Luke T. Nordquist

Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer

PURPOSE To compare the efficacy and safety of docetaxel plus high-dose calcitriol (DN-101) to docetaxel plus prednisone in an open-label phase III trial. PATIENTS AND METHODS Nine hundred fifty-three men with metastatic castration-resistant prostate cancer (CRPC) were randomly assigned to Androgen-Independent Prostate Cancer Study of Calcitriol Enhancing Taxotere (ASCENT; 45 μg DN-101, 36 mg/m(2) docetaxel, and 24 mg dexamethasone weekly for 3 of every 4 weeks) or control (5 mg prednisone twice daily with 75 mg/m(2) docetaxel and 24 mg dexamethasone every 3 weeks) arms. The primary end point was overall survival (OS), assessed by the Kaplan-Meier method. RESULTS At an interim analysis, more deaths were noted in the ASCENT arm, and the trial was halted. The median-follow-up for patients alive at last assessment was 11.7 months. Median OS was 17.8 months (95% CI, 16.0 to 19.5) in the ASCENT arm and 20.2 months (95% CI, 18.8 to 23.0) in the control arm (log-rank P = .002). Survival remained inferior after adjusting for baseline variables (hazard ratio, 1.33; P = .019). The two arms were similar in rates of total and serious adverse events. The most frequent adverse events were GI (reported in 75% of patients), and blood and lymphatic disorders (48%). Docetaxel toxicity leading to dose modification was more frequent in the ASCENT (31%) than in the control arm (15%). CONCLUSION ASCENT treatment was associated with shorter survival than the control. This difference might be due to either weekly docetaxel dosing, which, in a prior study, showed a trend toward inferior survival compared with an every-3-weeks regimen, or DN-101 therapy.

DNA Vaccines: An Active Immunization Strategy for Prostate Cancer

Immunotherapy is currently being investigated as a treatment for patients with asymptomatic, recurrent prostate cancer manifested only by a rising prostate-specific antigen (PSA) level. Several different approaches to active immunization against antigens found on cancer cells have been explored. Immunization with DNA overcomes many of the obstacles noted in previous studies. Injection of plasmid DNA encoding a xenogeneic differentiation antigen (prostate-specific membrane antigen [PSMA]) is a potent means to induce antibody and T-cell responses to these otherwise poorly immunogenic self proteins. Use of the xenogeneic DNA (ie, human PSMA DNA injected into mouse) has been shown to be an absolute requirement to overcome immunologic tolerance. We are currently conducting a phase I trial of human and mouse PSMA DNA vaccines in patients with recurrent prostate cancer, based on preclinical experiments described below.

Rapid Androgen Cycling as Treatment for Patients with Prostate Cancer

Purpose: To investigate the safety and feasibility of rapid androgen cycling for men with progressive prostate cancer. Experimental Design: Schedule 1 included a 4-week induction of androgen depletion, followed by 4-week treatment cycles of a monthly gonadotropin-releasing hormone agonist, testosterone on days 1 to 7, and an estrogen patch on days 8 to 21. Schedule 2 included a 12-week induction of androgen depletion followed by 4-week cycles of gonadotropin-releasing hormone agonist and testosterone, but no estrogens for patients with a prostate-specific antigen (PSA) nadir <1 ng/mL after induction. The primary end point was serially declining PSA trough values over six treatment cycles. Results: Thirty-six patients were treated; 27 were evaluable after cycling, of whom 8 of 12 (67%) and 9 of 15 (60%) on schedules 1 and 2, respectively, reached the end point. Five patients with PSA >1 ng/mL following induction did not cycle. No patient progressed radiographically or clinically during cycling. Three posttherapy PSA patterns were observed: a decline followed by a rapid increase in trough levels, a sustained decline with a plateau at a detectable nadir, and a decline to an undetectable nadir. Mean testosterone levels were castrate at the time of trough and in the normal physiologic range following androgen repletion. Major toxicities included grades 1 and 2 fatigue, hepatitis, gynecomastia, and hot flashes. Conclusions: Rapid hormonal cycling is feasible and well tolerated, and successive declines in PSA troughs are achievable. Although the sample size was small, the proportion of patients achieving declining PSA at the end of six cycles was comparable with that reached with continuous androgen depletion therapy.

Second-line hormonal therapy for men with chemotherapy-naive, castration-resistant prostate cancer: American society of clinical oncology provisional clinical opinion

Purpose ASCO provisional clinical opinions (PCOs) offer direction to the ASCO membership after publication or presentation of potential practice-changing data. This PCO addresses second-line hormonal therapy for chemotherapy-naïve men with castration-resistant prostate cancer (CRPC) who range from being asymptomatic with only biochemical evidence of CRPC to having documented metastases but minimal symptoms. Clinical Context The treatment goal for CRPC is palliation. Despite resistance to initial androgen deprivation therapy, most men respond to second-line hormonal therapies. However, guidelines have neither addressed second-line hormonal therapy for nonmetastatic CRPC nor provided specific guidance with regard to the chemotherapy-naïve population. Recent Data Six phase III randomized controlled trials and expert consensus opinion inform this PCO. Provisional Clinical Opinion For men with CRPC, a castrate state should be maintained indefinitely. Second-line hormonal therapy (eg, antiandrogens, CYP17 inhibitors) may be considered in patients with nonmetastatic CRPC at high risk for metastatic disease (rapid prostate-specific antigen doubling time or velocity) but otherwise is not suggested. In patients with radiographic evidence of metastases and minimal symptoms, enzalutamide or abiraterone plus prednisone should be offered after discussion with patients about potential harms, benefits, costs, and patient preferences. Radium-223 and sipuleucel-T also are options. No evidence provides guidance about the optimal order of hormonal therapies for CRPC beyond second-line treatment. Prostate-specific antigen testing every 4 to 6 months is reasonable for men without metastases. Routine radiographic restaging generally is not suggested but can be considered for patients at risk for metastases or who exhibit symptoms or other evidence of progression. Additional information is available at www.asco.org/genitourinary-cancer-guidelines and www.asco.org/guidelineswiki .

Re-treatment with radium-223 : first experience from an international, open-label, phase I/II study in patients with castration-resistant prostate cancer and bone metastases

Abstract Background Six radium-223 injections at 4-week intervals is indicated for patients with castration-resistant prostate cancer and symptomatic bone metastases. However, patients usually develop disease progression after initial treatment. This prospective phase I/II study assessed re-treatment safety and efficacy of up to six additional radium-223 injections. Patients and methods Patients had castration-resistant prostate cancer and bone metastases and six initial radium-223 injections with no on-treatment bone progression; all had subsequent radiologic or clinical progression. Concomitant agents were allowed at investigator discretion, excluding chemotherapy and initiation of new abiraterone or enzalutamide. The primary endpoint was safety; additional exploratory endpoints included time to radiographic bone progression, time to total alkaline phosphatase and prostate-specific antigen progression, radiographic progression-free survival, overall survival, time to first symptomatic skeletal event (SSE), SSE-free survival, and time to pain progression. Results Among 44 patients, 29 (66%) received all six re-treatment injections. Median time from end of initial radium-223 treatment was 6 months. Forty-one (93%) reported ≥1 treatment-emergent adverse event. No grade 4–5 hematologic treatment-emergent adverse events occurred. Only one (2%) patient had radiographic bone progression; eight (18%) had radiographic soft tissue tumor progression (three lymph node and five visceral metastases). Median times to total alkaline phosphatase and prostate-specific antigen progression were not reached and 2.2 months, respectively. Median radiographic progression-free survival was 9.9 months (12.8-month maximum follow-up). Five (11%) patients died and eight (18%) experienced first SSEs. Median overall survival, time to first SSE, and SSE-free survival were not reached. Five (14%) of 36 evaluable patients (baseline worst pain score ≤7) had pain progression. After 2 years of follow-up, 28 (64%) patients died, and the median overall survival was 24.4 months. Conclusions Re-treatment with a second course of six radium-223 injections after disease progression is well tolerated, with minimal hematologic toxicity and low radiographic bone progression rates in this small study with limited follow-up. Favorable safety and early effects on disease progression indicate that radium-223 re-treatment is feasible and warrants further evaluation in larger prospective trials.

757OGALETERONE IN 4 PATIENT POPULATIONS OF MEN WITH CRPC: RESULTS FROM ARMOR2

ABSTRACT Aim: Galeterone is an oral small molecule that disrupts androgen receptor (AR) signaling via multi-targeted mechanisms of action (MOA): (1) selective inhibition of CYP17 lyase; (2) competitive antagonism of androgen binding to AR; and (3) degradation of AR protein. Galeterone is a single molecule with potential advantage beyond approved CYP17 and AR inhibitors in that it combines AR degradation with AR antagonism and CYP17 suppression and has no steroid requirement. Methods: ARMOR2 (NCT#01709734) is a two part, Ph 2 study designed to confirm dose of reformulated galeterone (1700 mg-3400 mg QD for 12 wks) (Part 1) and assess safety and efficacy of 2550 mg QD for 12 wks (Part 2). As of April 18, 2014, 4 cohorts of CRPC patients (pts) have been treated at 2550 mg: non-metastatic treatment (tx) naive (TN) (M0 TN, n = 18), metastatic tx naive (M1 TN, n = 36), abiraterone refractory (Abi-R n = 21) and enzalutamide refractory (Enza-R, n = 2). Additional arms have been added. Results: PSA response was seen at 2550 mg in all tx groups. In 36 M1 TN pts, PSA declines of 30% and 50% (PSA30 and PSA50) were acheived in 89% and 81% of patients respectively. The M1 TN pts had best overall response per RECIST with 14/15 with stable disease (SD) and 1/15 with partial response (PR) in evaluable pts at 3 mos. Safety: galeterone was well tolerated at all doses (parts 1 and 2) with gr 1 or 2 treatment related AEs occurring in 57% of pts; the most frequent were nausea (34%), fatigue (23%) and pruritis (22%). There was a total of 19% gr 3 and 2% gr 4 related AEs. There was no mineralcorticoid excess (ME) or seizures. Maximum Response w/in 12 Weeks 2550 mg Dose N* PSA30 N (%) PSA50 N (%) Best Overall Response Per RECIST PR/SD (N**) M0 TN 14 10 (71) 9 (64) 0/2 (5) M1 TN 36 32 (89) 29 (81) 1/14 (15) Abi-R 12 2 (17) 0 (0) 0/5 (7) Enza-R 2 0 (0) 0 (0) NA Conclusions: Galeterone has shown signifiant biochemical and clinical activity and is well tolerated with no ME or seizures. The study will continue to explore safety and efficacy of galeterone in pts with progression following abiraterone and/or enzalutamide, chemotherapy and in additional arms. Also, data on CTCs will be presented and correlated with outcomes. Disclosure: M. Taplin: Advisory Boards: Medivation, Janssen, Dendron, Bayer, Tokai (individually

eRADicAte: A Prospective Evaluation Combining Radium-223 Dichloride and Abiraterone Acetate Plus Prednisone in Patients With Castration-Resistant Prostate Cancer

Background Multiple castration‐resistant prostate cancer (CRPC) therapies are approved by the United States Food and Drug Administration. Radium‐223 dichloride (Ra‐223) with abiraterone acetate plus prednisone have different mechanisms of action and distinct off‐target side‐effect profiles. We prospectively investigated their combined safety, tolerability, and patient‐reported outcome measures. Patients and Methods eRADicAte, an investigator‐initiated, phase II trial, studied 31 patients with metastatic CRPC, from 5 United States uro‐oncology research sites. Patients completed 6 cycles of Ra‐223 with concurrent abiraterone therapy. Quality of life and pain were assessed using the Functional Assessment of Cancer Therapy‐Prostate and the Brief Pain Inventory‐Short Form questionnaires and their subscales; we reported the number of subjects meeting standardized criteria for clinically meaningful improvements on each scale. Safety assessment included Eastern Cooperative Oncology Group performance status, laboratory changes, opioid use, radiographic responses, and adverse events (AEs). Results Twenty of 31 (65%) experienced positive clinically meaningful improvement changes on the Functional Assessment of Cancer Therapy‐Prostate, and 25 (81%) of 31 on the Prostate Cancer Subscale. Eighteen (58%) of 31 demonstrated reduced pain intensity and 12 (39%) of 31 demonstrated reduction of pain interference in their lives. At baseline, subjects averaged 11.6 ± 2.8 bone lesions; at the end of treatment, subjects averaged 5.6 ± 2.4 bone lesions (P = .0002). The most frequent AEs were diarrhea (17%), nausea (17%), and fatigue (14%). There were 6 serious AEs; 1 led to study withdrawal. Conclusions Patients experienced clinically meaningful improvements in quality of life and pain, without unexpected adverse toxicities. Phase III combination trials of Ra‐223 with novel oral hormonal agents are ongoing to further evaluate radiographic progression and overall survival benefit. Micro‐Abstract This is the first study to prospectively evaluate the combined use of radium‐223 dichloride and a novel oral hormonal therapy, abiraterone acetate, in men with metastatic castration‐resistant prostate cancer. The eRADicAte study showed that patients with metastatic castration‐resistant prostate cancer experienced clinically meaningful improvements in quality of life with decreased pain, reduction in bone lesions, and an acceptable safety and toxicity profile.

Hormonal induction followed by rapid hormonal cycling for prostate cancer (PC): the MEN's Cycle

4609 Background: Continuous androgen deprivation (AD) is a standard therapy for systemic PC. Rapid cyclic AD and androgen repletion (AR) after a 1 month induction with castration was shown to be feasible. This trial explores a longer induction period followed by rapid cyclic AD and AR in patients (pts) with limited prior hormone exposure. METHODS Eligible pts had a rising PSA after surgery or radiation, or radiographic metastases, and ≤ 6 months of prior hormone exposure. Treatment consisted of a 3 month induction (GnRH analog monthly & bicalutamide x 1 month) followed by monthly cycles of AR (topical testosterone (T) daily x 7 days) and AD (GnRH analog monthly). A PSA of ≤1ng/ml after induction was required to proceed with cycling. PSA and T levels were monitored post ablation (troughs) and post repletion (peaks). The primary endpoint was the proportion of pts with serially declining PSA troughs after 6 cycles. Treatment failures were defined as 3 sequential increases in PSA troughs prior to 6 cycles. RESULTS 23 pts were enrolled (5 pts: rising PSA only; 18 pts: metastatic disease). The median baseline PSA was 63ng/ml (2.6-546). The median baseline T level was 383ng/dl (181-654). All cycling pts achieved T levels within the normal reference range during AR and castrate troughs during AD. 5 pts (22%) did not achieve a PSA of ≤1ng/ml after induction and did not cycle. 3 pts were inevaluable. Of the 15 evaluable pts who cycled, 6 pts met the primary endpoint and 3 pts are still being evaluated at < 6 cycles. 6 pts were treatment failures (all continued standard AD off study, of whom 5 pts had further PSA declines). No pt progressed radiographically. Common toxicities included grade 1 fatigue and hot flashes. CONCLUSION Rapid hormonal cycling using a 3 month induction is feasible, well-tolerated, and successive declines in the PSA troughs can be achieved. Some pts did show evidence of AD resistance within 3 months by not achieving a PSA of ≤1ng/ml after induction. Based on these results, we have designed a phase II clinical trial using rapid hormonal cycling with no induction in combination with docetaxel in pts with limited prior hormone exposure. Support: CCPP, CA05826, Prostate Cancer Foundation No significant financial relationships to disclose.

Phase 1 open-label trial to evaluate the safety and immunogenicity of PAN-301-1, a novel nanoparticle therapeutic vaccine, in patients with biochemically relapsed prostate cancer.

e15166Background: PAN-301-1 is a first-in-class therapeutic vaccine candidate targeting human aspartyl (asparaginyl) β-hydroxylase ((HAAH), or aspartate β-hydroxylase (ASPH)). HAAH is an enzyme whi...

Changing characteristics of patients treated with sipuleucel-T (sip-T) over time: Real-world experience from the PROCEED registry.

320 Background: Sip-T is an autologous cellular immunotherapy approved by the FDA for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. PROCEED (NCT01306890) is a phase 4 registry evaluating men receiving sip-T therapy in the US. Patient characteristics and treatment trends were assessed from 2011 to 2013, when several agents with an overall survival benefit became commercially available. Methods: For patients enrolled from 2011 to 2013, baseline patient and disease characteristics at the first sip-T infusion, trends in prior therapy, and pre–sip-T baseline prostate-specific antigen (PSA) levels were examined year over year. Results: From 2011 to 2013, 1902 patients were enrolled and received ≥ 1 sip-T infusion: 2011, n = 145; 2012, n = 967; 2013, n = 790. During this time period, enrollment of African American men nearly doubled from 6.9% to 13.4%, and central venous catheter use to facilitate sip-T infusion decreased (from 53.8% to 44.1%). Median bas...