PRESTO: A Phase III, Open-Label Study of Intensification of Androgen Blockade in Patients With High-Risk Biochemically Relapsed Castration-Sensitive Prostate Cancer (AFT-19).

PURPOSE: Patients with biochemically recurrent prostate cancer (BRPC) after radical prostatectomy and a short PSA doubling time are at risk for distant metastases. Apalutamide, an androgen receptor antagonist, and abiraterone acetate plus prednisone (AAP) prolong survival in the metastatic setting. We evaluated whether intensification of androgen-deprivation therapy (ADT) improves outcomes in BRPC. PATIENTS AND METHODS: PRESTO is a randomized phase III, open-label trial in patients with BRPC and PSA doubling time ≤9 months (ClinicalTrials.gov identifier: NCT03009981). Patients were randomly assigned 1:1:1 to receive a finite 52-week treatment course with ADT control, ADT + apalutamide, or ADT + apalutamide + AAP. The primary end point was PSA progression-free survival (PSA-PFS), defined as serum PSA >0.2 ng/mL after treatment completion. RESULTS: Five hundred three patients were enrolled. The median PSA was 1.8 ng/mL (IQR, 1.0-3.6). At the first planned interim analysis, both experimental arms significantly prolonged PSA-PFS compared with the control arm (median, 24.9 months for ADT + apalutamide v 20.3 months for ADT; hazard ratio [HR], 0.52 [95% CI, 0.35 to 0.77]; P = .00047; median, 26.0 months for ADT + apalutamide + AAP v 20.0 months for ADT; HR, 0.48 [95% CI, 0.32 to 0.71]; P = .00008). Median time to testosterone recovery did not differ across treatment arms. The most common grade ≥3 adverse event was hypertension (7.5%, 7.4%, and 18% in ADT, ADT + apalutamide, and ADT + apalutamide + AAP arms, respectively). CONCLUSION: Intensified AR blockade for a finite duration prolongs PSA-PFS with a manageable safety profile, without adversely affecting time to testosterone recovery. The addition of apalutamide to ADT should be considered in patients with high-risk BRPC.

Dysregulation of the PRUNE2/PCA3 genetic axis in human prostate cancer: from experimental discovery to validation in two independent patient cohorts.

Background: We have previously shown that the long non-coding (lnc)RNA prostate cancer associated 3 (PCA3; formerly prostate cancer antigen 3) functions as a trans-dominant negative oncogene by targeting the previously unrecognized prostate cancer suppressor gene PRUNE2 (a homolog of the Drosophila prune gene), thereby forming a functional unit within a unique allelic locus in human cells. Here, we investigated the PCA3/PRUNE2 regulatory axis from early (tumorigenic) to late (biochemical recurrence) genetic events during human prostate cancer progression. Methods: The reciprocal PCA3 and PRUNE2 gene expression relationship in paired prostate cancer and adjacent normal prostate was analyzed in two independent retrospective cohorts of clinically annotated cases post-radical prostatectomy: a single-institutional discovery cohort (n=107) and a multi-institutional validation cohort (n=497). We compared the tumor gene expression of PCA3 and PRUNE2 to their corresponding expression in the normal prostate. We also serially examined clinical/pathological variables including time to disease recurrence. Results: We consistently observed increased expression of PCA3 and decreased expression of PRUNE2 in prostate cancer compared with the adjacent normal prostate across all tumor grades and stages. However, there was no association between the relative gene expression levels of PCA3 or PRUNE2 and time to disease recurrence, independent of tumor grades and stages. Conclusions: We concluded that upregulation of the lncRNA PCA3 and targeted downregulation of the protein-coding PRUNE2 gene in prostate cancer could be early (rather than late) molecular events in the progression of human prostate tumorigenesis but are not associated with biochemical recurrence. Further studies of PCA3/PRUNE2 dysregulation are warranted. Funding: We received support from the Human Tissue Repository and Tissue Analysis Shared Resource from the Department of Pathology of the University of New Mexico School of Medicine and a pilot award from the University of New Mexico Comprehensive Cancer Center. RP and WA were supported by awards from the Levy-Longenbaugh Donor-Advised Fund and the Prostate Cancer Foundation. EDN reports research fellowship support from the Brazilian National Council for Scientific and Technological Development (CNPq), Brazil, and the Associação Beneficente Alzira Denise Hertzog Silva (ABADHS), Brazil. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of New Mexico Comprehensive Cancer Center (CA118100) and the Rutgers Cancer Institute of New Jersey (CA072720).

The growing role of rucaparib in contemporary treatment of metastatic prostate cancer: a review of efficacy and guidance for side effect management.

INTRODUCTION: In May 2020, the approval of rucaparib - a poly-ADP-ribose polymerase (PARP) inhibitor - in the USA marked the arrival of a new class of targeted therapeutics for a subset of metastatic castration-resistant prostate cancer patients whose tumors harbor germline or somatic BRCA1/2 gene alterations. It has now become critical for physicians to be aware of the role and nuances of management of PARP inhibitor therapies in prostate cancer. AREAS COVERED: We focus on rucaparib's pharmacology, key clinical trials that support its current indication, the competitive landscape, and our considerations for management of adverse events. We also review the ongoing clinical trials that may expand its utility in prostate cancer in our expert opinion. Finally, we discuss the opportunities that exist for further development of this class of targeted agents in prostate cancer. EXPERT OPINION: We believe that the time has come to develop functional assays of HRR proficiency or deficiency in order to better guide PARP inhibitor selection for patients with prostate cancer and beyond.

A Phase Ib/II Study of the CDK4/6 Inhibitor Ribociclib in Combination with Docetaxel plus Prednisone in Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: Ribociclib, a CDK4/6 inhibitor, demonstrates preclinical antitumor activity in combination with taxanes. We evaluated the safety and efficacy of ribociclib plus docetaxel in a phase Ib/II study in metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Patients had chemotherapy-naïve mCRPC with progression on ≥ 1 androgen receptor signaling inhibitor (ARSI). The phase II primary endpoint was 6-month radiographic progression-free survival (rPFS) rate, with an alternative hypothesis of 55% versus 35% historical control. Circulating tumor cells (CTC) were collected at baseline and genomically profiled. RESULT: Forty-three patients were enrolled (N = 30 in phase II). Two dose-limiting toxicities were observed (grade 4 neutropenia and febrile neutropenia). The recommended phase II dose (RP2D) and schedule was docetaxel 60 mg/m2 every 21 days plus ribociclib 400 mg/day on days 1-4 and 8-15 with filgrastim on days 5-7. At the RP2D, neutropenia was the most common grade ≥ 3 adverse event (37%); however, no cases of febrile neutropenia were observed. The primary endpoint was met; the 6-month rPFS rate was 65.8% [95% confidence interval (CI): 50.6%-85.5%; P = 0.005] and median rPFS was 8.1 months (95% CI, 6.0-10.0 months). Thirty-two percent of evaluable patients achieved a PSA50 response. Nonamplified MYC in baseline CTCs was associated with longer rPFS (P = 0.052). CONCLUSIONS: The combination of intermittent ribociclib plus every-3-weeks docetaxel demonstrated acceptable toxicity and encouraging efficacy in ARSI-pretreated mCRPC. Genomic profiling of CTCs may enrich for those most likely to derive benefit. Further evaluation in a randomized clinical trial is warranted.

Co-Inhibition of Androgen Receptor and PARP as a Novel Treatment Paradigm in Prostate Cancer-Where Are We Now?

Metastatic prostate cancer remains lethal with a 5-year survival rate of about 30%, indicating the need for better treatment options. Novel antiandrogens (NAA)-enzalutamide and abiraterone-have been the mainstay of treatment for advanced disease since 2011. In patients who progress on the first NAA, responses to the second NAA are infrequent (25-30%) and short-lasting (median PFS ~3 months). With the growing adoption of NAA therapy in pre-metastatic castration-resistant settings, finding better treatment options for first-line mCRPC has become an urgent clinical need. The regulatory approval of two PARP inhibitors in 2020-rucaparib and olaparib-has provided the first targeted therapy option for patients harboring defects in selected DNA damage response and repair (DDR) pathway genes. However, a growing body of preclinical and clinical data shows that co-inhibition of AR and PARP induces synthetic lethality and could be a promising therapy for patients without any DDR alterations. In this review article, we will investigate the limitations of NAA monotherapy, the mechanistic rationale for synthetic lethality induced by co-inhibition of AR and PARP, the clinical data that have led to the global development of a number of these AR and PARP combination therapies, and how this may impact patient care in the next 2-10 years.

Telehealth in cancer care during COVID-19: disparities by age, race/ethnicity, and residential status.

PURPOSE: Telehealth may remain an integral part of cancer survivorship care after the SARS-CoV-2 pandemic. While telehealth may reduce travel/waiting times and costs for many patients, it may also create new barriers that could exacerbate care disparities in historically underserved populations, manifesting as differences in overall care participation, and in differential video versus phone use for telehealth. METHODS: We reviewed visits by cancer survivors between January and December 2020 at a designated cancer center in Minnesota. We used descriptive statistics, data visualization, and generalized estimating equation logistic regression models to compare visit modalities and trends over time by age, urban/rural status, and race/ethnicity. RESULTS: Among 159,301 visits, including 33,242 telehealth visits, older and rural-dwelling individuals were underrepresented in telehealth compared with in-person care. Non-Hispanic White individuals, those aged 18-69 years, and urban residents used video for > 50% of their telehealth visits. In contrast, those aged ≥ 70 years, rural residents, and most patient groups of color used video for only 33-43% of their telehealth visits. Video use increased with time for everyone, but relative differences in telehealth modalities persisted. Visits of Black/African American patients temporarily fell in spring/summer 2020. CONCLUSIONS: Our findings underscore reduced uptake of telehealth, especially video, among potentially vulnerable patient populations. Future research should evaluate reasons for differential telehealth utilization and whether visit modality (in-person versus video versus phone) affects cancer outcomes. IMPLICATIONS FOR CANCER SURVIVORS: A long-term cancer care model with integrated telehealth elements needs to account for specific barriers for vulnerable populations.

Rapidly evolving treatment paradigm and considerations for sequencing therapies in metastatic prostate cancer-a narrative review.

The treatment landscape of metastatic prostate cancer (mPCa) has evolved considerably over the past 15 years with approvals of targeted therapies such as poly-ADP-ribose polymerase inhibitors (PARPi) in castration-resistant [metastatic castration-resistant prostate cancer (mCRPC)] setting and novel antiandrogens and docetaxel in hormone-sensitive [metastatic hormone-sensitive prostate cancer (mHSPC)] setting. A number of promising clinical trials are now evaluating therapeutic combinations rooted in an improving understanding of tumor biology. Despite a plethora of effective treatment options, decisions regarding choice of therapy remain challenging due to the lack of head-to-head trials and a substantial overlap in selection criteria used in these trials. We summarize the data from key trials that led to approval of commonly used mPCa therapies and provides an easy-to-use clinical decision-making framework that incorporates patient-specific and disease-specific factors to aid selection of the optimal therapy. We outline the evolving use-cases for biomarker-guided treatment selection and our approach to incorporating these therapies in clinical practice. Finally, we highlight the rapidly growing pipeline of therapies that are in advanced stages of clinical development, such as combinations of novel antiandrogen and PARPi, vascular endothelial growth factor (VEGF) inhibitor and immunotherapy, as well as prostate specific membrane antigen (PSMA)-targeted therapies, many of which are poised to transform the landscape in the coming decade.

Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study.

BACKGROUND: Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients. METHODS: We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0-1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with ClinicalTrials.gov (NCT02501096) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants. FINDINGS: Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3-28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8-89·3) of 22 treatment-naive patients, seven (41·2%, 18·4-67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7-65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 [21%] of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia). INTERPRETATION: Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC. FUNDING: Eisai and Merck Sharp & Dohme.

Impact of clinical versus radiographic progression on clinical outcomes in metastatic castration-resistant prostate cancer.

OBJECTIVES: Unequivocal clinical progression (UCP)-a worsening of clinical status with or without radiographic progression (RAD)-represents a distinct mode of disease progression in metastatic prostate cancer. We evaluated the prevalence, risk factors and the impact of UCP on survival outcomes. METHODS: A post-hoc analysis of the COU-AA-302, a randomised phase 3 study of abiraterone plus prednisone (AAP) versus prednisone was performed. Baseline characteristics were summarised. Cox proportional-hazards model and Kaplan-Meier method were used for survival and time to event analyses, respectively. Iterative multiple imputation method was used for correlation between clinicoradiographic progression-free survival (crPFS) and overall survival (OS). RESULTS: Of 736 patients with disease progression, 280 (38%) had UCP-only and 124 (17%) had UCP plus RAD. Prognostic index model high-risk group was associated with increased likelihood of UCP (p<0.0001). Median OS was 25.7 months in UCP-only and 33.0 months for RAD-only (HR 1.39; 95% CI 1.16 to 1.66; p=0.0003). UCP adversely impacted OS in both treatment groups. Lowest OS was seen in patients with prostate specific antigen (PSA)-non-response plus UCP-only progression (median OS 22.6 months (95% CI 20.7 to 24.4)). Including UCP events lowered estimates of treatment benefit-median crPFS was 13.3 months (95% CI 11.1 to 13.8) versus median rPFS of 16.5 months (95% CI 13.8 to 16.8) in AAP group. Finally, crPFS showed high correlation with OS (r=0.67; 95% CI 0.63 to 0.71). CONCLUSIONS: UCP is a common and clinically relevant phenomenon in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with AAP or prednisone. UCP is prognostic and associated with inferior OS and post-progression survival. A combination of PSA-non-response and UCP identifies patients with poorest survival. When included in PFS analysis, UCP diminishes estimates of treatment benefit. Continued study of UCP in mCRPC is warranted.

Anti-S100A4 Antibody Therapy Is Efficient in Treating Aggressive Prostate Cancer and Reversing Immunosuppression: Serum and Biopsy S100A4 as a Clinical Predictor.

S100A4 oncoprotein plays a critical role during prostate cancer progression and induces immunosuppression in host tissues. We hypothesized that S100A4-regulated oncogenic activity in immunosuppressed prostate tumors promotes growth of neoplastic cells, which are likely to become aggressive. In the current study, we investigated whether biopsy-S100A4 gene alteration independently predicts the outcome of disease in patients and circulatory-S100A4 is druggable target for treating immunosuppressive prostate cancer. Aided by DECIPHER-genomic test, we show biopsy-S100A4 overexpression as predictive of (i) poor ADT response and (ii) high risk of mortality in 228 radical prostatectomy-treated patients. Furthermore, analysis of tumor genome data of more than 1,000 patients with prostate cancer (PRAD/SU2C/FHCRC studies) validated the association of S100A4-alteration to poor survival and metastasis. We show that increased serum-S100A4 levels are associated to the prostate cancer progression in patients. The prerequisite for metastasis is the escape of tumor cells via vascular system. We show that extracellular-S100A4 protein as a growth factor induces vascular transmigration of prostate cancer cells and bone demineralization thus forms an ideal target for therapies for treating prostate cancer. By employing surface plasmon resonance and isothermal titration calorimetry, we show that mab6B12 antibody interacts with and neutralizes S100A4 protein. When tested for therapeutic efficacy, the mab6B12 therapy reduced the (i) osteoblastic demineralization of bone-derived MSCs, (ii) S100A4-target (NFκB/MMP9/VEGF) levels in prostate cancer cells, and (iii) tumor growth in a TRAMPC2 syngeneic mouse model. The immuno-profile analysis showed that mAb6B12-therapy (i) shifted Th1/Th2 balance (increased Stat4+/T-bet+ and decreased GATA2+/CD68+/CD45+/CD206+ cells); (ii) modulated cytokine levels in CD4+ T cells; and (iii) decreased levels of IL5/6/12/13, sTNFR1, and serum-RANTES. We suggest that S100A4-antibody therapy has clinical applicability in treating immunosuppressive prostate cancer in patients.

Triple Aberrant Prostate Cancer (TAPC) - Aggregate role of aberrations in TP53, PTEN and RB1 on ETS gene fusions and prognosis in metastatic castrate resistant prostate cancer.

BACKGROUND: Aberrations in TP53, PTEN and RB1 are key drivers of therapy resistance in prostate cancer. Up to 50% of prostate cancers harbor ETS gene rearrangements, a potentially compounding aggressive biological event. Little is known about the impact of aggregate aberrations and gene fusion events in prostate cancer. METHODS: Using cBioportal for Cancer Genomics, an open-access resource for exploration of multidimensional cancer genomics data, we integrate whole-exome sequencing, gene expression, and histopathology with longitudinal clinical outcomes. Subsets of prostate tumors with aberrations in all three genes TP53, PTEN and RB1 were identified and correlated with prevalence of gene fusions. Prostate tumors with aberrations in TP53, PTEN, and RB1 were termed "triple aberrant prostate cancer" (TAPC). RESULTS: Of 479 metastatic prostate tumors, 195 (40.7%) were TAPC, versus 21 of 594 (3.5%) of primary prostate tumors. Patients with metastatic TAPC showed a trend toward poorer overall survival than patients harboring 0, 1 or 2 of these aberrations. Twenty-five distinct fusions were identified, all involving ETS transcription factors. Both primary and metastatic prostate cancers with ETS fusions were significantly more likely to be TAPC than those without ETS fusions. CONCLUSIONS: This study identified a unique molecular signature consisting of combined aberrations in TP53, PTEN and RB1 that is associated with poorer overall survival, as well as increasing prevalence of ETS gene fusions and differential gene expression patterns favoring aggressive disease and tumor progression. Identification of this subset of patients could inform prognostic decisions and provide a rationale for more aggressive or unique therapeutic approaches.

NK-Cell-Mediated Targeting of Various Solid Tumors Using a B7-H3 Tri-Specific Killer Engager In Vitro and In Vivo.

We improved the bispecific antibody platform that primarily engages natural killer (NK) cells to kill cancer cells through antibody-dependent cellular cytotoxicity (ADCC) by adding IL-15 as a crosslinker that expands and self-sustains the effector NK cell population. The overall goal was to target B7-H3, an established marker predominantly expressed on cancer cells and minimally expressed on normal cells, and prove that it could target cancer cells in vitro and inhibit tumor growth in vivo. The tri-specific killer engager (TriKETM) was assembled by DNA shuffling and ligation using DNA encoding a camelid anti-CD16 antibody fragment, a wild-type IL-15 moiety, and an anti-B7-H3 scFv (clone 376.96). The expressed and purified cam1615B7H3 protein was tested for in vitro NK cell activity against a variety of tumors and in vivo against a tagged human MA-148 ovarian cancer cell line grafted in NSG mice. cam1615B7H3 showed specific NK cell expansion, high killing activity across a range of B7-H3+ carcinomas, and the ability to mediate growth inhibition of aggressive ovarian cancer in vivo. cam1615B7H3 TriKE improves NK cell function, expansion, targeted cytotoxicity against various types of B7-H3-positive human cancer cell lines, and delivers an anti-cancer effect in vivo in a solid tumor setting.

Falsely Undetectable Prostate-Specific Antigen (PSA) Due to Presence of an Inhibitory Serum Factor: A Case Report and Review of Pertinent Literature.

BACKGROUND Few cases of falsely undetectable PSA due to the presence of an inhibitory serum factor have been reported in the world literature. We present a case of falsely low-to-undetectable PSA with data from a serum dilution series, the current literature on biochemical assay interference, and the implications for prostate cancer salvage treatment. CASE REPORT A 63-year-old man was treated with prostatectomy for high-risk prostate cancer and was found to have a rising PSA after approximately 3 years following surgery. He subsequently transferred his care to a different health system and was found to have an undetectable PSA. He was eventually found to have an elevated PSA once again after the particular assay at this institution was changed. He thus received salvage prostate radiotherapy and androgen deprivation therapy. CONCLUSIONS While falsely low PSA results cannot be explained by the presence of serum heterophile antibodies, competitive antibody interference against the immunoassay reagents or anti-PSA antibodies are possible explanations for the results of the dilution experiments performed in this case study. We suggest that unexpected PSA testing results should raise concern for assay interference and warrant further clinical workup.

Oligometastatic Prostate Cancer: A Shrinking Subset or an Opportunity for Cure?

Oligometastatic prostate cancer (OMPC), generally defined by presence of five or fewer metastatic sites on imaging, represents a transitional state between localized and widespread metastatic disease and encompasses a wide spectrum of disease biologies and clinical behaviors. A collaborative effort is ongoing to determine the genomics of OMPC. The prevalence of OMPC varies significantly in the literature and is likely to change further as substantial improvements in imaging improve our ability to reclassify a subset of patients with biochemical recurrence by conventional imaging as OMPC and another subset from OMPC to polymetastatic disease. The mainstay of OMPC treatment remains systemic therapy, either with androgen-deprivation therapy (ADT) alone or in combination with other agents (docetaxel, abiraterone, etc.). Focal therapies, including resection or radiotherapy (RT), to the primary tumor have demonstrated an improvement in outcomes, including failure-free survival in several retrospective studies. RT to the prostate has specifically demonstrated an overall survival (OS) advantage in patients with low-volume disease in a clinical trial. Improvement in outcomes has been observed with focal therapies for retroperitoneal and more distant metastatic sites in retrospective studies. Advancements in our understanding of the biology, imaging modalities, and treatments may allow for aggressive multimodality therapies in an effort to obtain deeper responses and, potentially, cures for selected patients with OMPC with favorable clinicopathologic characteristics. Participation in clinical trials or institutional registries is strongly encouraged for patients with OMPC who opt for an aggressive multimodality approach.

A review of avelumab in locally advanced and metastatic bladder cancer.

Urothelial carcinoma remains a devastating disease with a poor prognosis. Though immune therapy with Bacillus Calmette-Guérin (BCG) has been used for localized bladder cancer for years, only immune-checkpoint blockade with antiprogrammed cell-death 1 (anti-PD-1) and antiprogrammed cell-death ligand 1 (anti-PD-L1) inhibitors have demonstrated improvement in survival of patients with metastatic disease. Anti-PD-L1 antibody, avelumab, was recently given United States Food and Drug Administration (FDA) accelerated approval for the treatment of recurrent/metastatic urothelial carcinoma after failure of first-line chemotherapy, marking the fifth immune checkpoint inhibitor to be given FDA approval for the treatment of metastatic urothelial cancer. The following manuscript will review avelumab, its pharmacology, and the clinical experience that has led to its approval, as well as future plans for clinical development of avelumab for the treatment or urothelial cancer.

Survival outcomes for advanced kidney cancer patients in the era of targeted therapies.

BACKGROUND: Advanced renal cell carcinoma (RCC) results in over 14,000 deaths each year in the United States alone. The therapeutic landscape for advanced RCC changed dramatically with the approval of tyrosine kinase inhibitors (TKI) between 2006 and 2012. A large-scale analysis of survival trends has not been performed in the TKI era to determine their impact on outcomes for advanced RCC patients. METHODS: The Surveillance, Epidemiology and End-Results (SEER) database was queried for adult patients with advanced RCC diagnosed between 2000 and 2013. Patients were divided into two cohorts based on the year of diagnosis-pre-TKI cohort [2000-2006] and TKI cohort [2007-2013]. Kaplan-Meier survival and multivariate Cox proportional hazards analyses were performed. RESULTS: A total of 14,976 patients were included in our study. Median age at diagnosis was 64 years (range, 18-89 years). Median (cancer-specific) overall survival was 10.0 months in the TKI cohort compared with 8.0 months in the pre-TKI cohort, corresponding to a 13% improvement in survival in the TKI area [hazard ratio (HR) for death 0.87; 95% confidence interval (CI), 0.84-0.91, P<0.0001]. Median survival was improved by 2 months for patients with clear-cell RCC histology [HR for death 0.86; 95% CI, 0.84-0.91, P<0.0001]. Patients with non-clear cell RCC had a 25% higher risk of mortality compared with those with clear-cell RCC. Additionally, median survival for non-clear cell RCC patients was not statistically different between the two cohorts (HR for death 0.98; 95% CI, 0.88-1.09, P=0.714). Subgroup analysis showed that elderly patients (age 71 years and above) had a 45% higher risk of death from advanced RCC compared with young patients (aged 18-50 years) [HR for death 1.45; 95% CI, 1.36-1.54, P<0.0001]. Gender and racial disparities in outcomes were also noted with women having a 10% higher risk of death compared with men (HR for death 1.10; 95% CI, 1.06-1.14, P<0.001) and Black patients having a 15% higher risk of death compared with White patients (HR for death 1.15; 95% CI, 1.08-1.23, P<0.0001). CONCLUSIONS: Our study provides a largest registry-based analysis of survival outcomes in the TKI era. In majority of patients, the survival has improved significantly with the advent of TKIs as standard of care therapy. Survival for patients with non-clear cell RCC is clearly worse than clear-cell RCC and does not appear to have changed with TKIs. Elderly patients, women, and Black patients appear to have worse outcomes and these disparities merit further investigation.

Hemophagocytosis lymphocytosis presenting as pulmonary-renal syndrome: a case report and literature review.

Hemophagocytosis Lymphocytosis (HLH) is a rare and life-threatening illness that is more commonly seen in infants; however, its incidence in adults is becoming more common. Recognizing HLH in a complicated clinical scenario is key to early recognition, treatment, as well as improved morbidity and mortality.

Diffuse large B-cell lymphoma of the colon--a rare presentation.

Patients with diffuse large B-cell lymphoma (DLBCL) can present with nodal or extra-nodal disease. The most common extra-nodal site is the gastrointestinal tract, including the stomach or illeo-cecal region. Primary colonic diffuse large B-cell lymphoma (DLBCL) is uncommon and presents a unique diagnostic and therapeutic challenge. We present a case of a middle-aged man who presented with abdominal pain and pathological weight loss and underwent hemi-colectomy for suspected adenocarcinoma. Final pathology revealed DLBCL, completely changing the prognosis and subsequent management. We will discuss some of the aspects of this rare presentation and shed light on therapeutic strategies currently available.