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Targeting androgen receptor (AR) axis signaling by disrupting androgen-AR interactions remains the primary treatment for metastatic prostate cancer. Unfortunately, all men develop resistance to primary castrating therapy and secondary androgen deprivation therapies (ADTs). Resistance develops in part because castration-resistant prostate cancer (CRPC) cells adaptively up-regulate AR levels through overexpression, amplification, and expression of ligand-independent variants in response to chronic exposure to a low-testosterone environment. However, preclinical models suggest that AR overexpression represents a therapeutic liability that can be exploited via exposure to supraphysiologic testosterone to promote CRPC cell death. Preclinical data supported a pilot study in which 16 asymptomatic CRPC patients with low to moderate metastatic burden were treated with testosterone cypionate (400 mg intramuscular; day 1 of 28) and etoposide (100 mg oral daily; days 1 to 14 of 28). After three cycles, those with a declining prostate-specific antigen (PSA) continued on intermittent testosterone therapy monotherapy. Castrating therapy was continued to suppress endogenous testosterone production, allowing for rapid cycling from supraphysiologic to near-castrate serum testosterone levels, a strategy termed bipolar androgen therapy (BAT). BAT was well tolerated and resulted in high rates of PSA (7 of 14 evaluable patients) and radiographic responses (5 of 10 evaluable patients). Although all men showed eventual PSA progression, four men remained on BAT for ≥1 year. All patients (10 of 10) demonstrated PSA reductions upon receiving androgen-ablative therapies after BAT, suggesting that BAT may also restore sensitivity to ADTs. BAT shows promise as treatment for CRPC and should be further evaluated in larger trials.

The traditional treatment paradigm for prostate cancer focuses on targeting the tumor cells using hormonal ablation. However, in recent years, not only have novel chemotherapy regimens shown promise in men with prostate cancer, but new therapeutic targets have also been identified as our understanding of disease progression has deepened. The gold standard treatment for patients with hormone-refractory prostate cancer is now docetaxel every 3 wk plus low-dose prednisone. In addition, ongoing clinical investigations are evaluating docetaxel-based chemotherapy in combination with newer agents, such as bevacizumab, oblimersen, calcitriol, and thalidomide. A large number of agents are also being investigated in clinical trials that employ novel mechanisms of action, such as targeting bone metastases, the androgen receptor, or components of the tumor intracellular-signalling pathways. Furthermore, the encouraging results in the metastatic disease settings, have prompted the exploration of these treatment strategies in the adjuvant and neoadjuvant settings, where currently available treatment options fail to offer a cure to high-risk patients with locally advanced prostate cancer. The traditional treatment paradigm for prostate cancer, therefore, is being replaced by a multidisciplinary approach. To provide patients with prostate cancer with the best chance of survival and quality of life, urologists and oncologists must maintain close working relationships to determine the most appropriate treatment strategy for an individual patient.

OBJECTIVES In this phase II study, the combination of docetaxel and exisulind (a GMP phosphodiesterase inhibitor) was given to patients with metastatic androgen independent prostate cancer (AIPC) to establish efficacy, assess toxicity, and determine pharmacokinetics of docetaxel administered alone and in combination with exisulind. METHODS Fourteen patients with metastatic AIPC were registered to receive weekly docetaxel for 4 weeks, followed by 2 weeks of rest; repeated up to a maximum of 6 cycles. Exisulind 250 mg was given orally twice a day starting on day 8 of the study and taken continuously. RESULTS All patients were evaluable for toxicity, response and survival. Grade 3 reversible toxicities included: fatigue, nausea, diarrhea, abdominal pain, rash, syncope, pulmonary edema, deep vein thrombosis, congestive heart failure, and elevations in transaminases, requiring therapy delays and/or dose reductions, or removal from therapy. Only 3 out of 14 patients (21.4%) had a 50% decline in prostate specific antigen (PSA) level that lasted > or =4 weeks; 1 out of 14 patients (7%) had a lymph node response. Median survival was 17.28 months. Docetaxel pharmacokinetics for 11 patients demonstrated mean +/- SD clearance values that were similar during week 1 and week 3 when exisulind had been added. CONCLUSIONS : Overall, our trial indicated that the toxicity profile and efficacy of this regimen is unlikely to be substantially better than single agent docetaxel.

Recently, data from two randomized phase III studies that compared docetaxel-based chemotherapy to mitoxantrone-based therapy demonstrated that treatment with docetaxel can prolong life in a significant way for patients with hormone-refractory prostate cancer. For many patients who experience disease progression after androgen-deprivation therapy, however, chemotherapy may not be immediately indicated. Such cases include those individuals with hormone-refractory disease in the absence of clinical metastases, and those with asymptomatic metastatic disease, for example. As a result, clinicians treating patients with hormone-refractory disease must weigh the benefits of earlier chemotherapy against its risks, and may consider other therapies such as secondary hormonal approaches before initiating chemotherapy. This decision is further complicated by the fact that a phase III study designed to compare secondary hormonal therapy with chemotherapy has failed due to lack of accrual. Furthermore, the limitations of chemotherapy for prostate cancer are being clarified and include a lack of standard second-line therapy as well as uncertain benefits for those with nonmetastatic disease. In this review, we will highlight some of the issues that impact on the decision of when to start chemotherapy and in whom as well as the potential benefits of secondary hormonal approaches.

Purpose: Hypermethylation of the CpG island at the promoter region of the π-class glutathione S-transferase gene (GSTP1) is the most common somatic genome abnormality in human prostate cancer. We evaluated circulating cell-free DNA GSTP1 CpG island hypermethylation as a prognostic biomarker in the serum of men with prostate cancer. Experimental Design: Prostate cancer DNA GSTP1 CpG island hypermethylation was detected using a restriction endonuclease quantitative PCR technique. We analyzed preoperative serum from 85 men with clinically localized prostate cancer treated with radical prostatectomy and from 35 men with a negative prostate biopsy. We then assayed preoperative serum from a data set of 55 pairs of men with clinically localized prostate cancer treated with radical prostatectomy, matched for Gleason score, comprising 55 men suffering prostate-specific antigen (PSA) recurrence (median, 2 years) and 55 men who were free of disease at last follow-up (median, 3 years). The association of serum GSTP1 CpG island hypermethylation and PSA recurrence was determined. Results: Circulating cell-free DNA with GSTP1 CpG island hypermethylation was not detected in the serum of men with a negative prostate biopsy but was detected in 12% of men with clinically localized disease and 28% of men with metastatic cancer (P = 0.003). In the matched data set, eight men (15%) who developed PSA recurrence were positive for DNA with GSTP1 CpG hypermethylation, whereas no patient who was free of disease was positive for GSTP1 CpG island hypermethylation (McNemar test, χ2 = 6.1, P = 0.01). In a multivariable analysis that accounted for recognized prognostic factors, the presence of serum DNA with GTSP1 CpG island hypermethylation was the most significant predictor of PSA recurrence (hazard ratio, 4.4; 95% confidence interval, 2.2, 8.8; P < 0.001). Conclusion: Our study suggests that GSTP1 CpG island hypermethylation may be an important DNA-based prognostic serum biomarker for prostate cancer.

Purpose: To determine maximum-tolerated dose, toxicities, and pharmacokinetics associated with weekly intravesical gemcitabine therapy in patients with superficial bladder cancer. Patients and Methods: Fifteen patients with recurrent superficial transitional cell bladder carcinoma who experienced prior intravesical therapy failure were studied. Two to 4 weeks after complete transurethral resection, gemcitabine was administered intravesically, once weekly for 6 consecutive weeks. Dwell time was 2 hours. Pharmacokinetics of gemcitabine and its metabolite, 2′2′-difluorodeoxyuridine (dFdU), were studied in plasma and urine. Cystoscopy was repeated 6 weeks after therapy. Results: Three-patient cohorts were enrolled sequentially at doses of 500, 1,000, and 1,500 mg in 100 mL 0.9% NaCl. Two patients received 2,000 mg in 100 mL. An additional four patients received 2,000 mg in 50 mL. No grade 4 toxicity or clinically relevant myelosuppression was noted. Nine of 13 evaluable patients were recurrence-free at 12 weeks. Low concentrations of gemcitabine (≤ 1 μg/mL) were present transiently in plasma of all patients receiving 2,000 mg in 50 mL. Gemcitabine was undetectable in plasma of other patients. dFdU was undetectable in plasma of patients receiving less than 1,500 mg. At doses ≥ 1,500 mg, dFdU concentrations increased until 90 to 120 minutes and then declined little, if any. Plasma dFdU concentrations implied absorption of 0.5% to 5.5% of instilled dose. Between 61% and 100% of the gemcitabine dose was accounted for in voided urine. No dFdU was measured in voided urine. Conclusion: Intravesical gemcitabine, at doses up to 2 g/wk, is well tolerated, is associated with minimal systemic absorption, and has promising efficacy in treatment of superficial bladder cancer.

Differences in stability of the free and complexed molecular forms of prostate-specific antigen (PSA) may influence the clinical utility of assays for these forms, as well as the calculated ratios to total PSA (tPSA), such as percent free PSA (fPSA) and percent complexed PSA (cPSA). The objective of this study was to directly compare the short-term stability of fPSA and cPSA under different storage conditions. Specimens (3 with prostate cancer, 3 biopsy-negative without cancer, 2 normal) from 8 men were analyzed at baseline within 2 hours of collection, and at 4 hours, 8 hours, 24 hours, 48 hours, and 1 week after storage at room temperature, 4 degrees C, or -20 degrees C. Serum specimens were analyzed in duplicate on the Bayer Immuno 1 analyzer (tPSA, cPSA) and on the Beckman Coulter Access analyzer (tPSA, fPSA Tandem assays). Baseline tPSA values ranged from 0.7 to 62.0 ng/mL, with a median of 7.9 ng/mL (Immuno 1). Overall, all forms of PSA were stable up to 24 hours at the 3 temperatures, with the exception of fPSA and percent fPSA, which decreased when stored at 4 degrees C. After 1 week, tPSA levels decreased when stored at room temperature and at 4 degrees C, as did cPSA stored at room temperature. Over the 7 days, percent cPSA was stable at room temperature, but increased at 4 degrees C. There were no significant changes in any PSA form or calculated ratio with storage at -20 degrees C for up to 1 week. In summary, in the short term (1 week), fPSA is less stable with storage than tPSA or cPSA in a time- and temperature-dependent fashion. Thus, specimen handling should be considered when interpreting PSA results. It is recommended that specimens not analyzed the same day (within 8 hours of collection) be stored frozen at -20 degrees C.

The management of patients with high-risk, early-stage, prostate cancer represents a major challenge to all disciplines involved in the treatment of this common malignant neoplasm. Definition of the natural history of this disease, including the identification of key prognostic factors, in addition to the availability of active systemic therapeutic modalities for patients with advanced disease, are among the basic requirements that allow for early intervention in high-risk patients. Emerging new antiprogression approaches, targeted at various known stages of the metastatic cascade with the potential benefit of altering the natural history of early prostate cancer are attractive alternatives for early interventions with innovative programs. Studies on the natural history of patients with evidence of biochemical relapse following local treatment provide the basis for appropriate estimation of the risk ratio for development of clinical metastasis and selection of candidates for aggressive implementation of early treatment. The study of new candidate biomarkers of disease activity should be included in the context of clinical trials. Genotypic and phenotypic characterization of patients in clinical trials may enhance future therapeutic prospects in this disease.

Summary background Prostate cancer (PCa) is one of the most common cancers in men and has an increasing incidence. In 1999, 37 000 men died from PCa in the USA. Androgen deprivation therapy (ADT) with GnRH agonists is frequently employed in the treatment of recurrent and metastatic PCa by inducing medical castration, rendering these men hypogonadal. Because hypogonadism in men is associated with a wide range of complications, we attempted to determine the effects of long-term ADT in men with PCa. methods We conducted a cross-sectional study at a tertiary care centre to determine the effect of ADT on lean body mass (LBM), muscle strength, bone mineral density (BMD), sexual function, and quality of life (QOL) in men with PCa. Three groups of men were enrolled: (1) 20 men with PCa who were undergoing medical castration with GnRH agonists for at least 12 months prior to the onset of the study (ADT group); (2) 18 age-matched men with nonmetastatic PCa who were post prostatectomy and/or radiotherapy but had not yet undergone ADT (non-ADT group); and (3) 20 age-matched normal men who were healthy and ambulatory (control group). results Men on ADT had castrate levels of serum total testosterone (P

Patients with a rising prostate-specific antigen (PSA) levels after definitive local therapy now represent one of the largest and fastest growing groups of men with prostate cancer. The great majority of these men are asymptomatic with no other evidence of disease, and their clinical outcomes have been widely variable and poorly understood. Recently, several groups have analyzed their institutions' data and reported on certain pathologic and clinical variables that have increased our understanding of the natural history of these men, and to some extent allowed for the development of predictive models to aid in deciding who should be treated more aggressively and who should be watched. This article reviews and critically evaluates the most relevant available data for this group of men, and offers a summary of the most useful models and predictive variables after both radical prostatectomy and radiotherapy. This article also offers recommendations for strategies to improve our current knowledge of the natural history of these men, to facilitate the development and implementation of clinical trials in this population, and to ultimately be able to offer the most appropriate recommendations to our patients in the clinic.

PURPOSE: Endothelin receptors, particularly the ETA receptor, have been shown to participate in the pathophysiology of prostate and other cancers. Atrasentan, an endothelin antagonist, binds selectively to the ETA receptor. This study evaluated the safety, pharmacokinetics, and maximum-tolerated dose of atrasentan in cancer patients. PATIENTS AND METHODS: Patients who were 18 years or older and had histologically confirmed adenocarcinoma refractory to therapy enrolled in this 28-day, open-label, phase I study. Enrollment was planned for cohorts of three patients at doses escalating from 10 to 140 mg/d. When any patient had dose-limiting toxicity, that cohort was expanded. The primary outcome variable was safety; secondary outcome variables were pharmacokinetics, tumor response, and pain relief. RESULTS: Thirty-one cancer patients (14 prostate) were treated at daily atrasentan doses of 10, 20, 30, 45, 60, and 75 mg (n = 3 to 8 per cohort). The most common adverse events, such as rhinitis, headache, asthenia, and peripheral edema, were reversible on drug discontinuation and responded to symptom-specific treatment. Reversible hemodilution was apparent in laboratory findings and weight gain. Clinically significant headache was the dose-limiting adverse event; the maximum-tolerated dose was 60 mg/d. Pharmacokinetics were dose-proportional across the 10- to 75-mg dose range. Atrasentan was rapidly absorbed; the time to maximum observed concentration was approximately 1.5 hours. The terminal elimination half-life was approximately 24 hours, and steady-state plasma concentrations were achieved within 7 days. Decreases in prostate-specific antigen and pain relief were noted in a patient subset. CONCLUSION: Adverse events were consistent with atrasentan’s pharmacologic vasodilatory effect. Linear, dose-proportional pharmacokinetics suggest that atrasentan can be easily and consistently dosed.

5017 Background: Androgen receptor (AR) overexpression is a common adaptive resistance mechanism in mCRPC. High dose testosterone in this setting may induce tumor responses and restore normal AR expression. To evaluate BAT, we enrolled men with mCRPC progressing on enza to assess (1) responses to BAT and (2) enza re-challenge after BAT. Methods: Eligible men had minimally symptomatic mCRPC with progression on enza. Subjects received testosterone cypionate 400mg IM every 28d and continued gonadal suppression, until progression. Subjects were evaluated with PSAs each cycle, and CT/bone scans every 3 cycles. Upon progression on BAT, men were re-challenged with enza. The co-primary endpoints were > 50% PSA responses (PSA50) to BAT and PSA50 to enza re-challenge. The null hypothesis was a PSA50 rate of 5% for both endpoints, with alternative hypotheses of 20% to BAT and 25% to enza. 30 subjects were required for 90% and 83% power, respectively, with overall type 1 error of 0.1. Secondary endpoints were safety, objective response, progression-free survival (PFS), and effect on circulating tumor cell-based AR and AR-V7 expression. Results: 30 eligible subjects were accrued (2014-2016). No dose limiting toxicities were seen. 2 subjects had transient pain flares after BAT initiation. Common grade 1-2 adverse events (AE) were musculoskeletal pain (40%), increased hemoglobin (37%), breast tenderness (17%) and rash (17%). 3 Grade 3-4 AE potentially attributable to BAT occurred (pulmonary embolism, NSTEMI, and urinary obstruction). 9/30 men (30% [95% CI: 17-48%]) achieved a PSA50 to BAT. 5/14 men (36%) with measurable disease had an objective response by RECIST 1.1. The median clinical/radiographic PFS on BAT was 8.6 months. 21 subjects proceeded to enza re-challenge, yielding 15 PSA50 responses (54% by intention to treat [95% CI: 34-69%]), with a PFS of 4.8 months. 1/3 AR-V7+ subjects responded to BAT, and all had decreased AR-V7/AR ratios (2 converted to AR-V7-) after 3 cycles. Conclusions: The study met its primary endpoints, demonstrating preliminary efficacy of BAT in men with progressive mCRPC after enza. A randomized study comparing BAT to enza in mCRPC is ongoing. Clinical trial information: NCT02090114.

5020 Background: The importance of local treatment in oligometastatic prostate cancer (OPC) is unknown. Stereotactic ablative radiotherapy (SABR) is highly focused, high-dose radiation that is well suited for treatment of oligometastases. Here we report on the safety and preliminary clinical outcomes of SABR in a modern cohort of OPC men. Methods: Eighty four men who satisfied criteria of OPC diagnosed on imaging underwent consolidative SABR were then followed prospectively on our IRB approved registry by our GU multidisciplinary team. We collected demographic, clinical, toxicity and efficacy information. We examined the first 66 men in this preliminary report to allow for a minimum of 4.5 months follow-up. SABR was delivered in 1-5 fractions of 5-18 Gy. Kaplan-Meier method was used to assess local progression-free survival (LPFS), biochemical progression-free survival (bPFS; PSA nadir+2), distant progression free survival (DPFS), ADT-free survival (ADT-FS) and time-to-next intervention (TTNI). Results: Of the 66 OPC patients analyzed, 25 (38%) men presented as synchronous OPC and the remaining 41 had recurrent OPC. Median and mean follow-up was 61 and 66 weeks, respectively. Patient and disease factors as listed in the Table. Crude Grade 1 and 2 acute toxicities were 36% and 11%, respectively, with no Grade > 2 toxicity. SABR was delivered to 134 metastases: 89 bone (66%), 40 nodal (30%) and 5 (4%) visceral metastases. Overall LPFS at 1-year was 92%. The bPFS and DPFS at 1-year were 69% and 69%, respectively. Median TTNI was not reached yet. Of the 18 men with hormone sensitive prostate cancer who had their ADT deferred, 11/18 (56%) remain free of disease following SABR (1-year ADT-FS was 78%) and in 17 castration resistant men, 11 had > 50% PSA declines with 1-year TTNI of 30% with a median of 45 weeks. Conclusions: Consolidative SABRfor OPCis feasible and well tolerated. The preliminary clinical outcomes in our series is limited by heterogeneity and size but our data suggests that this approach is worthy of further prospective study. [Table: see text]

5035 Background: ARV7+ mCRPC is an aggressive phenotype with a median PFS of 3-4 mo and OS of 7-9 mo. We hypothesized that ARV7+ tumors would be enriched for DNA repair mutations, rendering them more responsive to combined immune checkpoint blockade. Methods: We enrolled 15 mCRPC pts with ARV7+ CTCs (using a CLIA-certified assay) into a single arm phase 2 study. Pts received Nivo 3 mg/kg plus Ipi 1 mg/kg every 3 wk x 4 doses, then maintenance Nivo 3 mg/kg every 2 wk. Targeted sequencing for DNA repair defects was performed on pretreatment tumor biopsies (n=11) or cell-free DNA (n=4). Primary endpoint: PSA50response rate. Secondary endpoints: objective response rate (ORR) in pts with measurable disease, durable PFS (lack of progression ≥24 wk), PSA‐PFS, radiographic (r)PFS, overall survival (OS), and frequency/intensity of AEs. Results: 15 ARV7+ men were enrolled, with median f/u 8.4 (range 1.9–10.5) mo. Median age was 65, 47% had ECOG ≥1, median PSA was 115 ng/mL, 67% had visceral/nodal mets, all had bone mets, and 60% had ≥4 prior regimens for mCRPC. Mean ARV7/AR ratio was 23% (range 3–75%). 6/15 men (40%) had pathogenic DNA repair gene mutations ( BRCA2, ATM, MSH6, FANCM, FANCA, POLH). Overall, the PSA50rate was 1/15 (7%), ORR was 2/8 (25%), durable PFS rate was 3/15 (20%), PSA-PFS was 3.0 (95%CI 2.1–4.9) mo, rPFS was 3.9 (95%CI 2.8–5.5) mo, and OS was 9.5 (95%CI 7.2–NA) mo. Outcomes appeared better in DNA repair deficient (DRD+) tumors vs. DNA repair proficient (DRD–) tumors (TABLE). 15 grade 3-4 treatment-related AEs occurred in 7/15 (46%) men (including 2 hepatitis, 2 colitis, 1 pneumonitis); there were no treatment-related deaths. Conclusions: In this first study targeting ARV7+ mCRPC, treatment with Ipi/Nivo had acceptable safety and encouraging efficacy, particularly in men with DRD+ tumors. DNA repair mutations may be enriched in ARV7+ prostate cancer. Clinical trial information: NCT02601014. [Table: see text]

5075 Background: We previously reported a relationship between PSADT and MFS in BRPC post RP (Pound 1999; Freedland 2007; Antonarakis 2012). In men with PSADT0.2ng/ml) with PSADT 1 PSA and scans at regular intervals until M+. Associations with MFS were compared using logrank test and Cox regression. The PP is the most recent value >6 months prior to M+/censor. Results: M+ occurred in 218 of 513 patients with BRPC (median follow up 9 years). Risk of M+ increased successively for PSADT 6.0-7.5, 4.5-6, 3.0-4.5, and 10ng/ml vs 20 years at PP 10ng/ml are independent predictors of MFS, adjusted for pT stage and Gleason score. PP ≥10ng/ml further define risk of M+ in BRPC with PSADT

134 Background: A better understanding of taxane sensitivity/resistance in mCRPC is needed to optimize treatment. Preclinically, taxane efficacy has been linked to the ability of microtubules (MT) to inhibit AR nuclear trafficking. In this prospective biomarker study, we used circulating tumor cells (CTCs) from patients (pts) in TAXYNERGY to perform real-time analysis of AR nuclear localization (ARNL) and MT stabilization (bundling; MTB) in order to predict taxane sensitivity. Methods: TAXYNERGY (NCT01718353) is a phase 2 trial randomizing chemo-naïve mCRPC pts 2:1 to docetaxel or cabazitaxel, with a switch to the alternative taxane in the absence of a ≥ 30% PSA drop by C4. Here we present the co-primary biomarker endpoints. CTCs at baseline (C1D1) were compared to CTCs after 1 week of taxane treatment (C1D8), and were analyzed by multiplex confocal microscopy for %ARNL (integrated AR intensity in the cell and nuclear areas) and MTB (assessed for increase compared to C1D1 on a scale from 0–3 from no to most MTB increase). Associations between %ARNL and MTB with clinical outcomes were sought. Results: Of 63 randomized pts, 26 had evaluable CTCs both at C1D1 and C1D8. At C1D8, mean %ARNL was significantly lower in pts achieving a ≥ 50% PSA drop by C4 vs those without (44% vs 64%; p = 0.004). A taxane-induced decrease in mean %ARNL (C1D8 vs C1D1) was associated with a higher rate of ≥ 50% PSA response (73% vs 13%; p = 0.009); mean %ARNL decreased by 18% in responders and increased by 2% in non-responders (p = 0.02). Finally, a taxane-induced increase in mean MTB trended higher in pts achieving a ≥ 30% PSA drop by C4 vs those without (0.69 vs 0.09; p = 0.09); increase in mean MTB score was indicative of response and observed in pts who did not require a taxane switch after C4 (0.75 vs 0.09; p = 0.06). Conclusions: We provide the first prospective data suggesting that taxane-induced shifts in ARNL and MTB (measured in CTCs) may serve as an early biomarker of taxane sensitivity. Consistent with preclinical data, AR nuclear exclusion caused by microtubule bundling may be a clinically-actionable marker of taxane efficacy. Funding: Sanofi Genzyme. Clinical trial information: NCT01718353.

248 Background: Pulverized muscadine grape ( Vitis rotundifolia) skin (MPX) is a potential therapeutic option for men with biochemically recurrent (BCR) prostate cancer (PCa) wishing to defer androgen deprivation therapy. MPX demonstrated antitumor effects in PCa through antioxidant activity of its principal polyphenol components, ellagic acid, quercetin, and resveratrol. A Phase I trial demonstrated safety of MPX in doses up to 4000 mg/day. Methods: This is a 12-month, multi-center, placebo-controlled, two-dose, double-blinded trial of MPX (manufactured by Muscadine Naturals Inc. in Warsaw, NC) in 125 men with BCR PCa. Participants were stratified by baseline PSADT and Gleason score, with no restrictions for PSADT and no upper limit PSA value. Patients were randomly assigned 2:2:1 to receive 4000 mg (8 capsules) of MPX, 500 mg (1 capsule) of MPX plus 7 capsules of placebo, or 8 capsules of placebo. PSA levels were obtained every 3 months The trial was powered to detect a statistically significant between-group difference of around 6 months (low dose) and 12 months (high dose) in PSADT relative to placebo. Results: The intention to treat (ITT) population included 116 patients, of which 97% were treated for up to 6 and 58% were treated for up to 12 months. This ITT population was 79% white, with median age 68 years, 47% with Gleason score ≤ 6 or 3+4, and 12% with ECOG status of 1. Median PSADT in the ITT population lengthened from 7.5 months at baseline (range 1.4 to 74.6) to 9.8 months after treatment (range 2.3 to 151.5) (p < 0.001). There was no significant treatment difference in PSADT between the control and the treatment groups (p = 0.84). Eighteen percent (21/116) of men had a post-baseline PSADT of more than 200% of baseline. No clinically significant toxicities were seen. Conclusions: These data suggest that both 500 and 4000 mg of MPX are safe. The lengthening PSADT in patients treated with MPX is not significantly greater than that provided by placebo. A subgroup analysis of patients more likely to benefit (those with the AA genotype of MnSOD) is ongoing. Clinical trial information: NCT01317199.

181 Background: To evaluate whether metformin (Met) a widely-used, nontoxic oral antidiabetic drug with putative anticancer properties leads to improvements in prostate cancer (PC) outcomes in the CHAARTED trial. Methods: In the CHAARTED database where metformin use at baseline was recorded prospectively, we identified patients with metastatic PC who underwent either ADT alone or ADT and docetaxel (D) chemotherapy. Cox proportional hazards models were used to determine the effect of Metformin on outcomes. Results: A total of 788 patients (median age, 63 y) had complete data after randomization. Comparison of ADT+D+Met (n = 39) to ADT+D (n = 357) and ADT+Met (n = 29) to ADT alone (n = 363) revealed similar clinicopathologic characteristics. Cause of death was PC in 13(81%) of ADT+D+Met, 72(85%) ADT+D, 9(82%) ADT+Met and 105(84%) ADT alone groups. See table for PC outcomes and overall survival by metformin use. Cox regression analysis for overall survival stratified by stratification factors at randomization demonstrates Met use was associated with a trend for worse overall survival (HR 1.47 95%CI: [0.95,2.26], p = 0.08) with adjustment for treatment arm and prior local therapy. In contrast, ADT+D use (HR 0.62; 95%CI: [0.47,0.81]) and prior local therapy with surgery or radiation (HR 0.56; 95% CI: [0.38, 0.82]) were associated with improved survival. Conclusions: In this study, baseline metformin did not improve PC outcomes. Partial support and drug supply by Sanofi. Clinical trial information: NCT00309985. [Table: see text]

137 Background: Prior work from SWOG 9346 revealed that PSA ≤ 0.2 ng/dL at 7 months (mo) is prognostic for longer OS with ADT alone. We sought to evaluate if this optimal decline remained predictive of better OS when D was added to ADT for initial mHSPC treatment. Methods: We performed a landmark survival analysis at 7 mo using the E3805 database (NCT00309985). Inclusion required at least 7 mo of followup and PSA levels at 7 mo from ADT initiation. Survival was defined from ADT start or randomization to death. SWOG 9346 PSA nadirs of ≤ 0.2, > 0.2-4 and > 4 were used as classifiers. Results: 719 patients were eligible for analysis: 358 treated with ADT plus D and 361 with ADT alone. Median follow-up was 23.1 mo. On multivariable analysis (MVA), achieving a PSA ≤ 0.2 at 7 mo was more likely if the patient received D and had lower volume disease, prior local therapy, and lower baseline PSAs (all p ≤ 0.01). Across all patients, median OS was significantly longer if PSA at 7 mo reached ≤ 0.2 compared to > 4 (p < 0.0001) (Table). On MVA, PSA ≤ 0.2 at 7 mo and low volume disease were prognostic of longer OS (all p < 0.01). On ADT, 28.8% achieved a PSA ≤ 0.2 at 7 mo vs. 45.3% on ADT+D. Patients on ADT alone who achieved a PSA nadir ≤ 0.2 had the best survival. These patients were more likely to have low volume disease (56.7%) compared to the ADT + D pts (46.3%). Conclusions: Achieving PSA ≤ 0.2 at 7 mo remains prognostic for longer OS with ADT for mHSPC, whether administered alone or with D. Adding D to ADT increased the likelihood of a lower PSA and improved survival. Partial support and drug supply by Sanofi. Clinical trial information: NCT00309985. [Table: see text]

136 Background: Patients with a low burden of metastatic disease and who relapse after localized therapy with curative intent have a longer overall survival. It is unclear whether these patients benefit from early docetaxel (D). Methods: Patients in GETUG-AFU15 (N = 385, median follow-up 84 mo) and CHAARTED (N = 790, median follow up 54 mo) were randomized to ADT alone or ADT + D and outcomes described using the same definition of high volume (HV) and low volume (LV) disease. (HV: visceral metastases and/or 4 or more bone metastases with at least one outside the axis) and whether the patients had prior local therapy or not. Results: Table 1 details across both studies that de novo HV group treated with ADT alone has the shortest overall survival and D has a consistent effect in improving OS. In contrast, in both studies patients with LV disease had a much longer OS with no evidence that D improved OS. Conclusions: There was no apparent survival benefit in CHAARTED and GETUG-15 studies with D for LV whether patients had prior local treatment or not. Across both studies, early D had a consistent effect and improved OS in HV pts especially those with no prior local therapy. Partial Support and drug supply by Sanofi. Clinical trial information: NCT00104715, NCT00309985. [Table: see text]

MDV3100 in Patients with Progressive Castration-resistant Prostate Cancer Previously Treated with Docetaxel-based Chemotherapy trial [AFFIRM]) that resulted in the US Food and Drug Administration (FDA) approval of these two compounds for metastatic castration-resistant prostate cancer (mCRPC) were conducted in patients who demonstrated evidence of disease progression after docetaxel-based chemotherapy. Based on COU-AA-302, abiraterone has received FDA approval for chemotherapy-naive patients, and it is likely that the same will happen with enzalutamide based on the PREVAIL data. The assumption that chemotherapy will be offered primarily to patients with evidence of disease progression after androgen-receptor (AR)-targeted compounds appears to be quite logical based on the four pivotal trials conducted with the two compounds. However, the recently released results of the Eastern Cooperative Oncology Group 3805 trial (a randomized study of androgen-deprivation treatment [ADT] with or without docetaxel [the CHAARTED trial]) highlight the fact that the optimal sequence of systemic treatments in men with metastatic prostate cancer needs to be more carefully evaluated. In the CHAARTED trial, men with hormone-naive metastatic disease were treated either with ADT or ADT plus six cycles of standard dose docetaxel [3]. Patients with highvolume disease, manifested by at least four bone lesions or any extranodal visceral metastases, demonstrated 3-yr overall survival of 63.4% in the docetaxel and ADT group versus 43.9% for ADT alone. Although full publication of the results from this trial will be more informative, the preliminary data released indicate that the practice of

To determine whether the pretreatment neutrophil-to-lymphocyte ratio (NLR), a measure of systemic inflammatory response, is associated with overall survival (OS) in men receiving chemotherapy with docetaxel for metastatic castration-resistant prostate cancer (mCRPC).Records from 238 consecutive patients who were treated with first-line docetaxel-containing chemotherapy for mCRPC at a single high-volume centre from 1998 to 2010 (and who had adequate information to enable calculation of NLR) were reviewed. Univariable and multivariable Cox regression models were used to predict OS after chemotherapy initiation.In univariable analyses, the NLR as a discrete variable (optimal threshold 3.0) was significantly associated with OS (P = 0.001). In multivariable analyses, a lower NLR (≤3.0) was associated with lower risk of all-cause mortality (P = 0.002). In Kaplan-Meier analysis, the median OS was higher (18.3 vs 14.4 months) in patients that did not have an elevated NLR than in those with an elevated NLR (log-rank; P0.001).Men who were treated with first-line docetaxel for mCRPC who had a low pretreatment NLR (≤3.0) had significantly longer OS. NLR may be a potentially useful clinical marker of systemic inflammatory response in predicting OS in men with mCRPC who receive docetaxel and may be helpful to stratify patients for clinical trials. These findings derived from a retrospective analysis need to be validated in larger populations in prospective studies, and in the context of different therapies.

Prostate cancer is a disease of older men. Weekly docetaxel (DPq1w) is often favored over the standard three-weekly regimen (DPq3w) due to concerns about safety and tolerability in this population.Two subgroup analyses of TAX 327 were conducted. Among patients receiving DPq3w, tolerability and efficacy were compared between three age groups:65, 65-74 and ≥75 years. For men ≥75 years, these outcomes were compared between DPq3w, DPq1w, and mitoxantrone (MP) arms. Tolerability outcomes included dose delivery, grade 3/4 adverse events and quality of life. Efficacy outcomes included overall survival and tumor response.Of 1006 men with metastatic castrate-resistant prostate cancer (mCRPC) in the trial, 335 received DPq3w. Among these, 20% were age ≥75 years. For DPq3w, there were non-significant associations of worse tolerability and efficacy with advancing age. Twenty-eight percent of men age ≥75 years had an objective pain response, compared to 38% and 34% of patients 65-74 and65 years, respectively. There were no significant differences in prostate-specific antigen (PSA) response (43-48%, p = 0.74) or measurable tumor response (7-17%, p = 0.30) according to age. Among men ≥75 years, DPq3w resulted in more dose reductions than DPq1w (22% versus 8%, p = 0.007), but tolerability was otherwise comparable. Both were associated with more favorable efficacy than mitoxantrone.Tolerability and efficacy of DPq3w appear less favorable with advancing age. Compared to DPq1w, DPq3w is associated with better survival outcomes, but similar tolerability, and remains the standard first-line chemotherapy option in mCRPC. Toxicity is substantial, therefore careful patient selection, close monitoring and early management of toxicities is advised.

There has been a rather impressive growth in the systemic therapeutic options for prostate cancer in a relatively short period of time. In addition, knowledge in the basic biology of prostate cancer growth appears to have reached a significant threshold where translational approaches are more likely to result in significant clinically meaningful advances. This book describes the recent developments in castration resistant disease in laboratory and clinical research. New potential treatments and the rationale behind their selection for testing as well methodological challenges involved are described and discussed.

Purpose: We present a structured debate supporting the premise that immediate hormonal intervention has not been conclusively shown to provide a survival advantage in the management of advanced prostate cancer.Materials and Methods: The literature emphasizing randomized trials was reviewed. Recommendations are based solely on a demonstrated advantage in survival.Results: In patients with stage Tx Nx Mo or MI disease who did not receive other primary therapy there is no demonstrated survival advantage to immediate hormonal therapy. In men with positive lymph nodes who underwent radical prostatectomy a relatively small study showed a survival advantage in favor of immediate hormonal treatment compared to deferred treatment. This study did not reach the projected accrual of 240 patients and results have not been supported by other trials. In men with stages T2-4 Nx Mx disease who underwent primary treatment with radiotherapy a survival advantage for early hormonal therapy is primarily limited to high risk su...

Twenty-two eligible patients with advanced renal carcinoma were treated with suramin utilizing a fixed dose regimen. Therapy was reasonably well tolerated with 3 of 22 patients (14%) developing grade 4 toxicity and 11 of 22 patients (50%) having a maximum toxicity of grade 3. There were no responders; median survival was 10 months. Suramin is not an active agent in advanced renal carcinoma.

PURPOSE: Validated end points are lacking for clinical trials in hormone-refractory prostate cancer (HRPC). Controversy remains regarding the utility of a posttreatment decline of prostate-specific antigen (PSA). The purpose of this study was to determine whether posttreatment declines in PSA were associated with clinical measures of improvement in a randomized phase III trial of suramin plus hydrocortisone versus placebo plus hydrocortisone. PATIENTS AND METHODS: A total of 460 HRPC patients were randomized to receive suramin plus hydrocortisone (n = 229) or placebo plus hydrocortisone (n = 231). All patients had symptomatic, metastatic HRPC requiring opioid analgesics. Clinical end points evaluated included overall survival, objective progression-free survival (OPFS), and time to pain progression (TTPP). An evaluation of overall survival, OPFS, and TTPP as a function of a PSA decline of ≥ 50%, lasting at least 28 days, was undertaken by using a landmark analysis at 6, 9, and 12 weeks. A multivariate analysis of the impact of PSA decline was performed on these clinical end points. RESULTS: A decline in PSA of ≥ 50% lasting ≥ 28 days was significantly associated with a prolonged median overall survival, OPFS, and TTPP, both in the entire group and the suramin plus hydrocortisone group at all three landmarks in both univariate and multivariate analysis. CONCLUSION: In this prospective, randomized trial of suramin plus hydrocortisone versus placebo plus hydrocortisone, a posttherapy decline in PSA of ≥ 50%, lasting 28 days, was associated with prolonged median overall survival, improved median progression-free survival, and median TTPP. This analysis suggests that a posttreatment decline in PSA may be a reasonable intermediate end point in HRPC trials and calls into question the clinical utility of preclinical assays evaluating the in vitro effect of given agents on PSA secretion.

Background: African-American men have earlier onset of prostate cancer, higher prostate-specific antigen (PSA) levels, more advanced stage at diagnosis, and higher mortality than white men. It is not known whether the poorer survival of African-American men with prostate cancer reflects their later stage at diagnosis or differences in the basic biology of their disease. To evaluate this question, we examined outcomes of African-American and white men with metastatic prostate cancer in the context of a randomized clinical trial. Methods: Southwest Oncology Group Study 8894 was a randomized phase III trial that compared orchiectomy with or without flutamide in men with metastatic prostate cancer. Using data from 288 African-American and 975 white men in the trial, we conducted a proportional hazards regression analysis to determine if ethnicity was an independent predictor of survival. All statistical tests were two-sided. Results: African-American men were more likely than white men to have extensive disease and bone pain and had poorer performance status, younger age at study entry, higher Gleason score, and higher PSA levels. After adjustment for these prognostic variables, the hazard ratio (HR) for all-cause mortality for African-American men relative to white men was 1.23 (P = .018). Further adjustment for initial quality-of-life assessments also resulted in higher HRs associated with African-American ethnicity relative to white ethnicity (HR = 1.39; P = .007). Conclusions: African-American men with metastatic prostate cancer have a statistically significantly worse prognosis than white men that cannot be explained by the prognostic variables explored in this study. These data should give increased impetus for efforts to detect the disease early in African-American men and for the development of more effective therapies based on potential biologic differences in this ethnic group.

BACKGROUND The combination of oral estramustine and oral etoposide has generated response rates of 40–50% in patients with hormone refractory prostate cancer in single institution trials. This study tested this regimen in a multi-institutional setting. METHODS Fifty-five patients were accrued over a period of 4 months between 1 March 1996 and 1 July 1996. Two patients were not analyzable and two patients were ineligible. They were given an oral regimen consisting of estramustine 15 mg/kg/day (capped at 1120 mg per day) and etoposide 50 mg/M2/day, days 1–21 every 28 days. Patients received a median of two cycles of therapy. RESULTS Toxicities included 11 patients (20%) with grades 3 or 4 granulocytopenia, 5 patients (10%) with grades 3 or 4 edema, and 3 patients (6%) with a thrombotic event. There were two treatment-related deaths, one as a result of anemia and the other as a result of a myocardial infarction. Of the 32 men who received at least 2 cycles of therapy, 7 men (22%) demonstrated a partial response to this regimen as measured by prostate-specific antigen (PSA) criteria of a 50% decline from pretreatment values. CONCLUSIONS This trial demonstrates the toxicity of estramustine delivered in high dose. It also illustrates the difficulty of conducting phase II trials in prostate cancer in the cooperative group setting where the experience and comfort level of oncologists with new agents is less than that of the physicians at the institution where the therapy was developed. As the activity of this regimen with low-dose estramustine is defined, further multi-institutional studies may be warranted. Prostate 46:257–261, 2001. © 2001 Wiley-Liss, Inc.

Obesity, smoking, hypertension, and diabetes are risk factors for renal cell carcinoma development. Their presence has been associated with a worse outcome in various cancers. We sought to determine their association with outcome of sunitinib treatment in metastatic renal cell carcinoma (mRCC).An international multicenter retrospective study of sunitinib-treated mRCC patients was performed. Multivariate analyses were performed to determine the association between outcome and the pretreatment status of smoking, body mass index, hypertension, diabetes, and other known prognostic factors.Between 2004 and 2013, 278 mRCC patients were treated with sunitinib: 59 were active smokers, 67 were obese, 73 were diabetic, and 165 had pretreatment hypertension. Median progression-free survival (PFS) was 9 months, and overall survival (OS) was 22 months. Factors associated with PFS were smoking status (past and active smokers: hazard ratio [HR]: 1.17, p = .39; never smokers: HR: 2.94, p.0001), non-clear cell histology (HR: 1.62, p = .011), pretreatment neutrophil-to-lymphocyte ratio3 (HR: 3.51, p.0001), use of angiotensin system inhibitors (HR: 0.63, p = .01), sunitinib dose reduction or treatment interruption (HR: 0.72, p = .045), and Heng risk (good and intermediate risk: HR: 1.07, p = .77; poor risk: HR: 1.87, p = .046). Factors associated with OS were smoking status (past and active smokers: HR: 1.25, p = .29; never smokers: HR: 2.7, p.0001), pretreatment neutrophil-to-lymphocyte ratio3 (HR: 2.95, p.0001), and sunitinib-induced hypertension (HR: 0.57, p = .002).Active smoking may negatively affect the PFS and OS of sunitinib-treated mRCC. Clinicians should consider advising patients to quit smoking at initiation of sunitinib treatment for mRCC.

Purpose: We summarized and critically assessed all available data from phase III clinical trials on complete androgen blockade versus surgical or medical castration alone.Materials and Methods: Published results in journals and abstracts of phase III trials, and published meta-analyses were reviewed. We also reviewed quality of life and toxicity issues associated with the addition of antiandrogens to medical or surgical castration. Finally, we discuss the original rationale for complete androgen blockade in the context of current knowledge.Results: A total of 27 clinical trials using various combinations of androgen deprivation were identified, of which 3 showed a statistically significant benefit for the complete androgen blockade arm. There were 5 publications of meta-analyses that each used different selection criteria for the inclusion of studies in the final analysis. Toxicity and quality of life have not been widely investigated in prospective fashion but the available data suggest a higher toxicity...

BACKGROUND Analysis of prostate carcinoma cells isolated from the peripheral blood suggested a classification based on three categories. METHODS Centrifugation density gradients and magnetic cell sorting were used to isolate circulating prostate carcinoma cells from peripheral blood. Immunocytochemistry staining and fluorescent in situ hybridization allowed characterization of isolated cancer cells. RESULTS Terminal cells can be divided into 3 classes: 1) large, buoyant, fragile cells with a large nucleus that were captured in a 1.068 g/mL gradient; 2) enucleate cells (4,6-diamidino-2-phenylindole [DAPI] negative) that were positive for cytokeratin and PSMA antibodies; and 3) cellular debris exhibiting cytokeratin and PSMA positive staining as well as nuclear debris identified by DAPI staining, which included cytoplasmic debris. Growing cells also exhibited three morphologic characteristics: those possessing stem cell–like morphology and characteristics such as small size, high density, developed cytokeratin systems, PSMA expression, and aneuploidy; those in M phase; and cell clusters. The majority of isolated cells exhibited intermediate characteristics and thus comprised the third group of circulating cancer cells. CONCLUSIONS Although the significance of the cluster remains undetermined, observation suggests that the cluster has the ability to circulate as a microtumor and subsequently arrest in the small veins and capillaries. It is hypothesized that the clusters could escape certain facets of immune surveillance and possibly gain a selective growth advantage over single cells in a distant site. Further hypothesis proposes that arrested cells recruit growth-promoting nutrients, which would result in the invasion of local blood vessels and vascularization. Cancer 2000;88:2787–95. © 2000 American Cancer Society.

During the past 12 years, routine use of serum prostate-specific antigen (PSA) has resulted in a major rise in the proportion of patients initially diagnosed with clinically localized disease and the average age at diagnosis has declined. 1,2 These important demographic changes, coupled with major improvements in surgical technique, resulted in a sharp increase in the number of advocates for radical prostatectomy (RP) as definitive treatment for prostate cancer. 3,4 After curative RP, the serum PSA level should become undetectable, and the detection of elevated levels at any time after about 4 weeks postoperatively reflects evidence of disease recurrence. 5 The incidence of disease recurrence while PSA is undetectable is extremely low, although it might be observed in very poorly differentiated tumors or neoplasms of distinct histologic subtypes. 6,7 The first evidence of disease recurrence after RP is manifested by a consistent elevation of serial serum PSA tests, usually without any associated objective findings. 5 The probability of biochemical relapse at 5 and 10 years, reported in several large series, has ranged between 20% and 31% and 27% and 53%, respectively. 7‐10 Various factors, including differences in patient populations, duration of followup, and the definition of PSA recurrence (0.2 to 0.6 ng/mL), might account for the variance in the reported rates. On the basis of the number of RPs performed and the cumulative figures of biochemical relapse rates, it can be estimated that thousands of patients present annually to clinicians throughout the world with an elevated PSA level as the only evidence of disease. At present, the natural history of the patient with biochemical relapse after RP remains poorly defined, and no criteria are uniformly accepted for implementation of treatment for these patients. The management philosophy has been influenced primarily by physicians’ and patients’ biases, and it is becoming obvious that despite the lack of consensus, early interventions are more commonly applied than observation only. Our objective was to review the published reports dealing with the evaluation, natural history, and treatment of patients with a rising PSA after RP for clinically localized prostate cancer and to provide the necessary groundwork for the development of clinical research on this challenging problem.

In this issue, Schroder et al report the results of European Organization for Research and Treatment of Cancer (EORTC) study 30846, which was designed to compare early endocrine treatment (EET) given at initial diagnosis with delayed endocrine treatment (DET) given at clinical progression in patients with newly diagnosed clinical T2-T3 pN1-3 M0 prostate cancer [1]. Endocrine treatment (ET) in both arms of the study consisted of monthly subcutaneous administration of goserelin acetate, and cyproterone acetate was given orally for the first 4 wk of treatment. Two hundred thirty-four patients were randomized between February 1986 and November 1998. The authors found that the results were inconclusive. I have a number of comments related to study design, interpretation of data, clinical considerations, and future perspectives.

PURPOSE: Prostate-specific antigen (PSA) is a glycoprotein that is found almost exclusively in normal and neoplastic prostate cells. For patients with metastatic disease, changes in PSA will often antedate changes in bone scan. Furthermore, many but not all investigators have observed an association between a decline in PSA levels of 50% or greater and survival. Since the majority of phase II clinical trials for patients with androgen-independent prostate cancer (AIPC) have used PSA as a marker, we believed it was important for investigators to agree on definitions and values for a minimum set of parameters for eligibility and PSA declines and to develop a common approach to outcome analysis and reporting. We held a consensus conference with 26 leading investigators in the field of AIPC to define these parameters. RESULT: We defined four patient groups: (1) progressive measurable disease, (2) progressive bone metastasis, (3) stable metastases and a rising PSA, and (4) rising PSA and no other evidence of metastatic disease. The purpose of determining the number of patients whose PSA level drops in a phase II trial of AIPC is to guide the selection of agents for further testing and phase III trials. We propose that investigators report at a minimum a PSA decline of at least 50% and this must be confirmed by a second PSA value 4 or more weeks later. Patients may not demonstrate clinical or radiographic evidence of disease progression during this time period. Some investigators may want to report additional measures of PSA changes (ie, 75% decline, 90% decline). Response duration and the time to PSA progression may also be important clinical end point. CONCLUSION: Through this consensus conference, we believe we have developed practical guidelines for using PSA as a measurement of outcome. Furthermore, the use of common standards is important as we determine which agents should progress to randomized trials which will use survival as an end point.

Background The androgen-receptor isoform encoded by splice variant 7 lacks the ligand-binding domain, which is the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of androgen-receptor splice variant 7 messenger RNA (AR-V7) in circulating tumor cells from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone. Methods We used a quantitative reverse-transcriptase–polymerase-chain-reaction assay to evaluate AR-V7 in circulating tumor cells from prospectively enrolled patients with metastatic castration-resistant prostate cancer who were initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status (positive vs. negative) and prostate-specific antigen (PSA) response rates (the primary end point), freedom from PSA progression (PSA progression–free survival), clinical or radiographic progression–free survival, and overall survival. Resul...

Combined androgen blockade for the treatment of metastatic prostate cancer consists of an antiandrogen drug plus castration. In a previous trial, we found that adding the antiandrogen flutamide to leuprolide acetate (a synthetic gonadotropin-releasing hormone that results in medical ablation of testicular function) significantly improved survival as compared with that achieved with placebo plus leuprolide acetate. In the current trial, we compared flutamide plus bilateral orchiectomy with placebo plus orchiectomy.We randomly assigned patients who had never received antiandrogen therapy and who had distant metastases from adenocarcinoma of the prostate to treatment with bilateral orchiectomy and either flutamide or placebo. Patients were stratified according to the extent of disease and according to performance status.Of the 1387 patients who were enrolled in the trial, 700 were randomly assigned to the flutamide group and 687 to the placebo group. Overall, the incidence of toxic effects was minimal; the only notable differences between the groups were the greater rates of diarrhea and anemia with flutamide. There was no significant difference between the two groups in overall survival (P=0.14). The estimated risk of death (hazard ratio) for flutamide as compared with placebo was 0.91 (90 percent confidence interval, 0.81 to 1.01). Flutamide was not associated with enhanced benefit in patients with minimal disease.The addition of flutamide to bilateral orchiectomy does not result in a clinically meaningful improvement in survival among patients with metastatic prostate cancer.

The kinetics of an antineoplastic drug, suramin, described by a three-compartment, open, linear model is studied in this report. A population pharmacokinetic model, describing the pharmacokinetics of suramin, was developed using the iterative-two stage approach, with maximum a posteriori-Bayesian priors. It was further validated using data from a subsequent study (validation data set). The population pharmacokinetic parameters were also estimated by generating bootstrap samples from the validation data set. When the prior distribution was close to the population distribution, there was no significant difference between the estimates obtained using the iterative-two stage approach and the bootstrap approach. However, when estimating population pharmacokinetic parameters, the iterative-two stage approach was less sensitive to prior distribution specification

Taxanes may partly mediate their effect in castration-resistant prostate cancer (CRPC) through disruption of androgen-receptor trafficking along microtubules. This raises the possibility of cross-resistance between androgen-directed agents and docetaxel.To evaluate docetaxel efficacy after abiraterone treatment in CRPC patients.This was a single-institution, retrospective analysis in CRPC patients (N=119) who either received abiraterone before docetaxel (AD) (n=24) or did not receive abiraterone before docetaxel (docetaxel-only; n=95). Men initiated docetaxel between December 2007 (the date abiraterone was first used at our center) and May 2013.The primary efficacy end points were prostate-specific antigen progression-free survival (PSA-PFS) and clinical/radiographic progression-free survival (PFS) on docetaxel. Differences between groups were assessed using univariate and multivariable analyses.Men in the AD group had a significantly higher risk for progression than those in the docetaxel-only group. Median PSA-PFS was 4.1 mo in the AD group and 6.7 mo in the docetaxel-only group (p=0.002). Median PFS was also shorter in the AD group (4.4 mo vs 7.6 mo; p=0.003). In multivariable analysis, prior abiraterone treatment remained an independent predictor of shorter PSA-PFS (hazard ratio [HR]: 3.48; 95% confidence interval [CI], 1.36-8.94; p=0.01) and PFS (HR: 3.62; 95% CI, 1.41-9.27; p=0.008). PSA declines ≥50% were less frequent in the AD group (38% vs 63%; p=0.02). The small size and retrospective nature of this study may have introduced bias.Men receiving abiraterone before docetaxel were more likely to progress on docetaxel and less likely to achieve a PSA response than abiraterone-naïve patients. Cross-resistance between abiraterone and docetaxel may explain these findings; however, larger, more definitive studies are still needed to confirm this.We examined the efficacy of docetaxel in castration-resistant prostate cancer patients who either did or did not receive prior abiraterone. We found that men receiving abiraterone before docetaxel were less likely to achieve a PSA response and were more likely to progress sooner on docetaxel than abiraterone-untreated patients. This may be due to cross-resistance.

In the current issue of European Urology, Mulder and colleagues report the results of a post hoc subgroup analysis of the COU-AA-301 (postdocetaxel) study focusing on the efficacy and safety of abiraterone in elderly patients (>75 yr of age) [1]. Although overall survival by subgroups was already presented in the final survival analysis of the study [2], these additional data confirm the relative efficacy and safety of abiraterone/prednisone exposure versus placebo/ prednisone in elderly patients. In this trial, 28% of the overall study population was 75 yr or older, allowing analysis of the interaction between age and abiraterone therapy. Treatment with abiraterone acetate yielded improved survival across the two age cohorts. The elderly (>75 yr) subgroup demonstrated hazard ratios (HRs) for death (HR: 0.64; 95% confidence interval [CI], 0.48–0.85) at least equivalent to younger patients (HR: 0.78; 95% CI, 0.65– 0.93). This finding is perhaps unsurprising because multiple trials in this setting have demonstrated similar survival benefits for several active agents in older men with metastatic castration-resistant prostate cancer (mCRPC). For example, post hoc analysis of the AFFIRM trial of enzalutamide demonstrated similar benefit in both older and younger subgroups [3]. Subgroup analysis of the TAX327 study of every 3 wk docetaxel demonstrated similar HRs for overall survival in elderly men using age cutoffs of 69 and 75 yr (HRs: 0.77 and 0.80, respectively, vs 0.81 for younger patients) [4]. A large retrospective study evaluating docetaxel therapy in the elderly in a real-world setting found that elderly patients with a good Eastern Cooperative Oncology Group performance status (PS) responded similarly to younger patients, although unsurprisingly those with a poor PS tolerated docetaxel quite poorly [5]. Because most patients in the COU-AA-301 study had a favorable PS, the relative benefit of this compound in a group of men with advanced age, significant comorbidities, and limited performance status cannot be determined. The extensive experience in mCRPC with various compounds (cytotoxic, radiopharmaceutical, and endocrine drugs) supports that age alone does not reduce the chances of benefit from systemic treatment. Previous concerns have been raised regarding the potential for increased toxicity in the elderly with the potential for polypharmacy/drug interactions and cardiac toxicity given abiraterone’s potential for causing mineralocorticoid excess. The data presented here are largely reassuring on that front, although there was a slightly increased incidence of atrial fibrillation and tachycardia in the elderly treated group, a difference not seen in the younger treated group. Treatment-emergent cardiac events leading to death were seen in only 2% of the elderly treated group versus 1% in the placebo group and 1% in the younger group. Additional follow-up of the COU-AA-302 study will further define the safety of abiraterone as the duration of drug exposure lengthens. An important consideration is that the population of elderly patients presented in this report is highly selected given that they maintained a PS 2, recovered from docetaxel without major functional and medical impairment, and were selected to exclude preexisting cardiac ailments. Extrapolation of the safety of abiraterone to a realworld elderly population should thus be performed with caution. Nevertheless, this study does provide additional evidence that age should not be the major consideration in the choice of therapy and that in elderly men (who were not previously treated with abiraterone, enzalutamide, or

Background: Since 2004, docetaxel has been the standard first-line systemic therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). With abiraterone recently becoming available in the predocetaxel setting, it is warranted to identify subgroups of patients who may obtain the greatest benefit from docetaxel and particularly qualify for receiving docetaxel as first-line treatment for mCRPC. Objective: We aimed to identify factors that could characterize subgroups of patients who obtain the greatest benefit from the use of docetaxel. Design, setting, and participants: TAX327 was multinational, randomized, phase 3 study that was conducted from 2000 to 2002 in 1006 men with mCRPC. Intervention: Patients were randomized to receive docetaxel every 3 wk (D3), weekly docetaxel (D1), or mitoxantrone every 3 wk (M3), each with prednisone. Outcome measurements and statistical analysis: We investigated whether patients with poorly differentiated tumors (Gleason score >= 7) at diagnosis had greater benefit from D3 compared with M3 than patients with better differentiated tumors (Gleason score = 7). In a time of shifting paradigms in mCRPC, with abiraterone becoming available prior to docetaxel chemotherapy, Gleason score may help in selecting patients who obtain the greatest benefit from docetaxel as first-line treatment for mCRPC. Prospective validation of these findings is warranted. (C) 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Squamous cell carcinoma of the penis represents approximately 0.5% of all cancers among men in the United States and other developed countries. Although rare, it is associated with significant disfigurement, and only half of the patients survive beyond 5 years. Proper evaluation of both the primary lesion and lymph nodes is critical, because nodal involvement is the most important factor of survival. The NCCN Clinical Practice Guidelines in Oncology for Penile Cancer provide recommendations on the diagnosis and management of this devastating disease based on evidence and expert consensus.

The therapeutic landscape for the treatment of advanced prostate cancer is rapidly evolving, especially for those patients with metastatic castration-resistant prostate cancer (CPRC). Despite advances in therapy options, the diagnostic landscape has remained relatively static, with few guidelines or reviews addressing the optimal timing or methodology for the radiographic detection of metastatic disease. Given recent reports indicating a substantial proportion of patients with CRPC thought to be nonmetastatic (M0) are in fact metastatic (M1), there is now a clear opportunity and need for improvement in detection practices. Herein, we discuss the current status of predicting the presence of metastatic disease, with a particular emphasis on the detection of the M0 to M1 transition. In addition, we review current data on newer imaging technologies that are changing the way metastases are detected. Whether earlier detection of metastatic disease will ultimately improve patient outcomes is unknown, but given that the therapeutic options for those with metastatic and nonmetastatic CPRC vary, there are considerable implications of how and when metastases are detected.

The current trial evaluated 2 common therapies for patients with advanced prostate cancer, docetaxel and hormonal therapy (HT), in the surgical adjuvant setting.TAX-3501 was a randomized, phase 3, adjuvant study post-radical prostatectomy (RP) in high-risk patients with prostate cancer (n=228) comparing 18 months of HT with (CHT) without docetaxel chemotherapy either immediately (I) or deferred (D). High-risk disease was defined as a 5-year freedom-from-disease-progression rate of ≤ 60% as predicted by a post-RP nomogram. Progression-free survival (PFS), including prostate-specific antigen disease recurrence, was the primary endpoint. The authors also assessed the accuracy of the nomogram and analyzed testosterone recovery in 108 patients treated with HT who had at least 1 posttreatment testosterone value.Between December 2005 and September 2007, 228 patients were randomized between the treatment cohorts. TAX-3501 was terminated prematurely because of enrollment challenges, leaving it underpowered to detect differences in PFS. After a median follow-up of 3.4 years (interquartile range, 2.3-3.8 years), 39 of 228 patients (17%) demonstrated PSA disease progression, and metastatic disease progression occurred in 1 patient. The median time to baseline testosterone recovery after the completion of treatment was prolonged at 487 days (95% confidence interval, 457-546 days). The nomogram's predicted versus observed freedom from disease progression was significantly different for the combination D(HT) and D(CHT) group (P.00001).TAX-3501 illustrated several difficulties involved in conducting postoperative adjuvant systemic trials in men with high-risk prostate cancer: the lack of consensus regarding patient selection and treatment, the need for long follow-up time, nonvalidated intermediate endpoints, evolving standard approaches, and the need for long-term research support. Except for selected patients at very high-risk of disease recurrence and death, surgical adjuvant trials in patients with prostate cancer may not be feasible.