 9 months, 2 and cisplatin-based combinations with a median overall survival of 12 to 15 months. 3 However, after platinum-based chemotherapy, there is no internationally accepted standard of care. Single-agent paclitaxel and docetaxel are commonly used worldwide, 4 , 5 and in Europe, vinflunine has been approved on the basis of an overall survival advantage of 2 months over best supportive care. 6 , 7 Because the median overall survival with second-line therapy is only 6 . . .

In a study involving nearly 1200 men with metastatic prostate cancer who had progressive disease after chemotherapy, enzalutamide, a novel androgen-receptor blocker, extended the median survival by nearly 5 months, as compared with placebo (18 months vs. 13 months). Prostate cancer is an androgen-dependent disease that initially responds but later becomes resistant to established therapies that reduce circulating testosterone levels or inhibit androgen binding to the androgen receptor. 1 – 4 Reactivation of the disease despite castrate levels of testosterone represents a transition to the lethal phenotype of castration-resistant prostate cancer. 5 , 6 This state was previously called androgen-independent or hormone-refractory prostate cancer but is now recognized to be driven by androgen-receptor signaling, in part due to overexpression of the androgen receptor itself. 7 , 8 In preclinical models of prostate cancer, androgen-receptor overexpression shortens the period of tumor latency and confers resistance to . . .

Metastatic castration-resistant prostate cancer (mCRPC) has a highly complex genomic landscape. With the recent development of novel treatments, accurate stratification strategies are needed. Here we present the whole-genome sequencing (WGS) analysis of fresh-frozen metastatic biopsies from 197 mCRPC patients. Using unsupervised clustering based on genomic features, we define eight distinct genomic clusters. We observe potentially clinically relevant genotypes, including microsatellite instability (MSI), homologous recombination deficiency (HRD) enriched with genomic deletions and BRCA2 aberrations, a tandem duplication genotype associated with CDK12 −/− and a chromothripsis-enriched subgroup. Our data suggests that stratification on WGS characteristics may improve identification of MSI, CDK12 −/− and HRD patients. From WGS and ChIP-seq data, we show the potential relevance of recurrent alterations in non-coding regions identified with WGS and highlight the central role of AR signaling in tumor progression. These data underline the potential value of using WGS to accurately stratify mCRPC patients into clinically actionable subgroups. Detecting genomic abnormalities in metastatic castration-resistant prostate cancer (mCRPC) may impact clinical treatment. Here, the authors present whole-genome sequencing of metastatic biopsies from 197 mCRPC patients, highlighting the landscape of microsatellite stability, homologous repair deficiency, and other genomic subgroups.

The KEYNOTE-057 trial evaluated activity and safety of pembrolizumab in patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer who were ineligible for or declined radical cystectomy. In cohort A (patients with carcinoma in situ, with or without papillary tumours) of the KEYNOTE-057 study, pembrolizumab monotherapy led to a complete response rate of 41% at 3 months, and 46% of responders maintained a response lasting at least 12 months. Here, we evaluate pembrolizumab monotherapy in cohort B of patients with papillary tumours without carcinoma in situ. KEYNOTE-057 is a single-arm, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. Cohort B eligible patients were aged 18 years and older, had an Eastern Cooperative Oncology Group performance status of 0–2, and had BCG-unresponsive high-risk non-muscle-invasive bladder cancer with papillary tumours (high-grade Ta or any-grade T1) without carcinoma in situ. Transurethral resection of bladder tumour within 12 weeks of first pembrolizumab dose was required. Patients received pembrolizumab 200 mg intravenously every 3 weeks for a maximum of 35 cycles. Primary endpoint was 12-month disease-free survival of high-risk non-muscle-invasive bladder cancer or progressive disease as assessed by cystoscopy, cytology, and central pathology and radiology review. Activity was assessed in all patients who received at least one dose of the study drug and had a baseline evaluation. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing. Between April 12, 2016, and June 17, 2021, 132 patients (104 [79%] men and 28 [21%] women) who had received a median of ten (IQR 9–15) previous BCG instillations were enrolled into cohort B of the study. Patients received a median of 10 cycles (IQR 6–27) of pembrolizumab. At data cutoff date, Oct 20, 2022, median follow-up was 45·4 months (IQR 36·4–59·3) and five (4%) of 132 patients remained on treatment. The 12-month disease-free survival was 43·5% (95% CI 34·9–51·9). Treatment-related adverse events occurred in 97 (73%) of 132 patients; 19 (14%) had a grade 3 or 4 treatment-related adverse event; the most common grade 3 or 4 treatment-related adverse events were colitis (in three [2%] patients) and diarrhoea (in two [2%]). 17 (13%) of 132 patients experienced serious treatment-related adverse events, of which colitis (three patients [2%]) was most common. No treatment-related deaths occurred. Pembrolizumab monotherapy showed antitumour activity and manageable toxicity in patients with BCG-unresponsive high-risk Ta or T1 bladder cancer without carcinoma in situ and could potentially be a suitable treatment option for patients who decline or are ineligible for radical cystectomy. Findings will need to be confirmed in a randomised controlled trial. Merck Sharp & Dohme.

Response to androgen receptor signaling inhibitors (ARSI) varies widely in metastatic castration resistant prostate cancer (mCRPC). To improve treatment guidance, biomarkers are needed. We use whole-genomics (WGS; n  = 155) with matching whole-transcriptomics (WTS; n  = 113) from biopsies of ARSI-treated mCRPC patients for unbiased discovery of biomarkers and development of machine learning-based prediction models. Tumor mutational burden ( q  < 0.001), structural variants ( q  < 0.05), tandem duplications ( q  < 0.05) and deletions ( q  < 0.05) are enriched in poor responders, coupled with distinct transcriptomic expression profiles. Validating various classification models predicting treatment duration with ARSI on our internal and external mCRPC cohort reveals two best-performing models, based on the combination of prior treatment information with either the four combined enriched genomic markers or with overall transcriptomic profiles. In conclusion, predictive models combining genomic, transcriptomic, and clinical data can predict response to ARSI in mCRPC patients and, with additional optimization and prospective validation, could improve treatment guidance. Prostate cancer is known to have a variable response to androgen receptor signalling inhibitors. Here, the authors use machine learning to predict response to therapy from genomic, transcriptomic and clinical data.

Circulating tumor DNA (ctDNA) has emerged as a potential new biomarker with diagnostic, predictive, and prognostic applications for various solid tumor types. Before beginning large prospective clinical trials to prove the added value of utilizing ctDNA in clinical practice, it is essential to investigate the effects of various preanalytical conditions on the quality of cell‐free DNA (cfDNA) in general and of ctDNA in particular in order to optimize and standardize these conditions. Whole blood samples were collected from patients with metastatic cancer bearing a known somatic variant. The following preanalytical conditions were investigated: (a) different time intervals to plasma isolation (1, 24, and 96 h) and (b) different preservatives in blood collection tubes (EDTA, CellSave, and BCT). The quality of cfDNA/ctDNA was assessed by DNA quantification, digital polymerase chain reaction (dPCR) for somatic variant detection and a β‐actin fragmentation assay for DNA contamination from lysed leukocytes. In 11 (69%) of our 16 patients, we were able to detect the known somatic variant in ctDNA. We observed a time‐dependent increase in cfDNA concentrations in EDTA tubes, which was positively correlated with an increase in wild‐type copy numbers and large DNA fragments (> 420 bp). Using different preservatives did not affect somatic variant detection ability, but did stabilize cfDNA concentrations over time. Variant allele frequency was affected by fluctuations in cfDNA concentration only in EDTA tubes at 96 h. Both CellSave and BCT tubes ensured optimal ctDNA quality in plasma processed within 96 h after blood collection for downstream somatic variant detection by dPCR. The effects of preanalytical conditions on the quality of circulating tumor DNA (ctDNA) were investigated using blood samples from patients with metastatic cancer. There was a time‐dependent increase in cell‐free DNA (cfDNA) in EDTA tubes, which decreased detection of somatic variant allele frequencies (VAF). Both CellSave and BCT tubes ensure optimal ctDNA quality for up to 96 h.