Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial.

BACKGROUND: The interim analysis of the ENZAMET trial of testosterone suppression plus either enzalutamide or standard nonsteroidal antiandrogen therapy showed an early overall survival benefit with enzalutamide. Here, we report the planned primary overall survival analysis, with the aim of defining the benefit of enzalutamide treatment in different prognostic subgroups (synchronous and metachronous high-volume or low-volume disease) and in those who received concurrent docetaxel. METHODS: ENZAMET is an international, open-label, randomised, phase 3 trial conducted at 83 sites (including clinics, hospitals, and university centres) in Australia, Canada, Ireland, New Zealand, the UK, and the USA. Eligible participants were males aged 18 years or older with metastatic, hormone-sensitive prostate adenocarcinoma evident on CT or bone scanning with 99mTc and an Eastern Cooperative Oncology Group performance status score of 0-2. Participants were randomly assigned (1:1), using a centralised web-based system and stratified by volume of disease, planned use of concurrent docetaxel and bone antiresorptive therapy, comorbidities, and study site, to receive testosterone suppression plus oral enzalutamide (160 mg once per day) or a weaker standard oral non-steroidal antiandrogen (bicalutamide, nilutamide, or flutamide; control group) until clinical disease progression or prohibitive toxicity. Testosterone suppression was allowed up to 12 weeks before randomisation and for up to 24 months as adjuvant therapy. Concurrent docetaxel (75 mg/m2 intravenously) was allowed for up to six cycles once every 3 weeks, at the discretion of participants and physicians. The primary endpoint was overall survival in the intention-to-treat population. This planned analysis was triggered by reaching 470 deaths. This study is registered with ClinicalTrials.gov, NCT02446405, ANZCTR, ACTRN12614000110684, and EudraCT, 2014-003190-42. FINDINGS: Between March 31, 2014, and March 24, 2017, 1125 participants were randomly assigned to receive non-steroidal antiandrogen (n=562; control group) or enzalutamide (n=563). The median age was 69 years (IQR 63-74). This analysis was triggered on Jan 19, 2022, and an updated survival status identified a total of 476 (42%) deaths. After a median follow-up of 68 months (IQR 67-69), the median overall survival was not reached (hazard ratio 0·70 [95% CI 0·58-0·84]; p<0·0001), with 5-year overall survival of 57% (0·53-0·61) in the control group and 67% (0·63-0·70) in the enzalutamide group. Overall survival benefits with enzalutamide were consistent across predefined prognostic subgroups and planned use of concurrent docetaxel. The most common grade 3-4 adverse events were febrile neutropenia associated with docetaxel use (33 [6%] of 558 in the control group vs 37 [6%] of 563 in the enzalutamide group), fatigue (four [1%] vs 33 [6%]), and hypertension (31 [6%] vs 59 [10%]). The incidence of grade 1-3 memory impairment was 25 (4%) versus 75 (13%). No deaths were attributed to study treatment. INTERPRETATION: The addition of enzalutamide to standard of care showed sustained improvement in overall survival for patients with metastatic hormone-sensitive prostate cancer and should be considered as a treatment option for eligible patients. FUNDING: Astellas Pharma.

Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer.

BACKGROUND: Enzalutamide, an androgen-receptor inhibitor, has been associated with improved overall survival in men with castration-resistant prostate cancer. It is not known whether adding enzalutamide to testosterone suppression, with or without early docetaxel, will improve survival in men with metastatic, hormone-sensitive prostate cancer. METHODS: In this open-label, randomized, phase 3 trial, we assigned patients to receive testosterone suppression plus either open-label enzalutamide or a standard nonsteroidal antiandrogen therapy (standard-care group). The primary end point was overall survival. Secondary end points included progression-free survival as determined by the prostate-specific antigen (PSA) level, clinical progression-free survival, and adverse events. RESULTS: A total of 1125 men underwent randomization; the median follow-up was 34 months. There were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group (hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.86; P = 0.002). Kaplan-Meier estimates of overall survival at 3 years were 80% (based on 94 events) in the enzalutamide group and 72% (based on 130 events) in the standard-care group. Better results with enzalutamide were also seen in PSA progression-free survival (174 and 333 events, respectively; hazard ratio, 0.39; P<0.001) and in clinical progression-free survival (167 and 320 events, respectively; hazard ratio, 0.40; P<0.001). Treatment discontinuation due to adverse events was more frequent in the enzalutamide group than in the standard-care group (33 events and 14 events, respectively). Fatigue was more common in the enzalutamide group; seizures occurred in 7 patients in the enzalutamide group (1%) and in no patients in the standard-care group. CONCLUSIONS: Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression. The enzalutamide group had a higher incidence of seizures and other toxic effects, especially among those treated with early docetaxel. (Funded by Astellas Scientific and Medical Affairs and others; ENZAMET (ANZUP 1304) ANZCTR number, ACTRN12614000110684; ClinicalTrials.gov number, NCT02446405; and EU Clinical Trials Register number, 2014-003190-42.).

Canadian consensus on TRK-inhibitor therapy for NTRK fusion-positive sarcoma.

Malignant sarcomas are rare accounting for <1% of all adult solid malignancies and approximately 11% to 13% of all pediatric malignancies. TRK-inhibitors have demonstrated robust and long-lasting responses in patients with NTRK fusion-positive solid tumors, including sarcoma. Access to these agents in many jurisdictions such as Canada remains limited. We undertook a modified Delphi consensus to articulate and convey the clinical importance of these agents for the Canadian sarcoma community. A systematic search of published and presented literature was conducted to identify clinical trials reporting outcomes on the use of TRK-inhibitors in relapsed/refractory NTRK fusion-positive sarcoma. Three main consensus questions were identified: (a) is there currently an unmet clinical need for systemic therapy options in relapsed/refractory sarcoma? (b) do TRK-inhibitors confer a clinical benefit to patients with NTRK fusion-positive sarcoma? (c) do phase I/II basket trials provide sufficient evidence to justify funding of TRK-inhibitors in NTRK fusion-positive sarcoma? Response rates to the first and second surveys were 57% (n = 30) and 42% (n = 22), respectively. There was strong agreement among the Canadian sarcoma community that there was unmet clinical need for effective systemic therapy options in relapsed/refractory sarcoma, that TRK-inhibitors are a safe and effective treatment option for patients with NTRK fusion-positive sarcoma, and that available phase I/II basket trials provide sufficient evidence to support funding of these agents in relapsed/refractory NTRK fusion-positive sarcoma. TRK-inhibitors are a safe and effective systemic therapy option for patients with relapsed/refractory NTRK fusion-positive sarcoma.

Pantoprazole Affecting Docetaxel Resistance Pathways via Autophagy (PANDORA): Phase II Trial of High Dose Pantoprazole (Autophagy Inhibitor) with Docetaxel in Metastatic Castration-Resistant Prostate Cancer (mCRPC).

BACKGROUND: Enhancing the effectiveness of docetaxel for men with metastatic castration-resistant prostate cancer (mCRPC) is an unmet clinical need. Preclinical studies demonstrated that high-dose pantoprazole can prevent or delay resistance to docetaxel via the inhibition of autophagy in several solid tumor xenografts. MATERIALS AND METHODS: Men with chemotherapy-naive mCRPC with a prostate-specific antigen (PSA) >10 ng/mL were eligible for enrolment. Men received intravenous pantoprazole (240 mg) prior to docetaxel (75 mg/m2) every 21 days, with continuous prednisone 5 mg twice daily. Primary endpoint was a confirmed ≥50% decline of PSA. The trial used a Simon's two-stage design. RESULTS: Between November 2012 and March 2015, 21 men with a median age of 70 years (range, 58-81) were treated (median, 6 cycles; range, 2-11). Men had received prior systemic therapies (median, 1; range, 0-3), and 14 had received abiraterone and/or enzalutamide. PSA response rate was 52% (11/21), which did not meet the prespecified criterion (≥13/21 responders) to proceed to stage 2 of the study. At interim analysis with a median follow-up of 17 months, 18 (86%) men were deceased (15 castration-resistant prostate cancer, 2 unknown, 1 radiation complication). Of the men with RECIST measurable disease, the radiographic partial response rate was 31% (4/13). The estimated median overall survival was 15.7 months (95% confidence interval [CI], 9.3-19.6) and median PFS was 5.3 months (95% CI, 2.6-12.9). There were no toxic deaths, and all adverse events were attributed to docetaxel. CONCLUSION: The combination of docetaxel and pantoprazole was tolerable, but the resultant clinical activity was not sufficient to meet the ambitious predefined target to warrant further testing. IMPLICATIONS FOR PRACTICE: To date, no docetaxel combination regimen has reported superior efficacy over docetaxel alone in men with metastatic castration-resistant prostate cancer (mCRPC). The PANDORA trial has demonstrated that the combination of high dose pantoprazole with docetaxel is tolerable, but the clinical activity was not sufficient to warrant further testing. The chemotherapy standard of care for men with mCRPC remains docetaxel with prednisone. Future studies of autophagy inhibitors will need to measure autophagy inhibition accurately and determine the degree of autophagy inhibition required to produce a meaningful clinical response.

Design and Implementing Pharmacogenomics Study in Cancer.

The advances in technology has shifted healthcare from a "one size fits all" model to focus on personalized therapy. Understanding the relationship of genome variations and its effect on drug response has led to individualized drug selection, maximizing drug efficacy and improving toxicity profile. The developments in pharmacogenomics has led to the discovery of predictive and prognostic biomarkers, and has transformed cancer research leading to the creation of pharmacogenomics databases. While challenges associated with the implementation of pharmacogenomics based medicine exist, integrating data amongst collaborative networks will be crucial for researchers to identify all the functional elements of the human genome sequence. Future advances in the area of pharmacogenomics research will eventually lead to the identification of the right therapeutic drug for the right patient.

Peri-operative allogeneic blood transfusion and outcomes after radical cystectomy: a population-based study.

INTRODUCTION: To describe factors associated with peri-operative blood transfusion (PBT) at radical cystectomy (RC) for patients with bladder cancer and evaluate its association on both early and late outcomes. METHODS: Electronic records of treatment and surgical pathology reports were linked to the population-based Ontario Cancer Registry to identify all patients who underwent RC between 2000 and 2008. Modified Poisson regression model was used to determine the factors associated with PBT. A Cox-proportional hazards regression model was used to explore the association between PBT and overall (OS) and cancer-specific (CSS) survival. RESULTS: Among 2593 patients identified, 62% received an allogeneic red blood cell transfusion. The frequency of PBT decreased over the study period (from 68 to 54%, p < 0.001). Factors associated with PBT included age, sex, greater co-morbidity, stage, and surgeon volume. PBT was associated with inferior outcomes, including median length of stay (11 vs. 9 days, p < 0.001), 90-day re-admission rate (38 vs. 29%, p < 0.001), and mortality (11 vs. 4%, p < 0.001). OS and CSS at 5 years were lower among patients with PBT on multivariate analysis (OS HR 1.33, 95% CI 1.20-1.48; CSS HR 1.39, 95% CI 1.23-1.56). CONCLUSIONS: Although rates are decreasing, these data suggest a very high utilization rate of PBT at time of RC in routine clinical practice. PBT is associated with substantially worse early outcomes and long-term survival. This association persists despite adjustment for disease-, patient-, and provider-related factors, suggesting that PBT is an important indicator of surgical care of RC.

Relevance of randomised controlled trials in oncology.

Well-designed randomised controlled trials (RCTs) can prevent bias in the comparison of treatments and provide a sound basis for changes in clinical practice. However, the design and reporting of many RCTs can render their results of little relevance to clinical practice. In this Personal View, we discuss the limitations of RCT data and suggest some ways to improve the clinical relevance of RCTs in the everyday management of patients with cancer. RCTs should ask questions of clinical rather than commercial interest, avoid non-validated surrogate endpoints in registration trials, and have entry criteria that allow inclusion of all patients who are fit to receive treatment. Furthermore, RCTs should be reported with complete accounting of frequency and management of toxicities, and with strict guidelines to ensure freedom from bias. Premature reporting of results should be avoided. The bar for clinical benefit should be raised for drug registration, which should require publication and review of mature data from RCTs, post-marketing health outcome studies, and value-based pricing.

Study of testosterone-guided androgen deprivation therapy in management of prostate cancer.

BACKGROUND: Androgen deprivation therapy (ADT) with luteinizing hormone releasing hormone (LHRH) agonists is an effective initial therapy for men with advanced prostate cancer. LHRH agonists are usually administered indefinitely at a fixed interval. METHODS: We recruited men with advanced prostate cancer who had been on fixed-schedule injections of an LHRH agonist for ≥1 year and had castrate serum testosterone [<1.75 nmol/l (approx. 50 ng/ml)]. Testosterone levels were measured at 6-week intervals and ADT was withheld until testosterone levels were no longer in the castrate range and then reinstituted. Time to reinstitution of ADT was the primary outcome and was analyzed by the Kaplan-Meier method; Cox regression was used to identify factors predicting delay in reinstitution of treatment. Influence on quality-of-life (QoL) was evaluated by the Expanded Prostate Index Composite (EPIC). RESULTS: Forty-six evaluable men who had received LHRH agonist injections every 12 weeks were recruited. Median time to testosterone recovery (defined as testosterone outside the defined castrate level) after previous injection was >1 year. In univariable analysis, lower baseline testosterone [≤1 vs. >1 nmol/l (approx. 30 ng/dl)] and longer time on ADT (>5 vs. ≤5 years) predicted for prolonged time to testosterone recovery, but only lower baseline testosterone remained significant in multivariable analysis (Hazard Ratio = 5.2, P = 0.03). Overall EPIC scores remained stable but improvement from baseline was observed in the hormonal domain (P = 0.002). Median per-patient saving in cost was approximately USD 3,100 (1,050-6,200). CONCLUSIONS: Testosterone-guided ADT reduces exposure to LHRH agonists, with reduction in cost and improvement in some symptoms from ADT. Testosterone-guided ADT should be considered an alternative to fixed schedule treatment by physicians and policy makers.

Retreatment of men with metastatic castrate-resistant prostate cancer with abiraterone.

BACKGROUND: Abiraterone acetate (AA), oral CYP17 inhibitor, is an active agent in the treatment of metastatic castrate-resistant prostate cancer (mCRPC). METHODS: We (R.L.A and N.A) retrospectively evaluated outcome in 12 men who were re-treated with AA following prior treatment with AA at the Princess Margaret Cancer Centre. RESULTS: All men were heavily pre-treated for mCRPC with a median of four prior lines of therapy, one of which was AA (given either pre- or post-chemotherapy). Eleven out of 12 (92%) men stopped their first treatment course of AA due to progression and one stopped for financial reasons. Seven men had a PSA decrease ≥50% following their first AA treatment, of which three (46%) had a PSA decrease ≥50% to AA re-treatment. The responses to AA re-treatment were generally short-lived with a median biochemical progression-free survival of 2.3 months and median treatment duration of 3.2 months. No PSA responses to AA re-treatment were seen in five men who did not have an initial PSA response to AA. CONCLUSIONS: Our data suggest that AA re-challenge may have limited benefit in select men with mCRPC, and warrants further formal research.

Simple prognostic score for metastatic castration-resistant prostate cancer with incorporation of neutrophil-to-lymphocyte ratio.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR), a marker of inflammation, has been reported to be a poor prognostic indicator in prostate cancer. Here we explore the use of the NLR to establish a simple prognostic score for men with metastatic castration-resistant prostate cancer (mCRPC) treated with docetaxel. METHODS: In the training cohort, the NLR and other known prognostic variables were evaluated among a cohort of chemotherapy-naïve patients treated with thrice-weekly docetaxel at the Princess Margaret Cancer Centre. Significant prognostic variables identified by univariable Cox regression were evaluated by the area under the receiver operating characteristic curves. Multivariable Cox regression was then used to derive a prognostic score where 1 risk point was assigned for each significant variable. The model was externally validated in a cohort of patients treated at the Royal Marsden. RESULTS: Three hundred fifty-seven patients were analyzed in the training cohort. Median age was 71 years, 12% had liver metastasis, and median overall survival (OS) was 14.7 months. Liver metastases, hemoglobin <12 g/dL, alkaline phosphatase >2.0× upper limit of normal (ULN), lactate dehydrogenase >1.2× ULN, and NLR >3 were associated with significantly worse OS in multivariable analysis. Four risk categories were subsequently established with 0, 1, 2, and 3-5 points. Two-year OS rates for these categories were 43%, 37%, 12%, and 3%, respectively. Area under the curve for the training cohort was 0.78 (95% CI, 0.72-0.84) compared with 0.66 (95% CI, 0.58-0.74) for the 215 patients in the validation cohort. CONCLUSIONS: This simple risk score provides good prognostic and discriminatory accuracy for men with mCRPC.

Effect of multifocality and multicentricity on outcome in early stage breast cancer: a systematic review and meta-analysis.

Women with multifocal or multicentric breast tumors (multifocality henceforth) have been reported to have greater probability of nodal metastasis and relapse and worse survival than women with unifocal tumors. However, these associations have been inconsistent and multifocality is not taken into account by staging guidelines and prognostic models. A systematic review of electronic databases identified publications exploring the association between multifocality and overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), and loco-regional relapse (LRR). The hazard ratios (HRs) for OS and DFS for multifocal compared to unifocal tumors were extracted from multivariable analyses and included in a meta-analysis. For studies not reporting multivariable analyses, odds ratios (OR) were estimated from Kaplan-Meier curves for all endpoints at 5 and 10 years. Twenty-two studies comprising 67,557 women were included. Multifocality was reported in 9.5 % of patients. Classical prognostic factors were well balanced between unifocal and multifocal populations. In multivariable analyses, multifocality was associated with significantly worse OS (HR 1.65; P = 0.02), and a non-significant association with worse DFS (HR 1.96; P = 0.07). In univariable analyses, multifocality was associated with worse OS, DFS, DSS, and LRR at 5 years (OR 1.39, P = 0.02; OR 1.52, P = 0.02; OR 1.56, P = 0.03; and OR 3.23, P = 0.02, respectively). Similar estimates were observed at 10 years, but statistical significance was only reached for DSS and LRR. Mutifocality appears to be associated with a worse prognosis, however, substantial inter-study heterogeneity limits the precise determination of increased risk. Further validation of the independent prognostic impact of multifocality is warranted.

NECTIN4 Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer.

PURPOSE: The anti-NECTIN4 antibody-drug conjugate enfortumab vedotin (EV) is approved for patients with metastatic urothelial cancer (mUC). However, durable benefit is only achieved in a small, yet uncharacterized patient subset. NECTIN4 is located on chromosome 1q23.3, and 1q23.3 gains represent frequent copy number variations (CNVs) in urothelial cancer. Here, we aimed to evaluate NECTIN4 amplifications as a genomic biomarker to predict EV response in patients with mUC. MATERIALS AND METHODS: We established a NECTIN4-specific fluorescence in situ hybridization (FISH) assay to assess the predictive value of NECTIN4 CNVs in a multicenter EV-treated mUC patient cohort (mUC-EV, n = 108). CNVs were correlated with membranous NECTIN4 protein expression, EV treatment responses, and outcomes. We also assessed the prognostic value of NECTIN4 CNVs measured in metastatic biopsies of non-EV-treated mUC (mUC-non-EV, n = 103). Furthermore, we queried The Cancer Genome Atlas (TCGA) data sets (10,712 patients across 32 cancer types) for NECTIN4 CNVs. RESULTS: NECTIN4 amplifications are frequent genomic events in muscle-invasive bladder cancer (TCGA bladder cancer data set: approximately 17%) and mUC (approximately 26% in our mUC cohorts). In mUC-EV, NECTIN4 amplification represents a stable genomic alteration during metastatic progression and associates with enhanced membranous NECTIN4 protein expression. Ninety-six percent (27 of 28) of patients with NECTIN4 amplifications demonstrated objective responses to EV compared with 32% (24 of 74) in the nonamplified subgroup (P < .001). In multivariable Cox analysis adjusted for age, sex, and Bellmunt risk factors, NECTIN4 amplifications led to a 92% risk reduction for death (hazard ratio, 0.08 [95% CI, 0.02 to 0.34]; P < .001). In the mUC-non-EV, NECTIN4 amplifications were not associated with outcomes. TCGA Pan-Cancer analysis demonstrated that NECTIN4 amplifications occur frequently in other cancers, for example, in 5%-10% of breast and lung cancers. CONCLUSION: NECTIN4 amplifications are genomic predictors of EV responses and long-term survival in patients with mUC.

Benefit and harms of new anti-cancer drugs.

Phase III randomized controlled trials (RCTs) assess clinically important differences in endpoints that reflect benefit to and harm of patients. Defining benefit of cancer drugs can be difficult. Overall survival and quality of life are the most relevant primary endpoints, but difficulty in measuring these mean that other endpoints are often used, although their surrogacy or clinical relevance has not always been established. In general, advances in drug development have led to numerous new drugs to enter the market. Pivotal RCT of several new drugs have shown that benefit appeared greater for targeted anticancer agents than for chemotherapeutic agents. This effect seems particularly evident with targeted agents evaluated in biomarker-driven studies. Unfortunately, new therapies have also shown an increase in toxicity. Such toxicity is not always evident in the initial reports of RCTs. This may be a result of a statistical inability to detect differences between arms of RCTs, or occasionally due to biased reporting. There are several examples where reports of new toxicities could only be found in drug labels. In some cases, the small improvement in survival has come at a cost of substantial excess toxicity, leading some to consider such therapy as having equipoise.

A real-world retrospective analysis of the management of metastatic castrate-resistant prostate cancer in Ontario, Canada from 2010 - 2018.

PURPOSE: We sought to quantify mCRPC patient treatment patterns and survival across multiple lines of therapy after prior androgen-receptor-axis-targeted therapy (ARAT) failure. METHODS: Individuals diagnosed with prostate cancer between 2010 and 2018 were identified in the Ontario Cancer Registry (OCR). An algorithm was created to identify patients with mCRPC that was aligned to Prostate Cancer Clinical Trials Working Group 3 criteria (PCWG3) and validated with Canadian clinical experts. In the mCRPC setting, treatment patterns were assessed by line of therapy, and survival was calculated from treatment initiation until death or lost to follow-up. RESULTS: 64,484 men were diagnosed withprostate cancer in Ontario between 2010 and 2018with 5,588 men assessed to have mCRPC and 2,970 (53%) of those received first-line systemic treatment. Across the first-, second- and third-line of therapy, ARATs (abiraterone and enzalutamide) were the most used therapies. Survival for mCRPC patients treated with ARATs in first-, second- and third-line were 13.0 (95% CI, 11.6 - 14.5), 11.5 (95% CI, 10.1 - 13.4) and 8.9 (95% CI, 7.4 - 10.2) months, respectively. Survival for mCRPC patients treated with taxanes in first, second- and third-line were 16.7 (95% CI, 14.8 - 18.0), 11.3 (95% CI, 10.1 - 12.5) and 7.8 (95% CI, 6.5 - 10.6) months, respectively. No statistical difference in overall survival was found between taxanes and ARATs. CONCLUSION: In this analysis of a large retrospective cohort of Canadian men with mCRPC, we found that survival in patients treated with ARATs and taxanes was fairly similar across all lines of therapy. Importantly, this trend was maintained in ARAT-exposed patients, where sequential ARAT and taxanes offered similar survival. These data may help inform optimal sequencing of therapies in mCRPC.

Can Oncogenic Driver Alterations be Responsible for the Lack of Immunotherapy Efficacy in First-line Advanced Urothelial Carcinoma?

Urothelial carcinoma (UC) harbors many oncogenic alterations and the limited efficacy of first-line immunotherapy in this setting suggests that oncogenic alterations could have potential as a predictive biomarker for treatment decision-making. Antibody-drug conjugates (ADCs) may offer new avenues for biomarker-driven treatment in advanced UC, especially for patients with oncogenic alterations.

Management of small HER2 overexpressing tumours.

Overexpression of the human epidermal growth factor receptor 2 (HER2) is found in 10-20 % of breast cancers and is associated with a worse prognosis. Several large studies have established the addition of trastuzumab to chemotherapy as the gold standard in early breast cancer that overexpresses HER2. Little is known about the role of such adjuvant treatment in node-negative subcentimeter tumours ('small tumours', pT1a/b) because these patients were generally excluded from the pivotal trials. Only the BCIRG006 study published in 2011 included such tumours if high-risk features were present. Here we review the literature of small HER2-positive tumours and present a meta-analysis of retrospective studies confirming a worse outcome in terms of disease-free survival (hazard ratio 2.6, p < 0.001) and a trend for higher odds of distant recurrence at 5 years (odds ratio [OR] 2.51, p = 0.11). We discuss these findings in the light of the increased risk of grade 3 and 4 cardiac toxicity (OR 7.6, p < 0.001) and other adverse events associated with the use of trastuzumab. Such treatment may well be a valuable option in selected patients with high-risk features but physicians should exercise caution given the small absolute benefits of adjuvant chemotherapy and trastuzumab for patients with small HER2-overexpressing tumours.

Chromophobe renal cell carcinoma: a review of an uncommon entity.

Renal cell carcinoma is the most common neoplasm of the kidney. It is a heterogeneous disease, comprised of different histological variants with a distinct clinical course, genetics and response to treatment. The various subtypes identified include clear cell, papillary and chromophobe, among others. Chromophobe renal cell carcinoma is a rare variant and accounts for 5% of all cases. These tumors are macroscopically larger when compared with other forms and are commonly diagnosed at an early stage. Despite significant advances in renal cell carcinoma therapeutics in the past decade, no standard treatment has been identified for advanced chromophobe renal cell carcinoma. Nevertheless, new molecular insights have recently become available. A familial form of renal cell carcinoma, the Birt-Hogg-Dubé syndrome, has been described and the knowledge obtained has opened research opportunities in the therapeutic arena of chromophobe renal cell carcinoma. The following manuscript will endeavor to provide an overview of this uncommon entity including pathology, epidemiology, genetics, clinical aspects, and current and future treatment options.

Adjuvant Radiotherapy for Upper Tract Urothelial Carcinoma: Systematic Review and Meta-Analysis.

PURPOSE: Upper tract urothelial carcinoma (UTUC) is a rare form of malignancy comprising only 5% of urothelial cancers. The mainstay of treatment is radical nephroureterectomy (RNU) with bladder cuff excision. Neoadjuvant or adjuvant chemotherapy is often used in locally advanced disease. The role of adjuvant radiotherapy (RT), however, remains controversial. To further explore the potential role of adjuvant RT, we performed a systematic review and meta-analysis of the literature from 1990 to present. METHODS AND MATERIALS: We identified 810 candidate articles from database searches, of which 67 studies underwent full-text review, with final inclusion of 20 eligible studies. Among the included studies, there were no randomized controlled trials and a single prospective trial, with the remainder being retrospective series. We performed quantitative synthesis of the results by calculating the pooled odds ratios (OR) for the primary outcome of locoregional recurrence (LRR) and secondary outcomes of overall survival (OS), cancer-specific survival (CSS) and distant recurrence (DR). RESULTS: Adjuvant RT, which was mostly prescribed for locally advanced or margin-positive disease following RNU, significantly reduced locoregional recurrence risk OR 0.43 (95% CI: 0.23-0.70), and the effect remained significant even following subgroup analysis to account for adjuvant systemic therapy. The effect of adjuvant RT on 3-year OS, 5-year CSS and DR was non-significant. However, 5-year OS was unfavourable in the adjuvant RT arm, but study heterogeneity was high, and analysis of small-study effects and subgroups suggested bias in reporting of outcomes. CONCLUSIONS: Adjuvant RT in the setting of locally advanced UTUC improves locoregional control following definitive surgery, but does not appear to improve OS. Higher-quality studies, ideally randomized controlled trials, are needed to further quantify its benefit in this setting, and to explore multi-modal treatments that include systemic agents given concomitantly or sequentially with RT, which may offer an OS benefit in addition to the locoregional control benefit of RT.

Complete response and survival outcomes in patients with advanced cancer on immune checkpoint inhibitors.

Aim: To evaluate overall survival in advanced cancer patients who achieved complete response (CR) with immune checkpoint inhibitor (ICI) therapy. Methods: This retrospective study included patients with advanced unresectable or metastatic cancer who received at least one cycle of palliative-intent ICI. Best overall response was used to define response groups. Results: 21 (7%) of 322 patients achieved CR. Multivariate analysis demonstrated that CR was independently associated with better overall survival compared with disease progression (hazard ratio: 0.012; 95% CI: 0.002-0.090) and stable disease (hazard ratio: 0.063; 95% CI: 0.009-0.464) as well as a nonsignificant trend toward better overall survival compared with partial response (hazard ratio: 0.169; 95% CI: 0.023-1.252) regardless of cancer type, ICI regimen or ICI line. Conclusion: Patients who achieved CR had longer survival compared with patients who did not achieve CR.

Primary results of STRONG: An open-label, multicenter, phase 3b study of fixed-dose durvalumab monotherapy in previously treated patients with urinary tract carcinoma.

BACKGROUND: Prior durvalumab (anti-PD-L1 agent) studies in platinum-refractory metastatic urothelial carcinoma evaluated a dose of 10 mg/kg administered every two weeks. The nonrandomised phase 3b STRONG study (NCT03084471) evaluated the safety and efficacy of fixed-dose durvalumab at a more convenient dosing schedule in a previously treated patient population, more similar to a real-world clinical setting. PATIENTS AND METHODS: 867 patients with urothelial or nonurothelial urinary tract carcinoma (UTC) who progressed on or after platinum or nonplatinum chemotherapy were treated with durvalumab 1500 mg every four weeks; 87% had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1, and 13% had an ECOG PS of 2. The primary end-point was the incidence of adverse events of special interest (AESIs), including immune-mediated AEs (imAEs). Secondary and exploratory end-points included overall survival (OS), objective response rate (ORR) and disease control rate (at six and 12 months) (DCR). RESULTS: AESIs of any grade were reported in 51% of patients (8% grade ≥ 3). The incidence of imAEs was 11% (2% grade ≥ 3). The median OS was 7.0 months (95% confidence interval [CI]: 6.4-8.2) and ORR was 18% (95% CI: 14.8-20.6), with complete responses in 5% of patients and a DCR at six months of 19% (95% CI: 16.1-22.1). CONCLUSION: Fixed-dose durvalumab monotherapy every four weeks has an acceptable safety profile and yields durable clinical activity in previously chemotherapy-treated patients with UTC. Safety and efficacy are consistent with previous durvalumab studies and other anti-PD-1/PD-L1 agents in this setting. CLINICALTRIALS. GOV IDENTIFIER: NCT03084471https://clinicaltrials.gov/ct2/show/NCT03084471.