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Background: Radium-223 is a targeted alpha-particle therapy that improves survival in men with metastatic castration resistant prostate cancer (mCRPC), particularly in men with elevated serum levels of bone alkaline phosphatase (B-ALP). We hypothesized that osteomimicry, a form of epithelial plasticity leading to an osteoblastic phenotype, may contribute to intralesional deposition of radium-223 and subsequent irradiation of the tumor microenvironment. Methods: We conducted a pharmacodynamic study (NCT02204943) of radium-223 in men with bone mCRPC. Prior to and three and six months after radium-223 treatment initiation, we collected CTCs and metastatic biopsies for phenotypic characterization and CTC genomic analysis. The primary objective was to describe the impact of radium-223 on the prevalence of CTC B-ALP over time. We measured radium-223 decay products in tumor and surrounding normal bone during treatment. We validated genomic findings in a separate independent study of men with bone metastatic mCRPC (n = 45) and publicly accessible data of metastatic CRPC tissues. Results: We enrolled 20 men with symptomatic bone predominant mCRPC and treated with radium-223. We observed greater radium-223 radioactivity levels in metastatic bone tumor containing biopsies compared with adjacent normal bone. We found evidence of persistent Cellsearch CTCs and B-ALP (+) CTCs in the majority of men over time during radium-223 therapy despite serum B-ALP normalization. We identified genomic gains in osteoblast mimicry genes including gains of ALPL, osteopontin, SPARC, OB-cadherin and loss of RUNX2, and validated genomic alterations or increased expression at the DNA and RNA level in an independent cohort of 45 men with bone-metastatic CRPC and in 150 metastatic biopsies from men with mCRPC. Conclusions: Osteomimicry may contribute in part to the uptake of radium-223 within bone metastases and may thereby enhance the therapeutic benefit of this bone targeting radiotherapy. [ABSTRACT FROM AUTHOR]

Background Several prognostic models for overall survival (OS) have been developed and validated in men with metastatic castration-resistant prostate cancer (mCRPC) who receive first-line chemotherapy. We sought to develop and validate a prognostic model to predict OS in men who had progressed after first-line chemotherapy and were selected to receive second-line chemotherapy. Methods Data from a phase III trial in men with mCRPC who had developed progressive disease after first-line chemotherapy (TROPIC trial) were used. The TROPIC was randomly split into training (n = 507) and testing (n = 248) sets. Another dataset consisting of 488 men previously treated with docetaxel (SPARC trial) was used for external validation. Adaptive least absolute shrinkage and selection operator selected nine prognostic factors of OS. A prognostic score was computed from the regression coefficients. The model was assessed on the testing and validation sets for its predictive accuracy using the time-dependent area under the curve (tAUC). Results The nine prognostic variables in the final model were Eastern Cooperative Oncology Group performance status, time since last docetaxel use, measurable disease, presence of visceral disease, pain, duration of hormonal use, hemoglobin, prostate specific antigen, and alkaline phosphatase,The tAUCs for this model were 0.73 (95% confidence interval [CI] = 0.72 to 0.74) and 0.70 (95% CI = 0.68 to 0.72) for the testing and validation sets, respectively. Conclusions A prognostic model of OS in the postdocetaxel, second-line chemotherapy, mCRPC setting was developed and externally validated. This model incorporates novel prognostic factors and can be used to provide predicted probabilities for individual patients and to select patients to participate in clinical trials on the basis of their prognosis. Prospective validation is needed. [ABSTRACT FROM AUTHOR]

Purpose: A prior report suggested that radical prostatectomy may confer a survival advantage to patients with metastatic castration recurrent prostate cancer. Therefore, a pooled analysis of 9 trials performed by Cancer and Leukemia Group B was done to determine if men with metastatic castration recurrent prostate cancer who underwent prior prostatectomy had improved clinical outcomes, such as overall, prostate specific, progression-free and PSA progression-free survival, than men who did not undergo prior prostatectomy. Materials and Methods: Data from 9 multi-institutional trials performed by Cancer and Leukemia Group B were combined. Eligible patients had progressive prostate cancer during androgen deprivation therapy, Eastern Cooperative Oncology Group performance status 0–2, and adequate hematological, renal and hepatic functions. The proportional hazards model was used to assess the prognostic importance of radical prostatectomy for predicting clinical outcomes. Results: Of 1,238 men 310 (25%) underwent prostatectomy. Median survival was 14.7 (95% CI 12.9–16.7) and 14.5 months (95% CI 13.5–15.7) in men who did and did not undergo prostatectomy, respectively. The HR for death was 1.03 (95% CI 0.90–1.19, p = 0.65) in men with vs without prostatectomy. Conclusions: Prior prostatectomy in men with metastatic castration recurrent prostate cancer who were subsequently enrolled on clinical trials for cancer treatment had similar survival compared to men who did not undergo prior prostatectomy. These data do not support another report suggesting that prior prostatectomy confers a subsequent survival advantage in men with castration recurrent prostate cancer. [Copyright &y& Elsevier]

Background: Institution of early hormone therapy in the PSA era coupled with demonstration of clinical benefit with chemotherapy in hormone refractory prostate cancer (HRPC) and acceptance of PSA decline as a surrogate for response has resulted in introduction of chemotherapy earlier in the natural history of disease. There now exists a need to identify, effective agents for second line chemotherapy. 9-Nitrocamptothecin (9-NC) a novel, oral camptothecin analogue was tested as second line chemotherapy for patients with progressive hormone refractory prostate cancer.Patients and methods: Eligible patients had metastatic hormone refractory prostate cancer with performance status (0–1) following progression on at least 1 prior cytotoxic chemotherapy. 9-NC was administered orally at the dose of 1.5 mg/m2/d for 5 days each week for 3 weeks, followed by rest for 1 week. Response was evaluated after 2 cycles according to the guidelines set forth for Phase II trials in HRPC by the PSA working group.Results: Thirty-five patients were recruited to the study within a period of 6 months; 33 were evaluable for analysis. No patients had a >50% decline in PSA levels. Two out of 8 (25%) patients with measurable disease and 5/25 (20%) patients with nonmeasurable disease showed stable disease. The median time to disease and PSA progression was 2 months [95% confidence interval (CI), 0.9–2.8]. The median overall survival was 10 months (95% CI = 5–12). Seven patients are alive after a median follow-up of 23 months.Conclusions: 9-Nitrocamptothecin failed to elicit clinical or PSA responses. Further study in pretreated HRPC patients is not warranted. [Copyright &y& Elsevier]