Castration-resistant Prostate Cancer Pts Research Articles

Hematologic safety of Ra-223 dichloride (Ra-223) in castration-resistant prostate cancer (CRPC) patients with bone metastases from the phase III ALSYMPCA trial.

5060 Background: In the updated analysis of the ALSYMPCA study, Ra-223 significantly improved median survival by 3.6 mo vs placebo (Pbo) in 921 CRPC patients (pts) with bone mets (HR = 0.695; 95% CI, 0.581-0.832; p = 0.00007) and had a highly favorable safety profile (Parker et al. ASCO 2012). The hematologic safety profile and results from a post hoc analysis assessing prognostic factors for changes in hematologic parameters in ALSYMPCA pts are presented. Methods: Pts were randomized 2:1 to 6 injections (inj) of Ra-223 (50 kBq/kg IV) q4wk or matching Pbo and stratified by prior docetaxel (D) use, total alkaline phosphatase (tALP), and current bisphosphonate use.Multivariate regression analysis was performed to explore the relationship of 6 baseline factors (Table) with maximum % change of hematologic parameters from baseline up to 24 wk on treatment (tx). Results: The updated analysis included 901 pts (safety population; Ra-223, n = 600; Pbo, n = 301). Overall grade 3/4 AEs were similar between Ra-223 and Pbo groups, with neutropenia in 2% and 1%, thrombocytopenia in 6% and 2%, and anemia in 13% and 13% of Ra-223 and Pbo groups, respectively. Tx with Ra-223, prior D use, extent of disease (EOD) > 6 bone mets, and tALP ≥ 220 U/L, but not current bisphosphonate use, were associated with decreases from baseline in hemoglobin (Hb), neutrophils, or platelets; prior EBRT to bone for pain was associated with an increase. The significance of the relationship between baseline factors and changes in hematologic parameters is summarized in the Table. Conclusions: Overall, there was a low risk for hematologic AEs with Ra-223 tx in CRPC pts with bone mets. The strongest prognostic factors for decreases in neutrophils and platelets were Ra-223 tx and prior D use. Baseline tALP ≥ 220 U/L was a strong predictor of decrease in Hb. Clinical trial information: NCT00699751. [Table: see text]

Randomized phase II study with window-design to evaluate anti-tumor activity of the survivin antisense oligonucleotide (ASO) ly2181308 in combination with docetaxel for first-line treatment of castrate-resistant prostate cancer (CRPC).

5019 Background: In prostate cancer, expression of survivin, a protein that inhibits apoptosis, is associated with resistance to taxanes and poor outcome. LY2181308 reduces survivin expression and consequently is expected to improve activity of taxanes, such as docetaxel. A randomized phase II study was conducted to assess the activity of the combination. Methods: Adult patients (pts) with CRPC, ECOG performance status <2, and no bone or CNSmetastases were randomized 1:2 to standard docetaxel/prednisone every 21 days (Arm A) or standard therapy combined with LY2181308 given as a 3-hr IV infusion (Arm B). Analysis was planned and performed after 130 pts progressed or died. This assessment provided a 70% chance of detecting a difference in progression-free survival (PFS) at the 10% significance level. Initially, LY2181308 was given as a loading dose (3 consecutive days) and then as a weekly 3-hr IV maintenance dose. Arm B also included a window treatment with LY2181308 monotherapy equivalent to a 21-day cycle of docetaxel before starting combined treatment. The primary endpoint was PFS. Results: This study enrolled 154 pts. The median PFS for Arm B was 8.64 (90% CI, 7.39–10.45) months vs. 9.00 (90% CI, 7.00–10.09) months in Arm A, showing no statistical difference (log rank p=0.755). The median overall survival (OS) for Arm B was 27.04 (90% CI, 19.94–33.41) months vs. 29.04 (90% CI, 20.11–39.26) months for Arm A (log-rank p= 0.838). The PSA responses (>50% reduction in PSA) were similar: 56.9% for Arm A and 56.1% in Arm B (p=0.856). Most pts had no pain or mild pain at baseline and during the active period. Pts treated in Arm B had a higher frequency of serious and nonserious adverse events (AEs) than those in Arm A. The observed AE and pharmacokinetic (PK) profiles were consistent with the known safety and PK profiles of LY2181308 and docetaxel. Conclusions: The addition of LY2181308 to a standard docetaxel/prednisone regimen showed no improvement in PFS, PSA response, and OS in first line CRPC pts. The safety profile of docetaxel and LY2181308 is predictable and consistent with the known safety profiles. Clinical trial information: NCT00642018.

Clinical outcome (CO) and predictive factors (PRE) evaluation of young (≤ 60 years) castration-resistant prostate cancer (CRPC) patients, treated with docetaxel (DOC): Preliminary results of an Italian multicenter retrospective study (CYCLOP study).

e16031 Background: CRPC is rare in pts ≤ 60 yrs and clinical outcomes of these pts are not clearly defined despite there is a common feeling of a worse prognosis for them. The present study is aimed to assess CO and PRE in this specific population. Methods: In this multicentric retrospective study, after Ethical Committee approval, we have reviewed the clinical records of all < 60 yrs CRPC pts from participating institutions, treated with DOC. We recorded the pre and post-DOC clinical history, the DOC treatment details and outcomes. We have also assessed the ability of a series of selected 18 clinical factors to predict DOC response through a logistic regression analysis. Continuous variables were categorized by quartiles and chosen for the initial model after a univariate chi-square analysis. Results: To date we have collected a consecutive series of 98 pts from 16 Italian hospitals. The median age was 57 yrs (range 41-60). The median baseline PSA was 84 ng/ml (range 2-2721); 93% of the pts had bone metastases while 49%, 9%, and 13% showed nodal, liver and lung metastases, respectively. All but 8 pts received DOC with a 3-week standard schedule: the median number of received DOC courses was 8 (range 1-14). The main grade 3-4 toxicities were anemia (4 pts), neutropenia (15 pts), febrile neutropenia (1 pt), peripheral neuropathy(1 pt). A PSA reduction > 50% was observed in 61% of the pts while 14% and 7% of the cases showed a partial and complete response, respectively. Having a Gleason score (GS) <8 [p= 0.032], a hemoglobin initial value >12 [p= 0.052], no nodal involvement [p= 0.101], resulted to be independently predictive of a PSA reduction > 50%. The median PFS and OS were 7 mos and 19 mos, while the 1-year PFS and OS rates were 17.3% and 70%, respectively. Conclusions: From these preliminary results, we failed to confirm a worse prognosis for younger CRPC since their survival outcomes are similar to those observed in the pivotal trials. Low GS, absence of nodal involvement and good hemoglobin levels are the only predictive factors.

NCIC CTG, IND-205: A phase II study of PX-866 in patients with recurrent or metastatic castration-resistant prostate cancer (CRPC).

5042 Background: PX-866 is an irreversible, pan-isoform inhibitor of Class I PI-3K. Mutations in PIK3CA and loss of PTEN activity lead to activation of AKT signaling; alterations in these genes occur frequently in prostate cancers while activation of the PI-3K/AKT signaling pathway is implicated in prostate cancer progression and treatment resistance. Hence, novel inhibitors of the pathway such as PX-866 are of interest. Methods: In this multicenter, two-stage, phase II study, docetaxel-naïve CRPC pts received PX-866, 8mg daily on a 6-week cycle. Primary endpoint was lack of progression at 12 weeks (PCWG2 criteria). Secondary endpoints included PSA and objective response rates and change in circulating tumor cells (CTC) during treatment. If ≤5 of the first 20 pts were progression free at 12 weeks, the study would stop. Otherwise, 40 pts would be accrued and PX-866 deemed worthy of further study if ≥16 pts were progression free at 12 weeks. Results: 43 pts were accrued after the criteria to progress to stage 2 were met. Median age was 70, ECOG PS was 0/1/2 in 27/15/1 pts, 23 pts had measurable disease, 24 patients had CTC ≥5. Median number of cycles was 2 (range 1–8). Most common adverse events (AE) were diarrhea (27 pts), nausea (25), fatigue (15), vomiting (13), anorexia (15) and grade 1 hypomagnesemia (11); 7 pts discontinued because of toxicity (3 GI, 3 LFTs, 1 fatigue). Grade 3 AEs were diarrhea (5 pts), AST/ALT elevation (4), fatigue (3). 11 patients were progression free at 12 weeks. 16 of the 24 pts with measurable disease were evaluable for response; there were no objective responses but 10 pts had stable disease (2.6-13.9m). One pt had a confirmed PSA response. CTC favorable conversion (from 5 at baseline to <5) was observed in 6/24 evaluable patients (25%). Correlative studies are ongoing. Conclusions: PX-866 is well tolerated and showed modest activity in CRPC but did not meet a priori benchmarks for further development as a single agent in unselected patients. As androgen receptor inhibition promotes PI3K activity in PTEN-loss PC models, the addition of PX-866 in pts whose PSA is rising on abiraterone may reverse resistance and phase B of the study is underway to test this hypothesis clinically. Clinical trial information: NCT01331083.

An exploratory analysis of bone scan lesion area (BSLA), circulating tumor cell (CTC) change, pain reduction, and overall survival (OS) in patients (pts) with castration-resistant prostate cancer (CRPC) treated with cabozantinib (cabo): Updated results of a phase II nonrandomized expansion (NRE) cohort.

5026 Background: The results of 144 pts with metastatic CRPC treated in a phase II NRE cohort with daily cabo 100 mg and 40 mg starting doses have been previously reported. Substantial rates of bone scan improvement, reductions in CTC counts and pain relief were observed. To better understand the implication of these effects, the association with OS was explored. Methods: Relevant baseline variables (LDH, BSLA, visceral disease, pain, hemoglobin, CTCs) and post-treatment changes at week 6: ≥30% reduction in BSLA using computer-aided assessment, CTC conversion (>5 vs. 4 or less/7.5 ml of blood), and pain intensity (7 day averaged worst pain score; BPI scale; using an IVR system) were associated with OS in 144 CRPC pts with bone metastasis who progressed within 6 months of docetaxel (D) treatment (≥225 mg/m2) in either bone or soft tissue. Median OS was compared between responders and non-responders for each of the above outcomes categories using a Cox proportional hazard model. The findings were examined further after adjusting for significant baseline covariates selected from a stepwise Cox regression model. Results: See Table. Conclusions: Recognizing the limitations of associating response with survival, this retrospective analysis of decreases in BSLA, CTC conversions and reductions in pain intensity support further study in ongoing phase III trials. Clinical trial information: NCT00940225. [Table: see text]

Impact of intermittent (I) first-line docetaxel (D)-based chemotherapy on quality of life (QL) of patients (pts) with castration-resistant prostate cancer (CRPC): Results of a phase II randomized trial.

90 Background: Eight consecutive courses of D are usually considered a standard first line treatment for CRPC pts. The pts quality of life (QL) may be worsened and an I administration could mitigate this effect. We verified if an I therapy may reduce the impact on pts’ QL compared to continuous (C) treatment. Methods: The treatment was D 70 mg/m2IV q 3 wks ± estramustine (E) 280 mg/TID PO for 5 days. Pts were randomized to receive 8 courses D±E continuously (C) or intermittently, with a 3-month rest period after the first 4 courses. QL was evaluated by EORTC QLQ C30 at baseline and every 6 weeks. For the study aim, we considered evaluable for QL pts who received at least 5 D±E courses and filled the QL instruments. Results: 148 CRPC pts were enrolled from 11/06 to 10/10 with 94 pts evaluable for QL (53 and 41 treated with I with C therapy, respectively). No statistically differences were observed between C and I treatments for QL outcomes: the table shows the median value of single EORTC QLQ C30 scales scores at each assessment time-point. Conclusions: The present study failed to demonstrate that I treatment may produce a QL advantage compared to C treatment which remains the reference therapy for first-line of CRPC pts. Clinical trial information: 2006-005728-17. [Table: see text]

Pain analysis from the phase III randomized ALSYMPCA study with radium-223 dichloride (Ra-223) in patients with castration-resistant prostate cancer (CRPC) with bone metastases.

19 Background: Bone metastases (mets), present in >90% of patients (pts) with CRPC, may cause severe pain. In a phase II dose-response study with Ra-223 treatment, pain response (pain reduction and stable analgesic consumption) was seen in up to 71% of CRPC pts with painful bone mets (Nilsson 2012). In the phase III ALSYMPCA study, which included 921 CRPC pts with bone mets randomized 2:1 to receive 6 injections of Ra-223 (50 kBq/kg IV) q4wk or matching placebo (Ra-223, n=614; placebo, n=307), Ra-223 significantly improved overall survival vs placebo (median 14.9 vs 11.3 mo; HR=0.695) and was well tolerated. Post hoc analyses of pain parameters in ALSYMPCA are presented. Methods: The hazard ratios for time to initial opioid use and time to external beam radiation therapy (EBRT) were analyzed using the Cox proportional hazards model. Pts with no opioid use at baseline were included in the pain analyses. Concomitant opioid use was recorded from first study drug injection to 12 weeks after last injection. Results: Baseline pain characteristics were similar between the treatment groups (approximately 55% of pts had moderate to severe pain and opioid use based on WHO ladder for cancer pain). Time to EBRT was significantly longer in the Ra-223 group vs placebo (HR=0.670, 95% CI: 0.525-0.854). Fewer Ra-223 pts reported bone pain as an AE compared to placebo pts (50% vs 62%). 269 pts in the Ra-223 group and 139 pts in the placebo group had no opioid use at baseline. Median time to initial opioid use was significantly longer in the Ra-223 group, with a risk reduction of 38% compared to placebo (HR=0.621, 95% CI: 0.456-0.846). Fewer pts in the Ra-223 group (36%) than in the placebo group (50%) required opioid use for pain relief. Conclusions: These ALSYMPCA results provide consistent evidence that, in addition to prolonging survival, Ra-223 reduces pain and opioid use in patients with CRPC and bone metastases. Clinical trial information: NCT00699751.

Population-based impact on overall survival (OS) after the introduction of docetaxel as standard therapy for metastatic castration resistant prostate cancer (CRPC).

77 Background: Docetaxel (DOC) was the first systemic therapy to improve OS (Hazard Ratio (HR) = 0.79) for patients (pts) with CRPC and a standard therapy since 2004. Because of the potential for severe toxicity with DOC, its use has been subject to pt selection. Even with this selective use, we sought to determine whether the introduction of docetaxel has improved OS at a population level. Methods: We performed aretrospective review of all CRPC pts treated with palliative radiotherapy (PRT) to bone metastases in the province of British Columbia, Canada. The pre-docetaxel cohort (pre-D) received PRT from 1998-2001. The docetaxel-era cohort (post-D)received PRT from 2006-2009. Time of first PRT to bone was used to select pts at a similar point in their disease state (i.e., onset of bone pain). Mortality and cause of death was attained from public registries. OS was calculated from time of first PRT using the Kaplan-Meier method and compared using the log-rank test. Results: Comparative baseline characteristics for the 1876 patients split into the pre-D (n=919) and post-D (n=957) eras were: metastatic at diagnosis 30% vs. 33% (p = 0.09), median age at PRT 75.5 vs. 76.7 years (p=0.04), time from diagnosis to PRT 3.9 vs. 3.1 years (p = 0.31), received DOC 7% vs. 37% (p < 0.0001). Median OS from time of first PRT was 7.5 months (m) vs. 10.3 m (HR: 0.79, 95% Confidence Interval 0.70 – 0.89, p < 0.0001) in the pre-D and post-D cohorts respectively. Within the post-D cohort, the median OS from time of RT was longer in pts receiving DOC at 13.9 m vs. 7.4 m for pts not receiving DOC (p=0.004). Conclusions: In this population based analysis, the introduction of DOC as a standard of care was associated with a significant improvement in OS even though DOC penetrance was <50%. This demonstrates for the first time the generalizability of the TAX-327 study results to the population at large. Even as the therapeutic landscape for CRPC evolves with the introduction of new agents that improve OS with favourable toxicity profiles, these data support the continued use of DOC in appropriately selected patients.

Evaluating the hypothalamic-pituitary-adrenal axis (HPAA) in men receiving ketoconazole for castrate-resistant prostate cancer (CRPC).

64 Background: Serum adrenal androgen (AA) levels may be prognostic for survival in men with CRPC treated with androgen synthesis inhibitors (ASIs) including ketoconazole (keto) and abiraterone. We hypothesize that up-regulation of the HPAA and adrenocorticotropic hormone (ACTH) may contribute to therapeutic resistance on ASIs. The current study explores the relationship between ACTH, AA, testosterone (T) and estradiol (E) among CRPC patients (pts) treated with ASI + corticosteroids. Methods: Phase 2 study of keto (400 mg TID) + hydrocortisone (HC) (30 mg/day) in pts with CRPC. Pts who achieved ≥ 30% PSA decline from baseline at week 12 continued keto/HC until progression, at which point HC was replaced by dexamethasone (dex). Serum hormone (H) levels were measured (in AM) at baseline and every 4 weeks using standard assays. Statistical tests include Spearman’s rank test for correlation between baseline H levels; Wilcoxon matched pairs for baseline vs. week 4 distribution; and Fisher’s exact test for associations between H levels (dichotomized at median) with PSA decline. Results: Of 30 pts enrolled and 24 evaluable for PSA response, 13 pts (54%) achieved ≥ 30% PSA decline at 12 weeks. Baseline ACTH was positively correlated with DHEA (r = 0.40; p = 0.04) and cortisol (r = 0.52; p = 0.007). Change from baseline to week 4 in H levels is shown in table. There was a significant increase in pts achieving a PSA decline of ≥ 30% if there was a decrease in E at week 4 vs. no decrease (83% vs. 18%; p = 0.003). Baseline and changes in other H levels were not associated with PSA outcome at week 12. Conclusions: ACTH is positively correlated with DHEA and cortisol in CRPC pts. Declines in E may serve as an additional predictive marker of benefit for ASI therapy. These observations require prospective validation. Analyses exploring changes in ACTH at disease progression and impact of substituting dex for HC are ongoing. Clinical trial information: NCT01036594. [Table: see text]

Updated analysis of radium-223 dichloride (Ra-223) impact on skeletal-related events (SRE) in patients with castration-resistant prostate cancer (CRPC) and bone metastases from the phase III randomized trial (ALSYMPCA).

11 Background: Ra-223 is a first-in-class alpha-pharmaceutical targeting bone metastases (mets) with high-energy, short-range (< 100 μm) alpha-particles. In the phase 3, double-blind, randomized, multinational ALSYMPCA study, Ra-223 significantly improved OS in CRPC patients (pts) with bone mets by a median increase of 3.6 months compared with placebo (median OS: 14.9 vs 11.3 mo; P < 0.001; HR = 0.69; 95% CI: 0.58-0.83). An updated analysis of the SRE secondary endpoint is presented. Methods: Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets on scintigraphy and no known visceral mets; were receiving best standard of care (BSoC); and either previously received docetaxel, or did not because they were docetaxel ineligible, or refused docetaxel. Pts were randomized 2:1 to receive 6 injections of Ra‑223 (50 kBq/kg IV) q4wk or matching placebo and stratified by prior docetaxel use, baseline alkaline phosphatase level, and current bisphosphonate use. Results: 921 pts were randomized (Ra-223, n = 614; placebo, n = 307); 40% had >20 mets. Ra-223 significantly delayed time to first SRE versus placebo by a median increase of 5.8 months (median time to SRE: 15.6 vs 9.8 mo; P < 0.001; HR = 0.66; 95% CI: 0.52-0.83). Ra-223 also reduced the risk of time to first event for all 4 SRE components versus placebo. Conclusions: Ra-223 significantly delayed time to first SRE with a reduction in risk observed for all 4 SRE components. Despite the longer time at risk, Ra-223 patients had an approximately 50% reduction in risk for SCC. Ra-223 is an effective therapy with a highly favorable safety profile and may provide a new standard of care for treatment of CRPC pts with bone mets. Clinical trial information: NCT00699751. [Table: see text]

Early response assessment and bone flare phenomenon on 18F-fluorocholine positron emission tomography/computed tomography (FCH-PET/CT) in patients (pts) with metastatic castration-resistant prostate cancer (CRPC) treated with abiraterone acetate.

134 Background: In this prospective study, in patients with CRPC previously treated with docetaxel, we evaluated prostate specific antigen (PSA) and FCH-PET/CT for early response assessment to abiraterone acetate, and assessed frequency of early FCH-PET/CT discordant with PSA and clinical response. Methods: Twenty nine metastatic CRPC pts progressing after docetaxel chemotherapy received abiraterone acetate 1,000 mg daily with prednisone 5 mg twice daily in continuous 28-day cycles. Patients were evaluated monthly for serological PSA response and safety. FCH-PET/CT was repeated after 4-6 weeks and a CT scan was done after 3 months of abiraterone acetate. FCH-PET/CT bone flare was defined as the combination, after 3 months of therapy, of an interpreting radiologist’s report indicating progressive disease (PD) in context of a ≥50% decline in PSA, no PD at 3-month CT scan, with FCH-PET/CT improvement or stability 2-3 months later. Results: Three of 29 patients treated with abiraterone acetate did not perform the follow-up FCH-PET/CT due to rapidly PD with a decline in performance status. Of the remaining 26 patients, 4 are still undergoing early response evaluation. Twenty two pts, median age was 71 yrs (range, 57-86 yrs) were evaluable for this analysis. A ≥50% PSA decline was observed in 15/22 (68%) evaluable pts. Undetectable PSA levels (≤0.1 ng/mL) occurred in one case. Early FCH PET/CT response assessment was as follows: complete response (n=2, 9%), partial response (n=7, 32%), stable disease (n=3, 14%), PD (n=10, 45%), but in 4 of 10 pts with PD a bone flare phenomenon on FCH PET/CT was observed. PSA decline ≥50% and FCH PET/CT response correlated in 19 of 22 pts (86%). Conclusions: Discordant findings between serologic PSA response and increases in early FCH-PET/CT bone lesion intensity are reported here for the first time in CRPC. Further investigation is needed to clarify the confounding effect of FCH-PET/CT bone flare on patient management and interpretation of results.

909P - Predictive and Prognostic Roles of Body Mass Index (BMI) in Docetaxel(D)-Treated Castrate-Resistant Prostate Cancer (CRPC)

ABSTRACT Introduction Studies have suggested that overweight and obese patients with early stage prostate cancer present with lower PSA, higher grade disease and have poorer outcomes. Data remains limited on the influence of BMI on CRPC receiving D. We previously reported lower pretreatment PSA and rate of PSA response in obese pts (Teo et al, ASCO GU 2011). With an expanded cohort, we sought to examine the influence of BMI on PSA kinetics and CRPC survival. Methods Two institutional databases were analysed to identify pts who received D for CRPC. Demographics and serial PSA levels were extracted. Pts were divided into Group A, B and C, based on BMI range of ≤25.0, 25.1-29.9 and ≥30 kg/m respectively. PSA responses and half life were calculated using PCWG2 guidelines. Results were compared with Mann-Whitney and Fisher's exact tests. Time to PSA progression (TPP) and overall survival (OS) were estimated with Kaplan Meier and logrank methods. Results 78 pts were identified, with median age of 66 yrs (44-80), median cycles of D of 7 (1-26), and median BMI of 28.5. Gleason score was evaluable in 75%, with a median score of 8. The number of pts in each BMI group was 21, 24 and 33, respectively. Pts in Gp C had significantly lower baseline PSA (table). More pts in Gp C were PSA non-responders compared to Gp A and B (p = .004). PSA nadir and rates of PSA reduction >30%, >50% and >90% at 3months were comparable in all groups. MMMMMedian TPP was 4.2 months in Gp A, 5.2 months in Gp B, and 4.4 months in Gp C (logrank p = .49). The longest median OS was observed in Gp A at 20 months, followed by Gp B at 19 months and Gp C at 15 months; these differences were not statistically significant (p = 0.38). Of 45 pts with treatment details, 24% had dose reduction and 44% had ≥1 infusion delays. Rates were similar across Gps A to C. Conclusions Obese CRPC pts have lower pre-D PSA levels and higher rate of non-responsive disease. However, BMI does not appear to influence PSA kinetics, tolerability of D and survival. BMI (kg/m2) p ≤25 25.1 - 29.9 ≥30 n 21 24 33 NS Baseline PSA, median ng/mL 131.0 236.6 81.6 0.007 PSA Reduction at 12wks, median % 34.4 47.2 41.4 NS PSA Nadir as % of Baseline, median 51.1 41.6 39.6 NS PSA Flare, % 9.5 25.0 14.8 NS PSA Non-Responders, % 0.0 4.2 25.9 0.004 >30% PSA Reduction at 12wks, % 66.7 79.2 70.4 NS >50% PSA Reduction at 12wks, % 47.6 62.5 59.3 NS >90% PSA Reduction at 12wks, % 9.5 29.2 14.8 NS PSA Half-life, days, median 51.1 41.6 39.6 NS Disclosure All authors have declared no conflicts of interest.

898PD - Updated Survival, Quality of Life (QOL), and Safety Data of Radium-223 Chloride (RA-223) in Patients with Castration-Resistant Prostate Cancer (CRPC) with Bone Metastases from the Phase 3 Double-Blind, Randomized, Multinational Study (ALSYMPCA)

ABSTRACT Introduction Ra-223 is a first-in-class alpha-emitter pharmaceutical that targets bone metastases with high-energy, very short range ( Methods Eligible pts previously received or refused docetaxel, or were docetaxel ineligible, and were randomized 2:1 to receive Ra-223 (50 kBq/kg IV) or Pbo every 4 weeks x 6. After the IA, an updated analysis of all enrolled pts prior to crossover assessed effects of Ra-223 on the primary (OS, using a stratified log-rank test) and secondary (eg, skeletal-related events [SREs], QOL, and safety) endpoints. QOL was assessed with the Functional Assessment of Cancer Therapy—Prostate (FACT-P) and EuroQoL (EQ-5D) instruments. Results The table shows the updated analysis data for 921 pts (Ra-223, n = 614; Pbo, n = 307). Median OS benefit for Ra-223 was 3.6 mos (HR 0.695). Time to first SRE was 6 mos longer with Ra-223. At week 16, Ra-223 pts reported significantly greater well-being (physical, emotional, functional, prostate cancer score, and total score) (FACT-P) and significantly better QOL (EQ-5D) compared to Pbo pts. The incidence of myelosuppression with Ra-223 was low: 2.2% grade 3/4 neutropenia; 6.3% grade 3/4 thrombocytopenia. Parameter Ra-223 + BSC (n = 614) Placebo + BSC (n = 307) P value Hazard ratio (95% CI) Median overall survival, mos 14.9 11.3 .00007 0.695 (0.581, 0.832) Median time to first SRE, mos 15.6 9.8 .00037 0.658 (0.522, 0.830) FACT-P * Physical well-being -0.93 -1.65 0.047 Emotional well-being -0.12 -1.27 Functional well-being -1.15 -2.23 0.011 Prostate cancer score -0.10 -1.74 0.012 Trial outcome index score -2.14 -5.16 0.011 FACT-P total score -2.53 -6.88 0.006 EQ-5D * Single index utility -0.0181 -0.0952 0.003 * Mean change from baseline at week 16. Conclusions The ALSYMPCA updated analysis substantiates that Ra-223 is an effective therapy that significantly improves OS and time to first SRE, with a highly favorable safety profile, in CRPC pts with bone mets. Ra-223 showed significantly better preservation of QOL, with improved functioning and well-being, compared to Pbo. Disclosure C. Parker: C. Parker has served in a consultant or advisory role for Algeta ASA (uncompensated) and Bayer. S. Nilsson: S. Nilsson has served in a consultant or advisory role for Algeta ASA. N. Vogelzang: N. Vogelzang has served in a consultant or advisory role for and has received grant/research support from Algeta ASA and Bayer. K. Staudacher: K. Staudacher is employed by and has an ownership interest in Algeta ASA. R. van Gool: R. Van Gool is employed by and has an ownership interest in Bayer. A.O. Sartor: O. Sartor has served in consultant or advisory roles for Algeta ASA and Bayer. All other authors have declared no conflicts of interest.

Updated analysis of the phase III, double-blind, randomized, multinational study of radium-223 chloride in castration-resistant prostate cancer (CRPC) patients with bone metastases (ALSYMPCA).

LBA4512 Background: Radium-223 chloride (Ra-223), a targeted alpha-emitter, targets bone metastases (mets) with high-energy alpha-particles of short range (<100 µm). ALSYMPCA, a phase III double-blind, randomized, multinational study, compared Ra-223 plus best standard of care (BSC) vs placebo plus BSC in CRPC patients (pts) with bone mets. In a planned interim analysis (n = 809), based on 314 events, Ra-223 significantly improved overall survival (OS) vs placebo (median 14.0 mo vs 11.2 mo, respectively; HR = .695; 95% CI, .552-.875; 2-sided p = .00185). Secondary endpoints were met and Ra-223 safety was favorable. An updated analysis was conducted prior to the crossover to further assess the effect of Ra-223 on the primary endpoint (OS), secondary endpoints including skeletal-related events (SREs), and safety. Methods: Eligible pts had confirmed symptomatic CRPC with ≥ 2 bone mets; no known visceral mets; and were post-docetaxel, unfit for docetaxel, or had declined docetaxel. Pts were randomized 2:1 to receive 6 injections of Ra-223 (50 kBq/kg IV) q4wks or matching placebo. An updated descriptive analysis of OS, based on 528 events, was performed including data from all randomized pts prior to implementing crossover to Ra-223 for placebo pts. Results: 921 pts (Ra-223, n = 614; placebo, n = 307) were randomized from 6/2008-2/2011. Ra‑223 significantly improved OS vs placebo (median 14.9 mo vs 11.3 mo, respectively; HR = .695; 95% CI, .581-.832; p = 0.00007), and time to first SRE was significantly prolonged (median 15.6 mo vs 9.8 mo, respectively; HR = 0.658; 95% CI, 0.522-0.830; p = 0.00037). Safety and tolerability of Ra-223 remained favorable, with low myelosuppression (e.g., gr 3/4 neutropenia in 2.2% and 0.7% and gr 3/4 thrombocytopenia in 6.3% and 2% of the Ra-223 and placebo groups, respectively). Conclusions: On updated analysis, the median OS benefit for Ra-223 increased from 2.8 to 3.6 months, with a hazard ratio of 0.695 (i.e., 30.5% reduction in risk of death). Ra-223 is an effective therapy that improves OS and time to first SRE with a highly favorable safety profile, and may provide a new standard of care for CRPC pts with bone mets.

Factorial phase II randomized trial of continuous (C) or intermittent (I) docetaxel (D) with or without estramustine (E) as first-line treatment for castration-resistant prostate cancer (CRPC): Preliminary results of HOPLITE trial.

e15160 Background: Pts who receive first line for CRPC are usually treated with 8-10 consecutive courses of D. The pts quality of life (QL) may be worsened and an I administration could limit this effect. E is an old drug showing a synergistic action with D. This study is aimed to compare QL of C and I D and whether E added to D improved its activity, in a 2 × 2 factorial design. Methods: CRPC pts were randomized to: C D 70 mg/m2 IV q 3 wks for 8 courses alone (arm A) or with E 280 mg/TID PO for 5 days starting 1 day prior to D (arm B), or the same treatments given with a 3-month rest period after the first 4 courses (arm C and D, respectively). The primary end points were QL (EORTC QLQ C30 and BPI) of A+B vs C+D and 1-y PFS (according to PCWG2) of A+C vs B+D. Results: 148 CRPC pts were enrolled from 11/06 to 10/10 with 128 pts evaluable at this time. The median age was 69 (range 42-81) and the median baseline PSA was 55.6 (range 0.33-4212). The major hematological toxicities were: anemia G3 (3 pts), neutropenia G3 (4 pts) – G4 (5 pts), febrile neutropenia (5 pts). Comparing C and I, QL outcomes were not statistically different in terms of general QL items. Comparing D and DE, 1-y PFS was superimposable (10% and 13.5%, respectively). The 2-y overall survival was not different between I and C arms 42.5% and 53.7% respectively) and between D and DE arms (42.8% and 53.5% respectively). Conclusions: These preliminary results suggest that I treatment did not produce a QL advantage compared to C treatment, while the addition of E to D did not improve 1-y PFS of CRPC pts.

SWOG S0421: Phase III study of docetaxel (D) and atrasentan (A) versus docetaxel and placebo (P) for men with advanced castrate resistant prostate cancer (CRPC).

4511 Background: The endothelin pathway has a mechanistic role in bone metastases (mets). Atrasentan (A), an endothelin receptor antagonist, has reported activity in CRPC. This trial tested the survival impact of A + docetaxel (D) vs. D+ placebo (P) in CRPC pts with bone mets. Methods: Eligible CRPC pts, stratified for progression type, baseline pain index (BPI), extraskeletal mets and bisphosphonate (BisP) use, were randomized 1:1 to D+A vs. D+P for 12 3-wk cycles. Non-progressors could continue blinded drug alone for 16 more wks. Co-primary endpoints: overall (OS) and progression-free survival (PFS). 930 pts were needed to detect a 25% increase in med OS with D+A (1-sided log-rank, α=0.025, 87% power). Results: 991/1,038 pts were eligible: med age 69, 16% non-white, 61% on BisP, 31% prior prostatectomy, 42% worst pain by BPI ≥ 4, 20% PSA only progression and 56% extraskeletal mets. Multivariate analysis of baseline prognostic factors predicting worse OS were: measurable or evaluable disease progression, high BPI and extraskeletal mets (all p<0.02). No differences in median OS, PFS, or response between arms. Toxicities were similar between arms. Most common toxicities were fatigue, dyspnea, neutropenia and anemia. Addition of A trended to worse OS in pts with visceral mets (HR=1.13 p=0.21) and better OS in those without: bone only (HR=0.86, p=0.20). 357 pts continued A or P up to 52 weeks, no OS difference was seen post-chemo for this subset (p=0.92). Conclusions: This phase III study found no benefit for the addition of A to D in CRPC. Unless specific biomarkers can stratify a population for benefit, endothelin modulators have limited future use in advanced CRPC. Further analyses will test putative surrogacy effects of PSA, serum bone markers and circulating tumor cell kinetics for OS. [Table: see text]

Temsirolimus (TEM) maintenance therapy after response of castration-resistant prostate cancer (CRPC) to docetaxel (TAX).

e15177^ Background: There are no standard treatments for men who have demonstrated a good response to TAX without signs of progression. The mTOR pathway is involved in many aspects of CRPC, and mTOR inhibitors have shown significant anti-CRPC activity in preclinical testing. Therefore, we designed a phase II trial to explore whether maintenance therapy with TEM has the potential to prolong response to TAX without compromising quality of life. Methods: For this single-arm, multicenter phase II trial we recruited CRPC pts with documented treatment response by PSA (> 50% decline from baseline) or RECIST (1.0) criteria following ≥ 6 to 10 cycles of TAX (75 mg/m2 q3wks). Subjects received weekly TEM (25 mg iv x 4/cycle). The primary endpoint was time to treatment failure (TTF; RECIST or symptomatic progression). Secondary endpoints included safety (NCI-CTCAE v3.0), quality of life (FACT-P, PPI), changes in PSA, objective tumor response rate, and overall survival. We were also studying surrogate markers of TEM activity, including the enumeration of circulating endothelial cells (CEC) as a potential indicator of the antiangiogenic effects of TEM. Results: 19 pts have been enrolled to data after a median of 7 cycles of TAX. The mean age was 68 years (range 51-82), and the median baseline PSA 17.3 (0.02-380.7). 15 pts had received prior local radiation therapy, 6 surgery. 17 pts had bone metastases, 9 visceral and 8 nodal disease. Pts received a median of 4 cycles of TEM (maximum 23 and continuing), resulting in a median TTF of 5.8 (95%CI 3.8-9.2) months. No PSA responses were seen (time to PSA progression 1.8 months), but 1 PR. 8 pts achieved SD. 12 pts have been discontinued due to treatment failure (RECIST [4], symptomatic [7], combined [1]), and 3 for other reasons, including TEM-associated toxicity (lymphedema [1]). TEM has been generally well tolerated without unexpected adverse events or negative impact on quality of life. The median overall survival has not yet been reached. There is a trend for TEM to reduce viable CEC amid large inter/intrapatient CEC variability. Conclusions: TEM maintenance therapy in CRPC pts that have responded to TAX appears to be well tolerated and results in meaningful prolonged TTF.

SWOG 0421: Prognostic and predictive value of bone metabolism biomarkers (BMB) in castration resistant prostate cancer (CRPC) patients (pts) with skeletal metastases treated with docetaxel (DOC) with or without atrasentan (ATR).

4547 Background: S0421, a phase III study of DOC +/- the endothelin antagonist ATR in CRPC pts with bone metastases, showed no overall survival (OS) benefit for DOC+ATR. While BMB may have a prognostic role in CRPC, their predictive role vis a vis bone-targeted therapy such as ATR is unknown. We prospectively assessed pre-treatment serum BMB from S0421 pts to validate their prognostic and predictive value. Methods: BMB for resorption (N-telopeptide, NTX and Pyridinoline, PYD) and formation (C-terminal collagen propeptide, CICP and bone alkaline phosphatase, BAP) were assayed [Quidel (PYD, CICP, BAP) and Wampole (NTX)]. Cox regression models for OS based on BMB adjusted for clinical variables were developed. An adjusted Cox model was fit with main effects and BMB x Treatment interaction to assess predictive value of ATR on OS. Results: Of 1,038 pts, 855 (82%) submitted baseline serum: 778 (91%) were usable and analyzable. Pt characteristics: median age = 69 years; PS 0-1 = 91%, Bisphosphonate use = 61%; Gleason >7 = 56%; median PSA = 68; and bone mets only = 45%. BMB values (median; range): NTX (14 nM; 9.3-23.9), BAP (64.7 u/L; 35-164), CICP (9.5 ng/mL; 6.5-17.4), and PYD (2.8 nmol/L; 2.2-3.9). Table below shows prognostic role of BMB. Pts with very high BMB (upper 25 %ile, n=47) not only have poor prognosis (HR = 4.3, p<0.001) but have OS benefit from ATR (HR=0.34, median OS = 13.6 vs. 6.7 months; interaction p=0.002**). Conclusions: S0421 validates the strong independent OS prognostic value of BMB in CRPC. Very high BMB levels appear to be significantly predictive of OS benefit with ATR. Further study of endothelin antagonists in CRPC should focus on this high-risk pt subset. (5R01-CA120469) [Table: see text]

Phase I clinical trial of galeterone (TOK-001), a multifunctional antiandrogen and CYP17 inhibitor in castration resistant prostate cancer (CRPC).

4665 Background: Galeterone is an oral steroid analog that suppresses prostate cancer growth by inhibiting CYP17, blocking androgen receptor and reducing androgen receptor levels. Methods: Open label, multicenter dose-finding study assessing the safety, pharmacokinetics and clinical effect of escalating doses of galeterone in chemotherapy naïve CRPC patients (pts). Pts were enrolled in cohorts from 650-2,600mg of galeterone daily for 12 wks. Study also explored effects of food supplement and scheduling. Pts remained on study until disease progression or dose limiting toxicity. Results: Pt characteristics included median age 69 (47-92), median PSA 24 (6-200), and 46.9% with metastases. 36 of 49 pts completed 12 wks of study with early discontinuation for toxicity (6), progression (5), or withdrawal of consent (2). Maximal tolerated dose was not reached. The frequency of AEs was 58% grade 1, 30% grade 2, 8% grade 3 and 1% grade 4. Transient LFT elevations were seen in 15 men (5 with suspected or confirmed Gilberts). There was no trend for increasing toxicity with dose escalation and no PK difference in Gilberts pts. 9 SAEs were reported with one considered related to galeterone (rhabdomyolysis with acute renal failure in the context of high dose statin use). Overall 11/49 pts (22%) demonstrated >50% PSA decline and an additional 13/49 (26%) had 30-50% declines. Partial response by RECIST was seen in 2 pts. Consistent with lyase inhibition, increased corticosteroids and suppressed androgens were seen with dose escalation. Analysis of limited plasma collected 4 - 30 hours after dosing showed high interpatient variability with no consistent relationship to dose or time after dosing. Conclusions: Galeterone was well tolerated in CRPC pts and demonstrated clinical activity. Galeterone is being reformulated with additional PK and phase II trials planned. [Table: see text]

Radium-223 chloride (Ra-223) impact on skeletal-related events (SREs) and ECOG performance status (PS) in patients with castration-resistant prostate cancer (CRPC) with bone metastases: Interim results of a phase III trial (ALSYMPCA).

4551 Background: Ra-223, a 1st-in-class alpha-pharmaceutical, targets bone metastases (mets) with high-energy alpha-particles of short range (<100 μm). ALSYMPCA, a phase III, double-blind, randomized, multinational study, compared Ra-223 plus best standard of care (BSC) v placebo (pbo) plus BSC in patients (pts) with bone mets in CRPC. The primary endpoint was OS; secondary endpoints included SREs and ECOG PS. Methods: Eligible pts had progressive, symptomatic CRPC with ≥ 2 bone mets on scintigraphy and no known visceral mets; were receiving BSC; and either previously received docetaxel, were docetaxel ineligible, or refused docetaxel. Pts were randomized 2:1 to 6 injections of Ra‑223 (50 kBq/kg IV) q4 wks or matching pbo and stratified by prior docetaxel use, baseline ALP level, and current bisphosphonate use. Results: 921 pts were randomized from 6/2008-2/2011. In a planned interim analysis (n = 809), Ra-223 significantly improved OS v pbo (median OS 14.0 v 11.2 mo, respectively; two-sided P = .00185; HR = .695; 95% CI, .552-.875).SREs were lower in the Ra-223 v pbo group, and time to 1st SRE was significantly delayed (median time to SRE 13.6 mo v 8.4 mo, respectively; P = .00046; HR = .610; 95% CI, .461-.807). The proportion of pts with ECOG PS deterioration (≥ 2 points) was less in Ra-223 v pbo group at Wk 12 and Wk 24 (4%, 15/389 v 9%, 16/180 and 7%, 16/236 v 12%, 10/83, respectively). Time to ECOG PS deterioration (≥ 2 points) was significantly delayed by Ra-223 v pbo (P = .003; HR = .62; 95% CI, .46-.85). Conclusions: Ra-233 significantly delayed time to 1st SRE and SRE components, notably SCC. Fewer pts in the Ra-223 group had ECOG PS deterioration. Ra-223 improves OS with excellent safety and may provide a new standard of care for CRPC pts with bone mets. [Table: see text]