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Simple Summary: Despite the increased risk of developing renal cell carcinoma (RCC) in patients with advanced chronic kidney disease (ACKD), little is known about the patient clinical characteristics and genetic mutations found in these RCC tumors. Using a multi-institutional research network, this study compiled clinical records and somatic tumor whole exome sequencing data of 296 adult patients with RCC, 61 of whom had ACKD. Patients with RCC and ACKD were more likely to be male, present with earlier stage RCC at diagnosis, and have lower rates of BAP1 mutations. Median overall survival was not reached in either group over a median follow-up of 31.3 months. These findings suggest RCC in patients with ACKD develops via a BAP1-independent mutational driver and further support BAP1 loss as a marker of disease aggressiveness. Background: Patients with advanced chronic kidney disease (ACKD) are at an increased risk of developing renal cell carcinoma (RCC), but molecular alterations in RCC specimens arising from ACKD and overall survival (OS) in affected patients are not well defined. Patients and Methods: Using the Oncology Research Information Exchange Network (ORIEN) Total Cancer Care® protocol, 296 consented adult patients with RCC and somatic tumor whole exome sequencing were included. Patients with ACKD were defined as those with serum creatinine ≥1.5 mg/dL prior to RCC diagnosis. Results: Of 296 patients with RCC, 61 met the criteria for ACKD. The most common somatic mutations in the overall cohort were in VHL (126, 42.6%), PBRM1 (102, 34.5%), and SETD2 (54, 18.2%). BAP1 had a decreased mutational frequency in RCC specimens from patients without ACKD as compared to those with ACKD (10.6% versus 1.6%), but this was not statistically significant in univariable (OR 0.14, p = 0.056) or multivariable (OR 0.15, p = 0.067) analysis. Median OS was not reached in either cohort. Conclusions: Using the clinicogenomic ORIEN database, our study found lower rates of BAP1 mutations in RCC specimens from patients with ACKD, which may reflect a BAP1-independent mutational driver of RCC in patients with ACKD. [ABSTRACT FROM AUTHOR]

Purpose: To assess differences in baseline and longitudinal quality of life among Black and White individuals in the US with advanced prostate cancer. Methods: Secondary analysis of data from the International Registry for Men with Advanced Prostate Cancer (IRONMAN) including US participants newly diagnosed with advanced prostate cancer and identifying their race as Black or White from 2017 to 2023. Participants completed the EORTC QLQ-C30 Quality of Life (QoL) Survey at study enrollment and every 3 months thereafter for up to 1 year of follow-up reporting 15 scale scores ranging from 0 to 100 (higher functioning and lower symptom scores represent better quality of life). Linear mixed effects models with race and month of questionnaire completion were fit for each scale, and model coefficients were used to assess differences in baseline and longitudinal QoL by race. Results: Eight hundred and seventy-nine participants were included (20% identifying as Black) at 38 US sites. Compared to White participants at baseline, Black participants had worse constipation (mean 6.3 percentage points higher; 95% CI 2.9–9.8), financial insecurity (5.7 (1.4–10.0)), and pain (5.1 (0.9–9.3)). QoL decreased over time similarly by race; most notably, role functioning decreased by 0.7 percentage points (95% CI −0.8, −0.5) per month. Conclusion: There are notable differences in quality of life at new diagnosis of advanced prostate cancer for Black and White individuals, and quality of life declines similarly in the first year for both groups. Interventions that address specific aspects of quality of life in these patients could meaningfully improve the overall survivorship experience. [ABSTRACT FROM AUTHOR]

We recently identified CD46 as a novel prostate cancer cell surface antigen that shows lineage independent expression in both adenocarcinoma and small cell neuroendocrine subtypes of metastatic castration resistant prostate cancer (mCRPC), discovered an internalizing human monoclonal antibody YS5 that binds to a tumor selective CD46 epitope, and developed a microtubule inhibitor-based antibody drug conjugate that is in a multi-center phase I trial for mCRPC (NCT03575819). Here we report the development of a novel CD46-targeted alpha therapy based on YS5. We conjugated 212Pb, an in vivo generator of alpha-emitting 212Bi and 212Po, to YS5 through the chelator TCMC to create the radioimmunoconjugate, 212Pb-TCMC-YS5. We characterized 212Pb-TCMC-YS5 in vitro and established a safe dose in vivo. We next studied therapeutic efficacy of a single dose of 212Pb-TCMC-YS5 using three prostate cancer small animal models: a subcutaneous mCRPC cell line-derived xenograft (CDX) model (subcu-CDX), an orthotopically grafted mCRPC CDX model (ortho-CDX), and a prostate cancer patient-derived xenograft model (PDX). In all three models, a single dose of 0.74 MBq (20 µCi) 212Pb-TCMC-YS5 was well tolerated and caused potent and sustained inhibition of established tumors, with significant increases of survival in treated animals. A lower dose (0.37 MBq or 10 µCi 212Pb-TCMC-YS5) was also studied on the PDX model, which also showed a significant effect on tumor growth inhibition and prolongation of animal survival. These results demonstrate that 212Pb-TCMC-YS5 has an excellent therapeutic window in preclinical models including PDXs, opening a direct path for clinical translation of this novel CD46-targeted alpha radioimmunotherapy for mCRPC treatment. [ABSTRACT FROM AUTHOR]

The treatment of prostate cancer continues to evolve. There is now a new imaging tool for identifying prostate-specific metastases and a radiopharmaceutical for treating one subtype of metastatic disease. [ABSTRACT FROM AUTHOR]

Introduction: The addition of the androgen-signaling inhibitors (ASI) apalutamide, enzalutamide and abiraterone acetate or docetaxel to standard androgen deprivation therapy (ADT) has been demonstrated to improve overall survival in men with hormone-sensitive metastatic prostate cancer (HSMPC).Areas Covered: The majority of men presenting with metastatic prostate cancer will now benefit from the addition of either a novel ASI or docetaxel to standard ADT. In the absence of comparative studies of these agents, clinicians are left with assessing the individual studies and attempting to individualize therapy.Expert Opinion: ADT with either docetaxel or androgen-signaling inhibitors (ASI) have changed the treatment landscape of HSMPC with clinically meaningful improvement in overall survival compared to ADT alone. Among the factors to consider in the selection of the optimal agent include the volume of disease, performance status and comorbidities, toxicity profile cost and drug availability, and further resistance or sequencing options. [ABSTRACT FROM AUTHOR]

PURPOSE: In prostate cancer, inactivating CDK12 mutations lead to gene fusion–induced neoantigens and possibly sensitivity to immunotherapy. We aimed to clinically, pathologically, and molecularly characterize CDK12 -aberrant prostate cancers. METHODS: We conducted a retrospective multicenter study to identify patients with advanced prostate cancer who harbored somatic loss-of-function CDK12 mutations. We used descriptive statistics to characterize their clinical features and therapeutic outcomes (prostate-specific antigen [PSA] responses, progression-free survival [PFS]) to various systemic therapies, including sensitivity to poly (ADP-ribose) polymerase and PD-1 inhibitors. RESULTS: Sixty men with at least monoallelic (51.7% biallelic) CDK12 alterations were identified across nine centers. Median age at diagnosis was 60.5 years; 71.7% and 28.3% were white and nonwhite, respectively; 93.3% had Gleason grade group 4-5; 15.4% had ductal/intraductal histology; 53.3% had metastases at diagnosis; and median PSA was 24.0 ng/mL. Of those who underwent primary androgen deprivation therapy for metastatic hormone-sensitive disease (n = 59), 79.7% had a PSA response, and median PFS was 12.3 months. Of those who received first-line abiraterone and enzalutamide for metastatic castration-resistant prostate cancer (mCRPC; n = 34), 41.2% had a PSA response, and median PFS was 5.3 months. Of those who received a first taxane chemotherapy for mCRPC (n = 22), 31.8% had a PSA response, and median PFS was 3.8 months. Eleven men received a PARP inhibitor (olaparib [n = 10], rucaparib [n = 1]), and none had a PSA response (median PFS, 3.6 months). Nine men received a PD-1 inhibitor as fourth- to sixth-line systemic therapy (pembrolizumab [n = 5], nivolumab [n = 4]); 33.3% had a PSA response, and median PFS was 5.4 months. CONCLUSION: CDK12 -altered prostate cancer is an aggressive subtype with poor outcomes to hormonal and taxane therapies as well as to PARP inhibitors. A proportion of these patients may respond favorably to PD-1 inhibitors, which implicates CDK12 deficiency in immunotherapy sensitivity. [ABSTRACT FROM AUTHOR]

Summary: Purpose Sunitinib is a vascular endothelial growth factor receptor (VEGFR) inhibitor with antitumor activity against bladder cancer. We hypothesized that treatment with sunitinib may decrease progression or recurrence in non-muscle invasive bladder cancer (NMIBC) refractory to intra-vesical BCG. Patients and Methods This is a single-arm phase II study of sunitinib in patients (pts) with NMIBC who progressed after BCG. Treatment included sunitinib 37.5 g daily for 12 weeks followed by 12± 2-week cystoscopy and surveillance for one year. The primary endpoint was the complete response rate at 12 months. Secondary endpoints included recurrence free survival (RFS), progression free survival (PFS), overall survival (OS), and safety of sunitinib. Correlative studies on effects of sunitinib on myeloid derived suppressor cells (MDSC) and humoral immune responses were also performed. This trial was registered on ClinicalTrials.gov, number NCT01118351. Results Between June 2011 and September 2011, 15/19 pts. completed 12 weeks of therapy. The remaining 4 pts. had treatment related adverse events leading to discontinuation of sunitinib with one patient withdrawing consent. On the 12-week cystoscopy, 44% (8/18) of the pts. showed remission, 50% (9/18) progression and 1/18 recurrence. Overall, 22% (4/18) of pts. remained free of progression for >12 months. Grade (G) 4 toxicities were noted in 2 pts. (anemia and thrombocytopenia) while G3 were noted in 58%. Sunitinib resulted in reversal of MDSC mediated immunosuppression. Conclusions In NMIBC refractory to BCG, treatment with sunitinib was safe but not associated with improved clinical outcomes. The immune effects of sunitinib deserve further investigation. [ABSTRACT FROM AUTHOR]

Summary: Background Despite definitive local therapy, patients with high-risk prostate cancer have a significant risk for local and distant failure. To date, no systemic therapy given prior to surgery has been shown to improve outcomes. The phosphatidilinositol 3-kinase/AKT/mTOR pathway is commonly dysregulated in men with prostate cancer. We sought to determine the clinical efficacy and safety of the mTOR/TORC1 inhibitor everolimus in men with high-risk prostate cancer undergoing radical prostatectomy. Methods This is a randomized phase II study of everolimus at two different doses (5 and 10 mg daily) given orally for 8 weeks before radical prostatectomy in men with high-risk prostate cancer. The primary endpoint was the pathologic response (histologic P0, margin status, extraprostatic extension) and surgical outcomes. Secondary endpoints included changes in serum PSA level and treatment effects on levels of expression of mTOR, p4EBP1, pS6 and pAKT. Results Seventeen patients were enrolled: nine at 10 mg dose and eight at 5 mg dose. No pathologic complete responses were observed and the majority of patients (88%) had an increase in their PSA values leading to this study being terminated early due to lack of clinical efficacy. Treatment-related adverse events were similar to those previously reported with the use of everolimus in other solid tumors and no additional surgical complications were observed. A significant decrease in the expression of p4EBP1 was noted in prostatectomy samples following treatment. Conclusions Neoadjuvant everolimus given at 5 mg or 10 mg daily for 8 weeks prior to radical prostatectomy did not impact pathologic responses and surgical outcomes of patients with high-risk prostate cancer. Trial registration NCT00526591. [ABSTRACT FROM AUTHOR]

Summary: Background Mammalian target of rapamycin (mTOR) pathway and angiogenesis through vascular endothelial growth factor (VEGF) have been shown to play important roles in prostate cancer progression. Preclinical data in prostate cancer has suggested the potential additive effect dual inhibition of VEGF and mTOR pathways. In this phase I/II trial we assessed the safety and efficacy of bevacizumab in combination with temsirolimus for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC). Methods In the phase I portion, eligible patients received temsirolimus (20 mg or 25 mg IV weekly) in combination with a fixed dose of IV bevacizumab (10 mg/kg every 2 weeks). The primary endpoint for the phase II portion was objective response measured by either PSA or RECIST criteria. Exploratory endpoints included changes in circulating tumor cells (CTC) and their correlation with PSA response to treatment. Results Twenty-one patients, median age 64 (53–82), with pre-treatment PSA of 205.3 (11.1–1801.0), previously treated with a median of 2 (0–5) lines of therapy for mCRPC received the combination of temsirolimus weekly at 20 mg (n = 4) or 25 mg (n = 17) with bevacizumab 10 mg/kg every 2 weeks (n = 21). Median time to progression was 2.6 months (95% CI, 1.2–3.9) and the median best PSA change from baseline to 12 weeks was a 32% increase (−40–632%) which met the predefined futility rule and led to early termination of the study. Nine patients (43%) had ≥ grade 3 toxicity that included fatigue (24%), anorexia (10%), nausea/vomiting (5%) and lymphopenia (5%). In exploratory analysis, a decrease in CTC levels was observed in 9 out of 11 patients. No association between PSA levels and CTC levels was detected. Conclusions The combination of temsirolimus and bevacizumab showed limited clinical activity in mCRPC patients previously treated with chemotherapy and was associated with significant adverse events (AEs). Transient decrease in CTC levels was independent from PSA response. NCT01083368. [ABSTRACT FROM AUTHOR]

Introduction Ketoconazole is CYP-17 inhibitor with demonstrated activity in men with castration-resistant prostate cancer (CRPC). Lenalidomide is an antiangiogenic and immunomodulatory agent with broad antitumor activity. We hypothesized that the modulation of the cellular immune response to apoptosis caused by ketoconazole may be increased with the addition of lenalidomide. Methods This is an open-label, non-randomized, single-arm phase II study evaluating the efficacy and safety of the combination of ketoconazole and lenalidomide in patients with CRPC. Treatment schema included standard ketoconazole 400 mg orally three times daily plus hydrocortisone orally (20 mg in the morning and 10 mg at night) in combination with lenalidomide 25 mg orally daily for 21 days in a 28-day cycle and aspirin 75 mg daily. The primary endpoint of this study was response (either by ≥ 50% PSA decline or objective disease assessed by RECIST v1.0). Exploratory endpoints included changes in T cell, dendritic cell (DC) marker counts, and their correlation with PSA response to treatment. Results A total of 34 CRPC patients, median age 69 years, 76% ECOG 0 and 76% with metastases participated in the study. Patients received a median of 2 cycles (range 1-35); nine patients (26%) received >10 cycles of treatment. PSA responses were observed in 17 patients (50%) with 11 patients (32%) achieving a PSA decline of >90%. Among the 9 patients with measurable disease, 2 patients (22%) had PR and 2 other (22%) had SD as best response. Median time to failure (TTF) was 2.7 months (range 0.2-32.8); and 8 patients were treated for ≥ 15 months. Most common adverse events included fatigue (76%), skin reactions (62%), lymphopenia (44%) and anemia (44%). One possible treatment-related death was noted. For 16 patients with available serial correlative data, there was a significant increase in the dendritic cells subsets BDCA-1 (+146.7, −20.1 to +501.1%, p = 0.018) and BDCA-3 (39.8%, −100 to 282.6%, p = 0.001) after 8 weeks of treatment. No association between immune cell counts and PSA response at 8 weeks was observed. Conclusion The combination of ketoconazole and lenalidomide was well tolerated but did not meet the primary endpoint of response, despite durable responses were observed in a selected group of patients. Although ketoconazole has now been replaced with more active novel agents, the combination of novel CYP-17 inhibitors with agents capable of modulating the immune system warrants further prospective investigation. NCT00460031. [ABSTRACT FROM AUTHOR]

Background Tivantinib is a non-ATP competitive inhibitor of c-MET receptor tyrosine kinase that may have additional cytotoxic mechanisms including tubulin inhibition. Prostate cancer demonstrates higher c-MET expression as the disease progresses to more advanced stages and to a castration resistant state. Methods 80 patients (pts) with asymptomatic or minimally symptomatic mCRPC were assigned (2:1) to either tivantinib 360 mg PO BID or placebo (P). The primary endpoint was progression free survival (PFS). Results Of the 80 pts. enrolled, 78 (52 tivantinib, 26 P) received treatment and were evaluable. Median follow up is 8.9 months (range: 2.3 to 19.6 months). Patients treated with tivantinib had significantly better PFS vs. those treated with placebo (medians: 5.5 mo vs 3.7 mo, respectively; HR = 0.55, 95% CI: 0.33 to 0.90; p = 0.02). Grade 3 febrile neutropenia was seen in 1 patient on tivantinib while grade 3 and 4 neutropenia was recorded in 1 patient each on tivantinib and placebo. Grade 3 sinus bradycardia was recorded in two men on the tivantinib arm. Conclusions Tivantinib has mild toxicity and improved PFS in men with asymptomatic or minimally symptomatic mCRPC. [ABSTRACT FROM AUTHOR]

Background The inhibition of insulin-like growth factor receptor-1 (IGF-1R) induces cell cycle arrest and enhancing the effect of castration by delay of progression of human prostate cancer models. Linsitinib is a small molecule and potent dual inhibitor of IGF-1R and insulin receptor tyrosine kinase activity. We report results of a single-arm, phase II study evaluating the safety and efficacy of linsitinib in men with chemotherapy-naïve asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer (mCRPC). Methods Patients received at 150 mg orally twice daily on a 28-day cycle. The primary endpoint was prostate specific (PSA) response at 12 weeks and correlative studies included circulating tumor cells (CTCs) and circulating endothelial cells (CECs). Results Seventeen patients, median age 68 (55-78) and pre-treatment PSA of 55.23 (2.46-277.60) were enrolled and completed 12 weeks of therapy. All but two patients discontinued therapy secondary to PSA progression, which met the predefined futility criteria and led to early termination of this study. Overall best response (RECIST v1.1) included a partial response in 1 patient and stable disease in 8 patients. Higher baseline CTCs were associated with higher pre-treatment PSA levels (Spearman r = 0.49, p = 0.04) but no correlation between PSA progression and CTCs/CECs were observed. Most common adverse events included fatigue, nausea/vomiting, AST/ALT changes and prolonged QT interval. Conclusions Single-agent linsitinib was safe and well tolerated but failed to show activity in men with mCRPC. These results highlight the complexity of using IGF-1R as a therapeutic target in this patient population. ClinicalTrials.gov NCT01533246. [ABSTRACT FROM AUTHOR]

Background: Axitinib is a potent inhibitor of the vascular endothelial growth factor (VEGF) receptor family with clinical activity in patients with metastatic renal cell carcinoma (mRCC). Given this biochemical potency, the clinical activity of subsequent treatment with targeted therapies in patients progressing on axitinib is of interest.Methods: Patients with advanced renal cell carcinoma of any pathologic subtype treated with at least one cycle (four weeks) of axitinib followed by at least one subsequent targeted therapy were investigated in a retrospective analysis. Patient characteristics, duration of treatment and clinical outcomes were analyzed for axitinib and each subsequent line of therapy by Response Evaluation Criteria in Solid Tumors (RECIST).Results: Twenty-five mRCC patients who received at least one approved targeted agent following axitinib were identified. Eight percent of patients achieved a partial response (one patient each to sunitinib and pazopanib) and 42 % had a best response of stable disease to the first therapy after axitinib. The estimated median duration of therapy was 4.4 months (range, 0.2-27.5+). Twelve patients received a second post-axitinib targeted therapy. Six out of 11 evaluable patients (55 %) had a best response of SD. The estimated median duration of treatment was 4.8 months (range, 0.7-19.1+).Conclusion: Objective responses and stable disease is observed to post-axitinib targeted therapies and prospective studies are needed for validating role of predictive biomarkers. [ABSTRACT FROM AUTHOR]

Prostate cancer resistance to castration occurs because tumours acquire the metabolic capability of converting precursor steroids to 5α-dihydrotestosterone (DHT), promoting signalling by the androgen receptor and the development of castration-resistant prostate cancer. Essential for resistance, DHT synthesis from adrenal precursor steroids or possibly from de novo synthesis from cholesterol commonly requires enzymatic reactions by 3β-hydroxysteroid dehydrogenase (3βHSD), steroid-5α-reductase (SRD5A) and 17β-hydroxysteroid dehydrogenase (17βHSD) isoenzymes. Abiraterone, a steroidal 17α-hydroxylase/17,20-lyase (CYP17A1) inhibitor, blocks this synthetic process and prolongs survival. We hypothesized that abiraterone is converted by an enzyme to the more active Δ4-abiraterone (D4A), which blocks multiple steroidogenic enzymes and antagonizes the androgen receptor, providing an additional explanation for abiraterone's clinical activity. Here we show that abiraterone is converted to D4A in mice and patients with prostate cancer. D4A inhibits CYP17A1, 3βHSD and SRD5A, which are required for DHT synthesis. Furthermore, competitive androgen receptor antagonism by D4A is comparable to the potent antagonist enzalutamide. D4A also has more potent anti-tumour activity against xenograft tumours than abiraterone. Our findings suggest an additional explanation-conversion to a more active agent-for abiraterone's survival extension. We propose that direct treatment with D4A would be more clinically effective than abiraterone treatment. [ABSTRACT FROM AUTHOR]

Background Exposure to ionizing radiation has been linked to myelodysplastic syndromes (MDS); it is not clear whether therapeutic radiation doses used for prostate cancer pose an increased MDS risk. Methods We performed a retrospective cohort study of prostate cancer patients diagnosed between 1986 and 2011 at Cleveland Clinic, comparing those who underwent definitive treatment with radical prostatectomy (RP) to radio-therapy either external beam radiotherapy (EBRT) or prostate interstitial brachytherapy (PI) and to population- based registries. Competing risk regression analyses were used to determine the cumulative risk of developing MDS. All statistical tests were two-sided. Results Of 10924 patients, 5119 (47%) received radiation (n = 2183 [43%] in EBRT group and n = 2936 [57%] in PI group) and 5805 (53%) were treated with RR Overall, 31 cases of MDS were observed, with age-adjusted incidence rates no higher than in population-based registries. In univariate analyses, advancing age (hazard ratio [HR] = 1.14; 95% confidence interval [CI] -- 1.09 to 1.20; P< .001) and radiotherapy exposure (HR = 3.44; 95% CI = 1.41 to 8.37; P= .007) were statistically significantly associated with development of MDS. In multivariable analyses, although advanced age (HR = 1.13; 95% CI= 1.06 to 1.19; P< .001) remained statistically associated with MDS, radiation did not, although a small non-statistically significant trend existed for PI-treated patients. MDS rates were no higher than in population-based registries. Conclusions With relatively short follow-up, prostate cancer patients definitively treated with radiation did not appear to have a statistically increased risk of subsequent MDS. [ABSTRACT FROM AUTHOR]

BACKGROUND Angiogenesis contributes to the progression of urothelial carcinoma (UC). In the current study, the authors investigated the role of maintenance sunitinib in patients with advanced UC. METHODS Patients with locally recurrent/metastatic UC and adequate organ function who achieved stable disease or a partial or complete response after 4 to 6 chemotherapy cycles were randomized to sunitinib at a dose of 50 mg/day (28 days on and 14 days off) or placebo. The primary endpoint was the 6-month progression rate. Secondary endpoints were safety, survival, change in serum vascular endothelial growth factor (VEGF)/soluble VEGF receptor-2 (sVEGFR2), and the activity of sunitinib in patients who developed disease progression while receiving placebo. A total of 38 eligible patients per treatment arm were required to select better therapy with 90% probability (α = .05). RESULTS A total of 54 eligible patients were randomized to either the sunitinib arm (26 patients) or the placebo arm (28 patients). The median number of cycles received was 2 cycles per treatment arm. The most common grade 3 to 4 adverse events (graded according to version 3.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events) among patients receiving sunitinib were thrombocytopenia, diarrhea, mucositis, fatigue, and hypertension. There were no grade 3 or 4 adverse events noted among > 5% of patients receiving placebo. The 6-month progression rate was 72% versus 64%. The median progression-free survival (PFS) was 2.9 months (range, 0.5 months-32.5 months) versus 2.7 months (range, 0.8 months −65 months) for the sunitinib versus placebo arms, respectively. Patients receiving placebo were found to have no changes in their serum VEGF/sVEGFR2 levels over time. Patients treated with sunitinib had no significant change in their VEGF level, but the sVEGFR2 level significantly decreased after cycles 1 and 2 ( P < .0001) and at the time of disease progression ( P = .0002). A baseline VEGF level that was at or greater than the median was found to be correlated with a longer PFS. Sixteen patients who were receiving placebo received sunitinib at the time of disease progression, with the best responses being 1 partial response (6.3%), 6 cases of stable disease (37.5%), and 5 cases of progressive disease (31.3%); 4 patients were not evaluable for response. The median PFS was 3.7 months (range, 0.1 months-22 months). CONCLUSIONS The current multicenter study was limited by premature closure and a small sample size. Maintenance sunitinib did not appear to improve the 6-month progression rate. Open-label sunitinib was found to have only modest activity. The sVEGFR2 level decreased among patients receiving sunitinib. Cancer 2014;120:692-701. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

Purpose Enzastaurin is an oral serine/threonine kinase inhibitor that inhibits the beta isoform of protein kinase C and which may have therapeutic activity in prostate cancer. We explored the efficacy of docetaxel/prednisone with or without enzastaurin in patients with castration-resistant metastatic prostate cancer. Methods A nonrandomized safety cohort consisting of 14 patients was followed by a double-blind randomized Phase II trial. Patients received standard doses of docetaxel (75 mg/m) with prednisone 10 mg daily with or without 500 mg/day of enzastaurin. Results There was no difference in the objective response rate between the enzastaurin and placebo arms (placebo: 7 [15.2 %]; enzastaurin: 6 [15.0 %]; P = 1.00). The median PFS was 229 days for patients in the enzastaurin arm versus 213 days for the placebo arm ( P = 0.524). The 1-year overall survival rates were almost identical, with 76.7 % and 75.1 % in the enzastaurin and placebo arms, respectively. Therapy was well tolerated although the combination of enzastaurin and docetaxel was more myelosuppressive than with docetaxel alone. Conclusions The clinical activity of docetaxel/prednisone plus enzastaurin cannot be distinguished from docetaxel/prednisone alone, given the limitations of a randomized Phase II design. Although the toxicity profile was favorable for the enzastaurin-containing regimen, there is no compelling rationale to move this combination forward for the treatment of castration-resistant metastatic prostate cancer. [ABSTRACT FROM AUTHOR]

BACKGROUND There have been no improvements in the treatment of metastatic urothelial cancer in the past several decades. A census of contemporary clinical research in this disease was performed to identify potential barriers and opportunities. METHODS These authors performed a search for clinical trials exploring interventions in muscle-invasive and metastatic urothelial cancer, using the ClinicalTrials.gov registry. Data extracted from the registry included title, recruitment status, interventions, sponsor, phase, enrollment, study design, and study sites. RESULTS Among 120 eligible trials exploring interventions in muscle-invasive and metastatic urothelial cancer, 73% were phase 2 and 73% were nonrandomized. The majority (63%) involved treatment in the metastatic disease state. The median planned enrollment size per trial was 45 patients (interquartile range, 47 patients). The majority of trials (55%) involved ≤ 3 study sites. Trials most commonly explored interventions in the first-line metastatic (30%) or second-line metastatic (37%) settings. Targeted therapeutics were studied in 58% of the trials. Among 56 trials that completed enrollment, the median time to complete accrual was 50 months (range, 10-109 months), and these trials enrolled a median of 40 patients per trial (interquartile range, 44 patients). CONCLUSIONS The majority of contemporary clinical trials in muscle-invasive and metastatic urothelial cancer are small, nonrandomized, phase 2 trials involving 1 to 3 study sites. Enhanced communication and collaboration among the urothelial cancer community, and other stakeholders, is needed to facilitate the design and conduct of trials capable of expediting progress in this disease. Cancer 2013;119:1994-1998. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

Purpose: To determine the safety, the maximal tolerated dose, and to assess for any clinical activity of pomalidomide given to patients with advanced solid tumors. Patients and methods: Patients with incurable solid tumors were enrolled. Two different dosing schedules were explored. In Cohort A patients were given pomalidomide once daily for 21 days followed by a 7 day rest. For Cohort B additional patients were recruited to receive pomalidomide given once daily for 28 consecutive days. Dose-limiting toxicity was defined as ≥grade 3 non-hematological toxicity that occurs during cycle 1 and that does not resolve to ≤grade 1 by day 35. Subjects must have received optimal symptomatic treatment for ≥grade 3 nausea, vomiting, or diarrhea to be considered a DLT. Grade 4 transaminitis was considered to be a DLT while grade 3 transaminitis must be present >7 days to be a DLT. Grade 3 febrile neutropenia was considered a DLT. Grade 4 neutropenia, without a fever, was a DLT if the neutropenia did not improve to ≤grade 1 by day 35 of cycle one. Platelet count ≤25,000/mm must improve to ≥75,000/mm by day 35 of cycle one in order not to be considered a DLT. If a patient did not complete one cycle of therapy, for reasons other than a DLT, a replacement subject was added to the same cohort level. Results: A total of 40 patients were enrolled. In Cohort A, three patients received pomalidomide at 5 mg daily without any significant toxicity. Two patients in the 10 mg cohort experienced dose-limiting toxicities of two episodes of grade 3 dyspnea and one grade 4 neutropenia. Six patients were then enrolled at the 7 mg daily of pomalidomide, and no dose-limiting events were observed. In Cohort B, 29 patients were enrolled and the maximal tolerated dose was 4 mg once daily. Stable disease in a variety of tumors was observed. Conclusions: Pomalidomide was well tolerated and the recommended phase II dosing schedules are 7 mg daily given for 21 days followed by a 7-day rest or pomalidomide 4 mg given on an uninterrupted daily schedule. [ABSTRACT FROM AUTHOR]

BACKGROUND: The current treatment of metastatic renal cell carcinoma (mRCC) with vascular endothelial growth factor (VEGF)-targeted agents is continuous therapy until progression of disease (PD) or unacceptable toxicity. Chronic mild to moderate toxicity and risk of long-term toxicity ensue for some patients. It is hypothesized that patients with an initial response to treatment can maintain disease control off all therapy for a period of time. METHODS: A retrospective study of patients with mRCC who initiated VEGF-targeted therapy between January 2004 and December 2009 at The Cleveland Clinic Foundation, Cleveland, Ohio, or Institut Gustave-Roussy, Villejuif, France, was conducted. Patients had achieved RECIST (Response Evaluation Criteria in Solid Tumors)-defined stable disease or better on therapy, and were then taken off all therapy for reasons not including disease progression. Patient, disease, and therapy characteristics were recorded. The primary objective was progression-free survival (PFS), measured as the time from discontinuation of therapy to RECIST-defined PD. RESULTS: Forty patients were identified. After a median follow-up of 29.7 months (range, 4.2 to 84.7 months), 25 patients (63%) had PD off therapy (median PFS, 10.0 months; range, 1.4-27.2 months). Among these patients, 8 (32%) had progression in sites that were not previously involved with disease. Heng risk group (hazard ratio, 2.49; 95% confidence interval, 1.19-5.22; P = .011) and achievement of a complete response prior to discontinuing therapy (hazard ratio, 0.20; 95% confidence interval, 0.04-0.86; P = .025) were independent predictors of PFS in a multivariable Cox proportional hazards model. CONCLUSIONS: A select subset of mRCC patients achieving stable disease or better on VEGF-targeted therapy can be observed off all therapy. Further prospective investigation is warranted. Cancer 2011. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

PURPOSE: Biomarkers that predict response or toxicity to antiangiogenic therapy are sought to favorably inform the risk/benefit ratio. This study evaluated the association of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) genetic polymorphisms with the development of hypertension (HTN) and clinical outcome in metastatic clear cell renal cell carcinoma (MCCRCC) patients treated with sunitinib. PATIENT AND METHODS: Sixty-three MCCRCC patients receiving sunitinib (50 mg 4/2) with available blood pressure (BP) data and germline DNA were retrospectively identified. A panel of candidate VEGF and VEGFR2 single nucleotide polymorphisms (SNPs) were evaluated for associations with the development of hypertension and clinical outcome. RESULTS: VEGF SNP −634 genotype was associated with the prevalence and duration of sunitinib-induced hypertension (as defined by systolic pressure ≥150 mmHg and/or diastolic pressure ≥90 mmHg) in both univariable analysis ( P = .03 and .01, respectively) and multivariable analysis, which adjusted for baseline BP and use of antihypertension medication ( P = .05 and .02, respectively). Patients with the GG genotype were estimated to have a greater likelihood of being hypertensive during treatment compared with patients with the CC genotype (odds ratio of 13.62, 95% confidence interval [CI] 3.71-50.04). No single VEGF or VEGFR SNPs were found to correlate with clinical outcome. However, the combination of VEGF SNP 936 and VEGFR2 SNP 889 were associated with overall survival after adjustment for prognostic risk group ( P = .03). CONCLUSIONS: In MCCRCC patients treated with sunitinib, VEGF SNP −634 is associated with hypertension and a combination of VEGF SNP 936 and VEGFR2 SNP 889 genotypes is associated with overall survival. Cancer 2012;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Study Type - Therapy (individual cohort) Level of Evidence 2b OBJECTIVE • To determine, in a phase I/II trial, the maximum tolerated dose (MTD), clinical activity and safety of concurrent subcutaneous (s.c.) interleukin-2 (IL-2), interferon-α2b (IFN-α) and granulocyte-macrophage colony-stimulating factor (GM-CSF). PATIENTS AND METHODS • Patients with metastatic renal cell carcinoma (RCC) received on a 3+3 trial design escalating doses of s.c. GM-CSF, IL-2 and IFN-α. • Dose-limiting toxicities (DLTs) during the first 6-week cycle were used to determine the MTD. • A phase II trial was then initiated to determine clinical activity. RESULTS • A total of sixty patients were enrolled in the study (phase I = 31; phase II = 29). • Two DLTs were observed (G3 nausea/vomiting and fatigue) and the MTD was determined to be GM-CSF 5.0 µg/kg/day, IL-2 9.0 mIU/m2/day and IFN-α 5.0 mU/m2/day. • Patients received a median (range) of four (one to 11) cycles of therapy. G3 adverse events were reported in 10 of 31 (32%) patients. • The overall response rate was 20% (one complete response and 11 partial responses), including patients who were rendered free of disease with surgery. • The median progression-free survival and overall survival were 6.0 and 23.4 months, respectively. CONCLUSIONS • Immunotherapy with concurrent s.c. GM-CSF, IL-2 and IFN-α is generally well tolerated. • The overall response rate observed with this combination continues to show the efficacy of immunotherapy in a selected group of metastatic RCC patients. [ABSTRACT FROM AUTHOR]

Introduction: Cycloxygenase-2 (COX-2) is an enzyme involved in prostaglandin E2 (PGE) synthesis associated with higher renal cell carcinoma stage. COX-2 inhibition enhances interferon (IFN-α) anti-tumor immune effects in pre-clinical models. A phase II trial of celecoxib and IFN-α in a targeted population of metastatic renal cell carcinoma patients with maximal COX-2 expression was conducted. Methods: Cytokine-naive metastatic renal cell carcinoma patients with tumors expressing ≥10% maximal COX-2 staining by immunohistochemistry received IFN-α 5 million units daily and celecoxib 400 mg orally twice daily in an open-label, single-arm phase II trial. Results: There were 3 partial responses among 17 patients (objective response rate 18%; 95% confidence interval, 4-43%). Time to progression was 5.6 months. Increased tumor staining 3+ for COX-2 was associated with increased baseline peripheral blood PGE levels, and these patients demonstrated less PGE decrease with therapy. Patients with more 3+ COX-2 staining had significantly more CD3 ( p = 0.004) and CD4 ( p = 0.002) IFN-γ T cells at baseline and a significantly greater decrease in these cells with therapy. Discussion: Celecoxib plus IFN-α in renal cell carcinoma (RCC) patients with maximally staining COX-2 tumors does not significantly enhance overall response rates over IFN monotherapy. Conclusion: COX-2-expressing RCC demonstrates inherent immunosuppression. COX-2 inhibition with IFN results in minimal immunomodulation and no augmented clinical activity in RCC. [ABSTRACT FROM AUTHOR]

Key controversies concerning the management of genitourinary cancers across the treatment continua were discussed at the second annual Interactive Genitourinary Cancer Conference (IGUCC) held in February 2010 in Athens, Greece. Prostate cancer is the most common form of cancer among western men and prevention strategies are needed. Trials evaluating 5α-reductase inhibitors have reported beneficial and clinically meaningful results, but uptake remains low for primary prostate cancer prevention. Prostate cancer detection programmes are also important as curative treatments for advanced disease are unavailable. Two large landmark randomized controlled trials reported conflicting results concerning screening efficacy and uncovered high levels of over-diagnosis and potential over-treatment. Tailored management strategies after diagnosis are important and predictive markers that distinguish between aggressive and indolent tumours are needed. The majority of newly diagnosed cases of prostate cancer are clinically localized. Active surveillance of favourable risk patients may be beneficial in the intermediate term, while an integrated approach of multi-modality therapy in patients with adverse features is recommended. The benefits of new technologies such as high-intensity focused ultrasound (HIFU) and robotic prostatectomy have not been established in prospective randomized trials vs current standards of care. A multidisciplinary approach is essential to evolving the management of advanced prostate cancer into a chronic disease paradigm. Docetaxel plus prednisone is the standard first-line chemotherapy for patients with metastatic castration-resistant prostate cancer (mCRPC), but the optimal timing of chemotherapy initiation has not been addressed in randomized clinical trials. Retrospective analyses suggest that asymptomatic patients with adverse prognostic factors for survival may also benefit from receiving chemotherapy. Bladder cancer is a common malignancy and the most expensive cancer per patient. Non-muscle-invasive bladder cancer is a heterogenous disease that requires dynamic multidisciplinary management. Aggressive early intervention may be beneficial in some cases. Platinum-based therapies represent the first-line standard of care for advanced bladder cancer, but the maximum benefit may have been reached for conventional chemotherapies and new strategies are needed. Several ongoing clinical trials are assessing combination chemotherapy and targeted therapy. [ABSTRACT FROM AUTHOR]

BACKGROUND: An important goal of noncurative therapy for metastatic renal cell carcinoma (mRCC) is tumor burden (TB) control. However, to the authors' knowledge, the impact of TB characteristics on clinical outcome has not been studied in patients with mRCC who were treated with vascular endothelial growth factor-targeted therapy. METHODS: Patients with clear cell mRCC who were treated with sunitinib between June 2004 and October 2007 were retrospectively identified. Computed tomography scans were re-reviewed from baseline, at the time of maximal TB shrinkage (TS) while receiving sunitinib, and at the time of progressive disease (PD). Measurements were recorded as per Response Evaluation Criteria In Solid Tumors (RECIST). RESULTS: A total of 69 patients were identified. The majority (54%) were classified as being of favorable risk using Cleveland Clinic Foundation Tyrosine Kinase Inhibitor (CCF TKI) risk group criteria. All patients underwent prior nephrectomy and 77% received prior systemic therapy. There were a median of 8 metastatic deposits across all organs (range, 1-27 deposits). The median TB at the initiation of therapy was 14.0 cm (range, 3.0 cm-42.2 cm). On multivariable analysis, baseline characteristics of disease confined to above the diaphragm (P = .03) and a total TB <13 cm (P = .09) were found to be independent positive predictors of progression-free survival. A+ baseline, total number of metastases <10 (P < .001) and TB above the diaphragm <6.5 cm (P = .05) were found to be independent positive predictors of overall survival (OS). Increased TS while receiving sunitinib was found to be significantly associated with OS (P < .001). At the time of PD, tumor location and pattern of disease progression were not found to be associated with survival as measured from the date of PD. However, total TB (P = .003) and total number of metastatic deposits (≤12 vs >12; P < .001) were found to be significant predictors of survival after PD. CONCLUSIONS: The results of the current study indicate that TB characteristics are associated with clinical outcome in patients with mRCC who are treated with sunitinib. [ABSTRACT FROM AUTHOR]

The article focuses on the integration of Sipuleucel-T into immunotherapy in castration-resistant prostate cancer (CRPC) in the U.S. It mentions that Sipuleucel-T(Provenge) which was an autologous active cellular immunotherapy product was reported to demonstrate an improvement in the survival of men with minimally symptomatic metastatic CRPC. It adds that further studies were needed for clinical trial designs such as the translational and clinical endpoints and appropriate patient selection.

BACKGROUND: Docetaxel is the standard of care for patients with metastatic, castrate-resistant prostate cancer (CRPC). Gemcitabine is a nucleoside analogue with broad antitumor activity. In a phase 2 study of combined docetaxel and gemcitabine, the authors assessed its safety and activity in patients with chemotherapy-naive, metastatic CRPC. METHODS: Eligible patients had untreated, metastatic CRPC with radiologic and/or biochemical evidence of progression after antiandrogen withdrawal with castrate testosterone levels, an Eastern Cooperative Oncology performance status (ECOG PS) of 0 to 2, and adequate organ function; no previous chemotherapy was permitted. Patients received gemcitabine (800 mg/m²) Days 1 and 8 and docetaxel (75 mg/m²) on Day 8 every 21 days for a maximum of 6 cycles. Response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) for measurable disease. A prostate-specific antigen (PSA) response was defined as a decline ≥50% in baseline PSA level. RESULTS: Thirty-five patients with chemotherapy-naive, metastatic CRPC were enrolled. The median age was 67 years, and 60% of patients had an ECOG PS of 0. PSA responses were observed in 49% of patients. Among the patients who had measurable disease (n = 25), 3 patients (12%) had a confirmed, RECIST-defined partial response (PR); 4 patients (16%) had an unconfirmed PR; and 15 patients (60%) achieved stable disease. The most common adverse events included grade 1 and 2 fatigue (69%), alopecia (80%), and nausea/vomiting (54%). No treatment-related deaths were noted, but an unusually high incidence of grade 3 and 4 neutropenia was observed. CONCLUSIONS: The efficacy of combined gemcitabine and docetaxel in metastatic CRPC was similar to that observed with single-agent docetaxel. In contrast to single-agent docetaxel, the combination was moderately toxic and had an impact primarily on bone marrow reserve. Cancer 2011;117:752-7. [ABSTRACT FROM AUTHOR]