Peritoneal metastases from primary appendiceal and colorectal carcinomas demonstrate distinct molecular identities on comprehensive tumor analysis.

BACKGROUND AND OBJECTIVES: Published data comparing peritoneal metastases from appendiceal cancers (pAC) and colorectal cancers (pCRC) remain sparse. We compared pAC and pCRC using comprehensive tumor profiling (CTP). METHODS: CTP was performed, including next-generation sequencing and analysis of copy number variation (CNV), microsatellite instability (MSI) and tumor mutational burden (TMB). RESULTS: One hundred thirty-six pAC and 348 pCRC samples underwent CTP. The cohorts' age and gender were similar. pCRC demonstrated increased pathogenic variants (PATHs) in APC (48% vs. 3%, p < 0.01), ARID1A (12% vs. 2%, p < 0.01), BRAF (12% vs. 2%, p < 0.01), FBXW7 (7% vs. 2%, p < 0.01), KRAS (52% vs. 41%, p < 0.05), PIK3CA (15% vs. 2%, p < 0.01), and TP53 (53% vs. 23%, p < 0.01), and decreased PATHs in GNAS (8% vs. 31%, p < 0.01). There was no difference in CNV, fusion rate, or MSI. Median TMB was higher in pCRC (5.8 vs. 5.0 mutations per megabase, p = 0.0007). Rates of TMB-high tumors were similar (pAC 2.1% vs. pCRC 9.0%, p = 0.1957). pCRC had significantly more TMB-high tumors at lower thresholds. CONCLUSIONS: Despite a reduced overall TMB, pAC demonstrated mutations distinct from those seen in pCRC. These may serve as discrete biomarkers for future study.

Survival After Robotic-assisted Prostatectomy for Localized Prostate Cancer: An Epidemiologic Study.

BACKGROUNDS: To determine the potential survival benefit associated with robotic-assisted laparoscopic prostatectomy (RALP) compared to open radical prostatectomy (ORP) for prostate cancer. SUMMARY OF BACKGROUND DATA: RALP has become the dominant surgical approach for localized disease in the absence of randomized clinical evidence and despite of the factor that RALP is more expensive than ORP. METHODS: We performed a cohort study involving patients who underwent RALP and ORP for localized prostate cancer at the Commission on Cancer- accredited hospitals in the United States. Overall survival was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score-matched analyses. An interrupted time-series analysis using the surveillance, epidemiology, and end results program database was also performed. RESULTS: From 2010 to 2011, 37,645 patients received RALP and 12,655 patients received ORP. At a median follow-up of 60.7 months, RALP was associated with improved overall survival by both univariate [hazard ratio (HR), 0.69; P < 0.001] and multivariate analysis (HR, 0.76; P < 0.001) compared with ORP. Propensity score-matched analysis demonstrated improved 5-year all-cause mortality (3.9% vs 5.5%, HR, 0.73; P < 0.001) for RALP. The interrupted time-series analysis demonstrated the adoption of robotic surgery coincided with a systematic improvement in the 5-year cancer-specific survival rate of 0.17% (95% confidence interval, 0.06-0.25) per year after 2003 (P = 0.004 for change of trend), as compared to the time before adoption of RALP (1998-2003, annual percentage change, 0.01%; 95% confidence interval, -0.06 to 0.08). Sensitivity analysis suggested that the results from the interrupted time-series analysis were consistent with the improvement in the all-cause mortality demonstrated in the survival analysis (P = 0.87). CONCLUSIONS: In this epidemiologic analysis, RALP was associated with a small but statistically significant improvement in 5-year all-cause mortality compared to ORP for localized prostate cancer. This is the first time in the literature to report a survival benefit with RALP. Our findings have significant quality and cost implications, and provide assurance regarding a dominant adoption of more expensive technology in the absence of randomized controlled trials.

Analysis of the Survival Impact of Postoperative Chemotherapy After Preoperative Chemotherapy and Resection for Gastric Cancer.

BACKGROUND: Perioperative chemotherapy is a standard-of-care treatment for patients with gastric cancer. However, the impact of the postoperative chemotherapy (postCTX) component on overall survival (OS) is not well defined. METHODS: The National Cancer Database (NCDB) 2006-2014 was queried for patients who received preoperative chemotherapy (preCTX) and resection for gastric cancer. Analysis was performed to identify factors influencing receipt of postCTX. The impact of postCTX on OS was evaluated in propensity-matched groups. RESULTS: Among 3449 patients who received preCTX and resection for gastric cancer, 1091 (31.6%) received postCTX. Independent predictors of receiving postCTX were diagnosis after 2010 (odds ratio [OR] 1.985), distal tumor location (OR 1.348), and 15 or more lymph nodes examined (OR 1.214). Predictors of not receiving postCTX were older age (OR 0.985), comorbidity score higher than 1 (OR 0.592), and black race (OR 0.791). After propensity-matching (1091 per group), the median OS was 56.8 months for those who did receive postCTX versus 52.5 months for those who did not (p = 0.131). Subset analysis according to tumor grade, lymphovascular invasion, number of lymph nodes evaluated, T and N class, and AJCC stage identified an improvement in OS for the patients with N1 disease who received postCTX compared with those who did not (79.6 vs 41.3 months; p = 0.025). However, no other subgroup had a significant survival benefit. CONCLUSIONS: Additional postCTX was administered to a minority of patients who received preCTX and gastrectomy for gastric cancer, and its influence on OS appeared to be limited. Future trials should aim to define patients who will benefit from postCTX.

NCCN Guidelines Insights: Kidney Cancer, Version 1.2021.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to certain systemic therapy recommendations for patients with relapsed or stage IV RCC. They also discuss the addition of a new section to the guidelines that identifies and describes the most common hereditary RCC syndromes and provides recommendations for genetic testing, surveillance, and/or treatment options for patients who are suspected or confirmed to have one of these syndromes.

Safety and Efficacy of Nivolumab in Patients With Advanced Non-Clear Cell Renal Cell Carcinoma: Results From the Phase IIIb/IV CheckMate 374 Study.

BACKGROUND: The open-label phase IIIb/IV CheckMate 374 study (NCT02596035) was conducted to validate the safety and efficacy of flat-dose nivolumab 240 mg every 2 weeks (Q2W) in previously treated advanced/metastatic renal cell carcinoma. Three cohorts included patients with predominantly clear cell histology, non-clear cell histologies, or brain metastases. We report safety and efficacy from the advanced non-clear cell RCC (nccRCC) cohort of CheckMate 374. METHODS: Eligible patients received 0 to 3 prior systemic therapies. Patients received nivolumab 240 mg Q2W for ≤24 months or until confirmed progression or unacceptable toxicity. The primary endpoint was incidence of high-grade (grade 3-5) immune-mediated adverse events (IMAEs). Exploratory endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: Forty-four patients had advanced nccRCC (papillary [n = 24], chromophobe [n = 7], unclassified [n = 8], other [n = 5]); 34.1% received ≥1 prior systemic regimen in the advanced/metastatic setting. With median follow-up of 11 (range, 0.4-27) months, no all-cause grade 3-5 IMAEs or treatment-related grade 5 adverse events were reported. ORR was 13.6% (95% confidence interval [CI], 5.2-27.4), with 1 complete response (chromophobe) and 5 partial responses (papillary [n = 2], chromophobe [n = 1], collecting duct [n = 1], and unclassified [n = 1] histology). Median PFS was 2.2 months (95% CI, 1.8-5.4). Median OS was 16.3 months (95% CI, 9.2-not estimable). CONCLUSIONS: Safety of flat-dose nivolumab 240 mg Q2W was consistent with previous results. Clinically meaningful efficacy was observed with responses in several histologies, supporting nivolumab as a treatment option for patients with advanced nccRCC, a patient population with high unmet need.

Safety and Efficacy of Nivolumab in Patients With Advanced Clear Cell Renal Cell Carcinoma: Results From the Phase IIIb/IV CheckMate 374 Study.

BACKGROUND: The open-label, phase IIIb/IV CheckMate 374 study (NCT02596035) was conducted to validate the safety and efficacy of flat-dose nivolumab monotherapy 240 mg every 2 weeks (Q2W) in previously treated advanced/metastatic renal cell carcinoma (RCC). Three cohorts included patients with predominantly clear cell histology, non-clear cell histologies, or brain metastases. We report safety and efficacy from the CheckMate 374 advanced clear cell RCC (ccRCC) cohort. PATIENTS AND METHODS: Eligible patients received prior treatment regimens (1-2 antiangiogenic; 0-3 systemic) with progression on/after last treatment and ≤ 6 months of enrollment. Patients received nivolumab 240 mg Q2W for ≤ 24 months or until confirmed progression/unacceptable toxicity. The primary endpoint was incidence of high-grade (grade 3-5) immune-mediated adverse events (IMAEs). Exploratory endpoints included objective response rate, progression-free survival, and overall survival. RESULTS: Ninety-seven patients had advanced predominantly ccRCC; 75.3% received only 1 prior systemic regimen in the advanced/metastatic setting. After a median follow-up of 17 months (range, 0.4-26.9 months), no grade 5 IMAEs occurred, and 9.3% of patients reported grade 3/4 IMAEs (hepatitis, 4.1%; diabetes mellitus, 2.1%; nephritis and renal dysfunction, 1.0%; rash, 1.0%; adrenal insufficiency, 1.0%). The objective response rate was 22.7% (95% confidence interval [CI], 14.8%-32.3%). Three patients had a complete response; 19 had partial responses. The median progression-free survival was 3.6 months (95% CI, 2.0-5.5 months). The median overall survival was 21.8 months (95% CI, 17.4 months to not estimable). CONCLUSIONS: This study validates the safety and efficacy of nivolumab 240 mg Q2W flat-dose monotherapy for previously treated advanced ccRCC and adds to previous safety and efficacy data using the 3 mg/kg Q2W dose.

The utilization and impact of adjuvant therapy following neoadjuvant therapy and resection of pancreatic adenocarcinoma: does more really matter?

BACKGROUND: Although neoadjuvant therapy is increasingly administered to patients with pancreatic ductal adenocarcinoma (PDAC), the impact of additional adjuvant therapy (AT) following resection is not well defined. METHODS: The National Cancer Database (NCDB) was queried for patients who received neoadjuvant therapy followed by R0 or R1 resection for PDAC. Factors influencing survival, including the receipt of AT were evaluated. RESULTS: Of patients receiving neoadjuvant therapy and resection 680 (33.8%) received AT and 1331 (66.2%) did not. For R0 resected patients (n = 1800), lymphovascular invasion (HR 1.24, p = 0.034) and increasing N classification (N1: HR 1.27, p = 0.019; N2: HR 1.51, p = 0.004) were associated with increased risk of death while AT was not associated with improved overall survival (OS) (HR 0.88, p = 0.179). Following R1 resection (n = 211), AT was associated with reduced risk of death (HR 0.57, p = 0.038). Within propensity matched cohorts, median OS for patients receiving and not receiving AT was 32.1 and 30.0 months after R0 resection (p = 0.184), and 23.6 and 20.5 months after R1 resection (p = 0.005). CONCLUSION: This analysis demonstrated that AT did not yield OS benefit for patients who had neoadjuvant therapy and R0 resection and a statistically significant, although relatively short, improvement in OS for patients who underwent R1 resection.

PSMA ADC monotherapy in patients with progressive metastatic castration-resistant prostate cancer following abiraterone and/or enzalutamide: Efficacy and safety in open-label single-arm phase 2 study.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a well-established therapeutic and diagnostic target overexpressed in both primary and metastatic prostate cancers. PSMA antibody-drug conjugate (PSMA ADC) is a fully human immunoglobulin G1 anti-PSMA monoclonal antibody conjugated to monomethylauristatin E, which binds to PSMA-positive cells and induces cytotoxicity. In a phase 1 study, PSMA ADC was well tolerated and demonstrated activity as measured by reductions in serum prostate-specific antigen (PSA) and circulating tumor cells (CTCs). To further assess PSMA ADC, we conducted a phase 2 trial in metastatic castration-resistant prostate cancer (mCRPC) subjects who progressed following abiraterone/enzalutamide (abi/enz) therapy. METHODS: A total of 119 (84 chemotherapy-experienced and 35 chemotherapy-naïve) subjects were administered PSMA ADC 2.5 or 2.3 mg/kg IV q3w for up to eight cycles. Antitumor activity (best percentage declines in PSA and CTCs from baseline and tumor responses through radiological imaging), exploratory biomarkers, and safety (monitoring of adverse events [AEs], clinical laboratory tests, and Eastern Cooperative Oncology Group performance status) were assessed. RESULTS: PSA declines ≥50% occurred in 14% of all treated (n = 113) and 21% of chemotherapy-naïve subjects (n = 34). CTC declines ≥50% were seen in 78% of all treated (n = 77; number of subjects with ≥5 CTCs at baseline and a posttreatment result) and 89% of chemotherapy-naïve subjects (n = 19); 47% of all treated and 53% of chemotherapy-naïve subjects had a transition from ≥5 to less than 5 CTCs/7.5 mL blood at some point during the study. PSA and CTC reductions were associated with high PSMA expression (CTCs or tumor tissue) and low neuroendocrine serum markers. In the chemotherapy-experienced group, the best overall radiologic response to PSMA ADC treatment was stable disease in 51 (60.7%) subjects; 5.7% of subjects in the chemotherapy-naïve group had partial responses. The most common treatment-related AEs ≥Common Terminology Criteria for AE (CTCAE) grade 3 were neutropenia, fatigue, electrolyte imbalance, anemia, and neuropathy. The most common serious AEs were dehydration, hyponatremia, febrile neutropenia, and constipation. Two subjects who received 2.5 mg/kg died of sepsis. CONCLUSIONS: PSMA ADC demonstrated some activity with respect to PSA declines, CTC conversions/reductions, and radiologic assessments in abi/enz treated mCRPC subjects. Clinically significant treatment-related AEs included neutropenia and neuropathy.

NCCN Guidelines Insights: Kidney Cancer, Version 2.2020.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal cell carcinoma, and are intended to assist with clinical decision-making. These NCCN Guidelines Insights summarize the NCCN Kidney Cancer Panel discussions for the 2020 update to the guidelines regarding initial management and first-line systemic therapy options for patients with advanced clear cell renal cell carcinoma.

Definitive Pelvic Radiotherapy and Survival of Patients With Newly Diagnosed Metastatic Anal Cancer.

Background: Chemotherapy with or without pelvic radiotherapy (RT) is included in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for metastatic anal cancer (MAC), despite limited clinical evidence for RT in this setting. In addition, increasing evidence shows that local therapies, including RT, may increase patient survival for some types of metastatic cancers. The purpose of this study was to evaluate the patterns of care and association between definitive pelvic RT and overall survival (OS) for patients with MAC. Methods: The National Cancer Database was analyzed to evaluate OS of patients with newly diagnosed MAC treated with chemotherapy with or without pelvic RT. Those who did not undergo treatment, treated with surgery, or without baseline variables were excluded. OS was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score-matched analyses. Results: From 2004 through 2015, 437 patients received chemotherapy alone and 1,020 received pelvic chemoradiotherapy (CRT). At a median follow-up of 17.3 months, CRT was associated with improved OS on univariate (P<.001) and multivariate analysis (hazard ratio [HR], 0.70; 95% CI, 0.61-0.81; P<.001). Propensity score-matched analysis demonstrated superior median survival (21.3 vs 15.9 months) and 2-year OS rates (46% vs 34%) with CRT compared with chemotherapy alone (P<.001). Landmark analyses limited to long-term survivors of ≥1, ≥2, and ≥4 years showed improved OS with CRT in all subsets (all P<.05). CRT with therapeutic doses (≥45 Gy) was associated with longer median survival than palliative doses (<45 Gy) and chemotherapy alone (24.9 vs 10.9 vs 15.6 months, respectively; P<.001). The benefit of CRT was present among not only those with distant lymph node metastasis (HR, 0.63; P=.04) but also those with distant organ disease (HR, 0.74; P<.001). Conclusions: In this large hypothesis-generating analysis, patients with newly diagnosed MAC who received definitive pelvic RT with chemotherapy lived significantly longer than those who received chemotherapy alone. Prospective trials evaluating definitive local RT for MAC are warranted.

Reciprocal feedback inhibition of the androgen receptor and PI3K as a novel therapy for castrate-sensitive and -resistant prostate cancer.

Gain-of-function of the androgen receptor (AR) and activation of PI3K/AKT/mTOR pathway have been demonstrated to correlate with progression to castration-resistant prostate cancer (CRPC). However, inhibition of AR or PI3K/mTOR alone results in a reciprocal feedback activation. Therefore, we hypothesized that dual inhibition of the AR and PI3K/mTOR pathway might lead to a synergistic inhibition of cell growth and overcome drug resistance in CRPC. Here, we reported that androgen-depletion increased AR protein level and Akt phosphorylation at Ser473 and Thr308 in LNCaP cells. Moreover, we developed resistance cell lines of LNCaP to Enzalutamide (or MDV3100), an AR inhibitor (named as LNCaP 'MDV-R') and PF-04691502, a PI3K/mTOR inhibitor (named as LNCaP 'PF-R'). MTS analysis showed that LNCaP 'PF-R' was strongly resistant to Enzalutamide treatment, and on the other hand, LNCaP 'MDV-R' was 6-fold resistant to PF-04691502 treatment. Mechanistically, LNCaP 'MDV-R' cells had significantly reduced AR, loss of PSA and increase Akt activity in contrast with LNCaP 'PF-R' cells. Combined inhibition of PI3K/mTOR and AR pathways with a variety of small molecular inhibitors led to a synergistic suppression of cell proliferation and a profound increase of apoptosis and cell cycle arrest in both androgen-dependent LNCaP and independent CRPC 22Rv1 cell lines. In conclusion, this study provides preclinical proof-of-concept that the combination of a PI3K/mTOR inhibitor with an AR inhibitor results in a synergistic anti-tumor response in non-CRPC and CRPC models.

A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas.

BACKGROUND: Trametinib, an oral mitogen/extracellular signal-related kinase (MEK)1/2 inhibitor, holds promise for malignancies with rat sarcoma (RAS) mutations, like pancreas cancer. This phase II study was designed to determine overall survival (OS) in patients with pancreas cancer treated with trametinib and gemcitabine. Secondary end-points included progression-free survival (PFS), overall response rate (ORR) and duration of response (DOR); safety end-points were also assessed. METHODS: Adults with untreated metastatic adenocarcinoma of the pancreas were randomised (1:1) to receive intravenous gemcitabine 1000 mg/m(2) (weekly × 7 for 8 weeks, then days 1, 8 and 15 of 28-day cycles) plus trametinib or placebo 2mg daily. RAS mutations were determined in circulating free DNA (cfDNA) and archival tumour tissue. OS was evaluated in kirsten rat sarcoma viral oncogene homolog (KRAS) mutant and wild-type subgroups. RESULTS: Baseline characteristics for 160 patients were similar in both treatment arms. There was no significant difference in OS (hazard ratio (HR) 0.98; 95% confidence interval (CI), 0.67-1.44; P=.453); median OS was 8.4 months with gemcitabine plus trametinib and 6.7 months with gemcitabine plus placebo. Median PFS (16 versus 15 weeks), ORR (22% versus 18%) and median DOR (23.9 versus 16.1 weeks) were also similar for trametinib and placebo arms, respectively. KRAS mutation-positive patients (n=103) showed no difference in OS between arms. Thrombocytopenia, diarrhoea, rash and stomatitis were more frequent with trametinib, as was grade 3 anaemia. CONCLUSIONS: The addition of trametinib to gemcitabine did not improve OS, PFS, ORR or DOR in patients with previously untreated metastatic pancreas cancer. Outcomes were independent of KRAS mutations determined by cfDNA.

A randomised phase 2 study combining LY2181308 sodium (survivin antisense oligonucleotide) with first-line docetaxel/prednisone in patients with castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) is partially characterised by overexpression of antiapoptotic proteins, such as survivin. In this phase 2 study, patients with metastatic CRPC (n=154) were randomly assigned (1:2 ratio) to receive standard first-line docetaxel/prednisone (control arm) or the combination of LY2181308 with docetaxel/prednisone (experimental arm). The primary objective was to estimate progression-free survival (PFS) for LY2181308 plus docetaxel. Secondary efficacy measures included overall survival (OS), several predefined prostate-specific antigen (PSA)-derived end points, and Brief Pain Inventory (BPI) and Functional Assessment of Cancer Therapy-Prostate (FACT-P) scores. The median PFS of treated patients for the experimental arm (n=98) was 8.64 mo (90% confidence interval [CI], 7.39-10.45) versus 9.00 mo (90% CI, 7.00-10.09) in the control arm (n=51; p=0.755). The median OS for the experimental arm was 27.04 mo (90% CI, 19.94-33.41) compared with 29.04 mo (90% CI, 20.11-39.26; p=0.838). The PSA responses (≥ 50% PSA reduction), BPI, and FACT-P scores were similar in both arms. In the experimental arm, patients had a numerically higher incidence of grades 3-4 neutropenia, anaemia, thrombocytopenia, and sensory neuropathy. In conclusion, this study failed to detect a difference in efficacy between the two treatment groups.

Phase II trial of fulvestrant with metronomic capecitabine for postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer.

BACKGROUND: In this phase II study, we explored efficacy and toxicity of combined endocrine and low-dose metronomic chemotherapy therapy consisting of fulvestrant and capecitabine in estrogen and/or progesterone receptor-positive, HER2-negative MBC. PATIENTS AND METHODS: Patients with ≤ 1 previous hormonal treatment in the metastatic setting received an injection fulvestrant loading dose 500 mg on day 1, 250 mg on days 15 and 29 followed by 250 mg every 28 days along with continuous oral capecitabine in divided doses. The total fixed daily dose of capecitabine was either 1500 mg or 2000 mg, depending on the patient's weight (< 80 kg vs. ≥ 80 kg). Primary end points were PFS and TTP. Toxicity was assessed by continuous evaluations of treatment-emergent adverse events (AEs) and changes from baseline in laboratory values. RESULTS: Forty-one women, with a mean age of 64.5 years, were enrolled. Patients completed a median of 11 monthly treatment cycles. Median PFS was 14.98 months (95% confidence interval [CI], 7.26-upper limit [UL] not estimated) and median TTP was 26.94 months (95% CI, 7.26-UL not estimated). Median overall survival was 28.65 months (95% CI, 23.95-UL not estimated). Treatment was well tolerated with < 10% Grade 3 palmar-plantar erythrodysesthesia. Overall, the most frequent AEs were palmar-plantar erythrodysesthesia, fatigue, and nausea. CONCLUSION: Fulvestrant with metronomic capecitabine demonstrates substantial activity in hormone receptor-positive MBC and is well tolerated. Combined chemoendocrine approaches should be further explored considering the low toxicity of the combination with meaningful TTP.

Treatment patterns and clinical effectiveness in metastatic castrate resistant prostate cancer after first-line docetaxel.

BACKGROUND: Treatment for metastatic castrate-resistant prostate cancer in community settings is not well understood. OBJECTIVE: To examine treatment patterns, sequencing, and outcomes in patients receiving second- and third-line treatment after first-line docetaxel. METHODS: We used a community oncology database to identify patients who progressed after line 1 docetaxel (D) and received line 2 cabazitaxel (DC), abiraterone (DA), or other therapy (DO). Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan- Meier and Cox regression models. Line 3 included subsets DCA and DAC. RESULTS: Line 2 groups (DC = 60 patients, DA = 71, DO = 153) did not differ significantly on demographic and clinical characteristics or median PFS on docetaxel therapy. Cox regression for OS by line 2 groups showed increased risk for DA compared with DC (HR, 1.69; P = .026) when 24 untreated DO patients were excluded. A similar nonsignificant pattern was observed when the 24 untreated patients were included. Of patients receiving DC in line 2, a nominally greater proportion received A in line 3 (57%, 34 of 60 patients) than did patients who received DA in line 2 followed by C in line 3 (25%, 18 of 71). LIMITATIONS: There was a small sample for line 3, and unexamined confounds and selection biases in observational research. Conclusions Treatment patterns in community settings following docetaxel are complex and may involve multiple hormonal agents prior to disease progression. Cabazitaxel may not be optimally used in advanced disease. Although Cox regression showed increased risk of death for DA compared with DC, results need to be validated prospectively. CONCLUSIONS: Treatment patterns in community settings following docetaxel are complex and may involve multiple hormonal agents prior to disease progression. Cabazitaxel may not be optimally used in advanced disease. Although Cox regression showed increased risk of death for DA compared with DC, results need to be validated prospectively.

A randomized, double-blind, placebo-controlled, Phase II study with and without enzastaurin in combination with docetaxel-based chemotherapy in patients with castration-resistant metastatic prostate cancer.

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(2)) 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.

Oral enzastaurin in prostate cancer: a two-cohort phase II trial in patients with PSA progression in the non-metastatic castrate state and following docetaxel-based chemotherapy for castrate metastatic disease.

PURPOSE: Enzastaurin is an oral serine/threonine kinase inhibitor of the beta isoform of protein kinase C that may have therapeutic activity in prostate cancer. We explored the efficacy of enzastaurin on two cohorts of patients with prostate cancer progression in the castrate state. PATIENTS AND METHODS: A two-cohort phase II trial was conducted, with both groups participating simultaneously. Cohort 1 consisted of patients with non-metastatic castrate prostate-specific antigen progressive disease. Cohort 2 consisted of patients with castrate metastatic disease with progression following docetaxel-based chemotherapy. Patients in both cohorts received 500 mg/day enzastaurin. RESULTS: Therapy was well tolerated in both cohorts. One complete response was observed in Cohort 1, with limited activity in the majority of patients. In Cohort 2, no objective responses were seen and the median progression-free survival (11 weeks [90% confidence interval: 7.6, 11.7]) did not differ from the historical control. CONCLUSIONS: Enzastaurin as a single agent has limited activity in castrate progressive prostate cancer. Evaluation in combination with docetaxel is ongoing.

An open-label, multicenter, phase I/II study of single-agent AT-101 in men with castrate-resistant prostate cancer.

PURPOSE: AT-101 binds and inhibits the antiapoptotic function of Bcl-2, Bcl-xL, Mcl-1, and Bcl-w and is a potent stimulator of proapoptotic proteins. In this multi-institution phase I/II trial, we evaluated the safety and efficacy of single-agent AT-101, in men with chemotherapy naïve, castrate-resistant prostate cancer (CRPC). EXPERIMENTAL DESIGN: Patients with progressive CRPC were to be treated with escalating doses of AT-101 on a continuous daily basis until the maximally tolerated dose was achieved. At the recommended phase 2 dose, an additional 21 patients were planned to assess for preliminary evidence of efficacy. RESULTS: Twenty-three patients were enrolled. The phase I starting dose was 30 mg/day on a continuous basis; however, ongoing trials with AT-101 showed increased gastrointestinal toxicity with this daily schedule when given for repetitive cycles. As a result, the phase II starting dose was chosen to be 30 mg/day for 21 of 28 days. The most frequent observed adverse events (any grade) were diarrhea (43.5%), fatigue (34.8%), nausea (21.7%), anorexia (21.7%), and small intestinal obstruction (21.7%). Due to the high incidence of grade 3 small intestinal obstruction (n = 5; 21.7%), a reduction in dose to 20 mg/day for 21 of 28 days was mandated for all patients. Two patients had a confirmed > or =50% posttherapy prostate-specific antigen decline. No objective responses (Response Evaluation Criteria in Solid Tumors) were observed. CONCLUSION: AT-101 administered at 20 mg/day for 21 of 28 days was well-tolerated. Evidence of single-agent clinical activity was observed with prostate-specific antigen declines in some patients. Further investigation of AT-101 in prostate cancer is warranted and trials combining AT-101 with androgen deprivation, as well as with docetaxel chemotherapy are ongoing.