Citations

303 Background: Small cell (SC) neuroendocrine carcinoma of the prostate has very poor prognosis and does not respond well to androgen receptor (AR)-targeted therapies. Neuroendocrine prostate carcinomas are increasingly recognized to show a spectrum of morphologic changes, and may not always be distinguishable from adenocarcinoma (adeno) based on morphology alone. Here we hypothesize that SC carcinoma harbor a unique gene expression signature that, when measured in primary prostatic adenocarcinoma, may help guide subsequent management. Methods: In total, 617 whole genome expression profiles were retrieved from the Decipher GRID providing gene expression data for 1.4 million markers. 17 morphologically-diagnosed SC carcinoma samples were compared to 32 Gleason 8-10 and 77 Gleason 6 RP adeno samples with no prior treatment and no evidence of metastasis, and this comparison was used to define SC Genomic Fingerprint (SCGFt) through adjusted median fold difference and Wilcoxon test. An additional 493 RP adeno from Mayo Clinic and John Hopkins Hospital were used to evaluate the utility of the SCGFt for predicting outcome. Results: Based on genomic prognostic tests calculated using the Decipher assay including Decipher, Penney and microarray-derived Cell Cycle Progression, SC carcinomas have very poor prognosis compared to high grade adeno. A total of 356 genes defined the SCGFt with 258 gene upregulated in SC and 98 down-regulated. PEG10, HELLS and RB1-loss program are the most overexpressed genes in SC and AR-related genes the most down-regulated. As expected, SC lacked ERG and alternative ETS expression and showed relatively low SPINK1 expression. A median summarization of the 356 genes in SCGFt was used to build a small cell genomic score (SCGS). Evaluating SCGS in RP adeno cohorts showed that patients with high SCGS are at higher risk of developing metastasis after RP in a natural history cohort or after adjuvant hormonal therapy based on Kaplan Meier analysis (both p< 0.001). When restricted to patients with high Decipher scores, SCGS provided independent prognostic information. Conclusions: SC carcinoma has a distinct genomic profile that may be useful for treatment management of patients with adenocarcinoma.

3 Background: Previous reports suggested that AAT when combined with salvage RT following RP in patients may improve prostate cancer control outcomes. Methods: Post-RP patients with pT3pN0 or with pT2pN0 and positive margins who had or developed elevated PSA levels from 0.2 to 4.0 ng/ml were randomized on a phase III, double-blind, trial of RT + placebo (64.8 Gy in 36 fractions of 1.8 Gy) vs. RT + AAT (24 months bicalutamide, 150 mg daily) during and after RT. The primary end-point was overall survival. Trial design required 725 patients and provided 80% power to detect a reduction in death rate by at least 28.5% and a 1-sided significance level of 0.046. Results: From 3/98 to 3/03, 761 eligible patients (median age 65) were randomized to RT + AAT (384) or RT + placebo (377). 248 patients (33%) were pT2pN0 and 513 (67%) were pT3pN0. 671 (88%) had a PSA nadir after RP of < 0.5 ng/ml. 649 (85%) had an entry PSA value of <1.6, 112 patients (15%) had an entry PSA of 1.6-4. Median follow up was 12.6 years. Actuarial overall survival at 10 years was 82% for RT plus AAT and 78% for RT + placebo and a hazard ratio of 0.75 (95% CI: 0.58-0.98) with a 1-sided p value of 0.018 (2-sided p = 0.036). The 12-year incidence of PC central-reviewed deaths were 2.3% for RT + AAT and 7.5% for RT + placebo ( p< 0.001).The cumulative incidence of metastatic PC at 12 years was less in the RT + AAT arm, 14% (51 patients), vs. 23% (83 patients) in the RT + placebo arm (p < 0.001). Subgroup analyses of the relative benefits of the addition of AAT to RT are planned and will be presented. Late grade III and IV toxicity were similar in the AAT and placebo arms. The combined grade III and IV toxicities for RT + AAT and RT + placebo were: bladder 7.0% vs. 6.7%, bowel 2.7% vs. 1.6%. Gynecomastia differed significantly by treatment arm, 70% vs. 11%. Conclusions: 24 months of AAT using 150mg bicalutamide daily during and after salvage RT significantly improved long term overall survival and reduced the incidence of metastatic PC and PC death. Support: NCI grants U10CA21661, U10CA180868, U10CA180822, and U10CA37422 and AstraZeneca. Clinical trial information: NCT00002874.

256 Background: B7-H3 (CD276), part of the B7 superfamily, has been shown to play an immunomodulatory role, however its regulation, receptor and mechanism of action remain unclear. Protein levels of B7-H3 have been previously shown to relate to prostate cancer outcomes and currently, humanized monoclonal antibodies are being developed for clinical use (MGA271, Macrogenics). Here we use genomic expression data to examine the relationship of B7-H3 to prostate cancer outcomes and molecular subtypes. Methods: Prostatectomy tissue from 905 patients were profiled using the Affymetrix HuEx 1.0 ST microarray. Kruskal-Wallis tests were used to identify significant associations of B7-H3 expression with clinico-pathologic variables, and survival analysis were used to evaluate the prognostic value of B7-H3. Pearson’s correlation analyses were also performed to assess the relationship of B7-H3 expression with molecular subtypes and individual transcripts. Androgen receptor (AR) occupancy of promoter regions was derived in silico from chromosomal immune-precipitation (ChIP) data. Results: B7-H3 expression was positively associated with Gleason score (p < 0.01) and tumor stage (p < 0.01). High B7-H3 expression also correlated with the development of metastasis and prostate cancer specific mortality (HR of 3.4 and 2.4 respectively, p < 0.05 for both), but this was not significant on multi-variable analysis. B7-H3 was positively associated with ERG+ disease (n = 670, r = 0.85, p < 0.05) and AR expression (n = 670, r = 0.46, p < 0.001). B7-H3 was found to be one of the most correlated genes with AR (95th percentile) and ChIP analysis revealed AR binding upstream of B7-H3, suggesting potential androgen dependent regulation. Conclusions: B7-H3 expression correlates with high Gleason grade and advanced prostate cancer stage with higher quartiles of expression portending poor oncologic outcomes in two independent prostatectomy cohorts. B7-H3 expression appears to relate to the androgen receptor.

255 Background: The purpose of this study was to identify site-specific recurrence patterns for patients (pts) with biochemical recurrence (BCR) after prostatectomy (RP) using C-11 Choline PET/CT (C11Ch) and 3T pelvic MRI with endorectal coil (pMRI). Methods: Between 2008 and 2006, 2,466 men underwent C11Ch and pMRI for BCR after RP. From this cohort, we identified 261 pts who received no adjuvant or salvage therapy (androgen deprivation or radiation). Suspected radiographic relapse was confirmed by biopsy (46%) or progression/response to treatment in concordance with subsequent rise/decline in PSA (54%). Results: Of the 261 men evaluated, 202 (75%) had positive pMRI, C11Ch or both. Seventy nine (39%), 105 (52%) and 18 (9%) pts had high, intermediate, and low risk CaP, respectively at RP. Median PSA at the time of positive scan was 2.3 ng/mL, with a median time from BCR to radiographic disease identification of 15 months. Of these 202 men, 67 (33%) harbored prostate fossa recurrence only, 44 (22%) had a combination of local and metastatic disease and 91 (45%) had metastatic disease without local recurrence. Forty (20%) pts had pelvic nodal recurrence only and 18 (9%) had perirectal nodal involvement. Median PSA for pts with local only recurrence, distant metastases only, and local + distant disease was 2.3, 2.7 and 2.2 ng/mL, respectively, with a median interval from BCR to positive scan of 16.7, 7.9 and 11 months. Imaging revealed that 33% to 66% of our cohort would have all sites of disease treated by salvage RT depending on the extent of the treatment field Conclusions: C11Ch and pMRI were used to identify recurrence patterns in pts with BCR after RP only. At median PSA of 2.3 ng/ml, our study demonstrates a low rate of local-only recurrence, higher than anticipated frequency of metastatic recurrence with peak frequency within the pelvic lymph nodes, and substantial perirectal recurrences. Despite the high rates of distant recurrences, 2/3 of our cohort had their disease limited to the pelvis and could be potential candidates for local therapies, including salvage radiation.

237 Background: AA/P is an approved treatment for mCRPC but there are no known predictive markers of response or resistance. We conducted a prospective trial to evaluate if Androgen Receptor (AR) & AR-variant (ARV) expression in tissue metastases can predict resistance to AA/P. Methods: mCRPC stage patients (pts) initiating pre-chemo AA/P underwent metastatic site biopsies prior to (pre-AA/P) and after 12 weeks of treatment. Composite progression at 12 weeks, (primary endpoint) was evaluated with PSA, RECIST, bone scan and symptoms (per PCWG2). mRNA expressions of pre-AA/P ARFL, ARV3, ARV7, ARV9, ARV23, ARV45, four cell cycle division genes, Chromogranin-A (CHGA) together with PSA/testosterone levels, Gleason Score (GS) at initial diagnosis; high versus low volume disease; time from starting hormone therapy to mCRPC stage and serum CHGA levels were evaluated using a logistic regression model for predicting resistance at 12 weeks of therapy. A final multivariate model fitted only those factors thought to be clinically relevant or with an entry threshold of p ≤ 0.3 in univariate analysis. Results: Between 6/2013 & 3/2015, 82 pts were enrolled of which 52 had complete mRNA expression & disease assessment data at the12-week time point for analysis. Median age of the cohort was 72.5 yrs (IQR: 68.5-78); median pre-AA/P PSA was 18 ng/ml (IQR: 8.1- 46.6); GS distribution at initial diagnosis for GS 2-6; 7; 8-10 was 11; 14; 27 respectively. Progression was observed in 21/52 pts after 12 weeks. At the univariate level elevated pre-AA/P expression of ARV3 (p = 0.08), ARV7 (p = 0.26), ARV9 (p = 0.04), and cell division cycle gene CDC45 (p = 0.19) along with GS at diagnosis (p = 0.29) met the threshold for inclusion into multivariate analysis. Elevated expression of pre-therapy ARV9 in metastases alone was associated with progression at 12 weeks (OR: 3.9; CI 1.07 – 14.16; C-Index: 0.63). The 12-week biopsy of pts with progression had increased ARV9 mRNA expression compared to pts responding at 12 weeks (p = 0.14). Conclusions: Increased ARV9 mRNA expression in metastases is associated with early resistance to AA/P. This observation will need further validation in comparable datasets. Clinical trial information: NCT #0195364.

213 Background: Daily oral prednisone (P) has been employed for the therapy of mCRPC, alone or in combination regimens. Despite palliative benefits and PSA responses, the overall clinical impact of P is unknown and it may foster resistance mechanisms. We performed a pooled analysis of control arms of randomized trials which either did or did not administer single agent P to evaluate its impact on overall survival (OS) and toxicities. Methods: Individual patient data from control arms ofrandomized trials of post-docetaxel men receiving placebo or P + placebo were eligible for analysis. Patient demographics, survival, and toxicity data were collected. The impact of P on OS and toxicities was investigated in Cox regression models adjusted for known clinical and laboratory prognostic factors. Statistical significance was defined as a p-value < 0.05 and all tests were two-sided. Results: The control arms of 2 randomized phase III trials were available totaling 794 men: the COU-AA-301 trial (n = 394) administered P plus placebo and the CA184-043 trial (n = 400) administered placebo alone. P plus placebo was not significantly associated with OS compared to placebo alone in a multivariable analysis (HR = 0.89 [95% CI 0.72-1.10], p = 0.27). Other factors associated with poor OS were Eastern Cooperative Oncology group (ECOG)-performance status (PS) ≥ 1, Gleason Score ≥ 8, liver metastasis, high PSA, hypoalbuminemia, and elevated LDH.In contrast, CTCAE grade ≥ 3 therapy-related toxicities were significantly increased with P plus placebo compared to placebo alone (HR = 1.48 (1.03-2.13), p = 0.034) in a multivariable analysis. Other baseline factors significantly associated with a higher risk of grade ≥ 3 toxicities were ECOG-PS ≥ 1, hypoalbuminemia and elevated LDH. Conclusions: P plus placebo compared with placebo alone for post-docetaxel men with mCRPC was not associated with extension of OS, but was associated with higher grade ≥ 3 toxicities. With the exception of the use of P in combination with abiraterone, P alone or in combination regimens should be questioned given its unclear palliative benefits and association with increased toxicities.

202 Background: Cabazitaxel and prednisone (Cbz/pred) extend survival in mCRPC patients (pts) following docetaxel and first-line studies comparing Cbz to docetaxel are ongoing. Mito/pred also has anti-tumor activity in mCRPC and a non-overlapping mechanism of action and toxicity profile with Cbz. A multicenter phase 1 trial was initiated to establish the maximally tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of Cbz, Mito, and Pred(CAMP). Methods: Chemotherapy (chemo)-naive pts with mCRPC were enrolled in an accelerated titration design. The primary objective was to determine the MTD and RP2D of CAMP; secondary objectives included PSA response rate and duration of response. Cbz 20 and 25 mg/m2 were evaluated in combination with escalating doses of Mito (starting dose 4 mg/m2), both administered on day 1 of a 21-day cycle. Pred 5 mg BID and pegfilgrastim were given with each cycle. Results: 23 pts were enrolled. The median age was 66 (range 51-78) and the median baseline PSA was 62.5 (range 3-791.2). There were 2 DLTs (sepsis and febrile neutropenia) observed at the dose level of Cbz 25 mg/m2 + Mito 10 mg/m2 (n = 4). There was 1 DLT (febrile neutropenia) observed with Cbz 20 mg/m2 (N = 12), establishing Cbz 20 mg/m2 + Mito 12 mg/m2 as the MTD and RP2D. The most common grade ³ 3 related adverse events were hematologic (neutropenia, n = 9; thrombocytopenia, n = 3; febrile neutropenia, n = 3). The median number of treatment cycles was 7.5 (range 2-16), and 2 pts remain on study. Greater than or equal to 50% maximal PSA declines from baseline were observed in 12 of 19 evaluable pts(63%). The median duration of response has not been reached (range 4.9-10.0+ months). Conclusions: The approved single-agent dose of Mito (12 mg/m2) was safely combined with Cbz 20 mg/m2, a dose with demonstrated activity in mCRPC and potentially less hematologic toxicity than 25 mg/m2. Preliminary efficacy data are encouraging with durable control of disease observed in a subset of pts. Further study of the treatment combination is warranted. Clinical trial information: NCT01594918.

122 Background: We have previously shown baseline prostate atrophy (PA) was independently associated with lower prostate cancer (PC) risk. Beyond PC risk, for those who develop PC it is unclear whether PA is associated with smaller, less aggressive and/or less advanced tumors. Thus, we evaluated whether baseline PA and PA severity in men with initial negative biopsy for PC was associated with PC volume at the 2-year repeat prostate biopsy. Methods: Retrospective analysis of 763 men 50-75 years-old with negative baseline prostate biopsy and positive 2-year repeat biopsy for PC with complete data in the REDUCE study. Presence and severity of PA, and tumor volume were determined by central pathology. The association of PA at baseline biopsies with 2-year repeat biopsy cancer volume variables was evaluated with linear and Poisson regressions and controlling for age, race, body-mass index (BMI), digital rectal exam (DRE), prostate volume, baseline and pre-repeat biopsy prostate-specific antigen (PSA) and treatment arm. Results: PA was detected in 458 (60%) baseline biopsies and was considered mild in 398 (87%) and moderate in 60 (13%) cases. Patients with PA had significantly larger prostates and lower baseline and pre-repeat biopsy PSA (P < 0.01). PA was unrelated to race, BMI, DRE or treatment arm. At 2-year biopsy, men with baseline PA had significantly lower overall mean total tumor volume (2.04µL vs 3.02µL; P = 0.006), mean number of biopsy cores involved (1.79 vs 2.11; P = 0.001), mean percent of cores involved (17.9% vs 21.2%; P = 0.001), average core involvement (0.20µL vs 0.30µL; P = 0.001) and overall mean percent tumor involvement (1.64% vs 2.35%; P = 0.006) than those without PA. The results were virtually unchanged in multivariable analysis (all P < 0.05 except for overall percent tumor involvement where P = 0.061). In the analysis of PA severity, a biological gradient was observed where moderate PA was associated with greater reduction in tumor volume compared to mild PA (data not shown). Conclusions: In a cohort of men with 2-year repeat prostate biopsy positive for PC after a negative baseline biopsy, baseline PA was associated with lower PC volume. These results suggest PA may be associated with less aggressive PC.

12 Background: In 3 published randomized trials, adjuvant radiation therapy (ART) for prostate cancer (PCa) resulted in improved progression free survival. However, the impact on metastases and overall survival is unclear. To date, there have been no published prospective trials examining the impact of salvage radiation therapy (SRT) in this disease state. Hence, we conducted a retrospective, nonrandomized comparative study of ART, SRT, or no radiation following radical prostatectomy (RP) for men with pT3 disease or positive margins (adverse pathologic features, APF). Methods: 422 PCa men treated at 4 institutions with RP and having APF were analyzed with a primary end point of clinical metastasis. ART (n = 111), early SRT (n = 70) and delayed SRT (n = 83) were defined by PSA levels of < 0.2, 0.2 to 0.5, and ≥ 0.5 ng/mL, respectively, prior to RT initiation. Remaining 157 men who did not receive additional therapy prior to metastatic onset formed the no RT arm. Clinical-genomic risk was assessed by CAPRA-S and Decipher. Cox multivariable (MVA) model was used to evaluate the impact of treatment on outcome. Results: During study follow-up, 37 men developed metastasis with a median follow-up of 8 years. Both CAPRA-S and Decipher had independent predictive value on MVA for metastatic outcome (both p < 0.05). On MVA adjusting for clinical-genomic risk, delayed SRT and no RT had an HR of 4.31 (95%CI, 1.20-15.47) and 5.42 (95% CI, 1.59-18.44) for metastasis compared to ART. No significance difference was observed between early SRT and ART (p = 0.28). Men with low to intermediate CAPRA-S and low Decipher have a low rate of metastatic events regardless of treatment selection. In contrast, men with high CAPRA-S and Decipher benefit from ART, however the cumulative incidence of metastasis remains high. Conclusions: The decision as to the timing and need for additional local therapy following RP is nuanced and requires providers and men to balance risks of morbidity with improved oncologic outcomes. This analysis provides the most robust and accurate quantification of risk for these men. Post-RP treatment can be safely avoided for men who are low risk by clinical-genomic risk, whereas those at high risk should favor enrollment in clinical trials.

116 Background: Prostateinflammation is linked with prostate cancer. However, whether prostate inflammation varies by race is unclear. Methods: We analyzed baseline acute and chronic prostate inflammation by race in REDUCE. REDUCE was a 4-year, multicenter, placebo-controlled study where all men received a single, negative prostate biopsy within 6 months prior to enrollment. Among 8,046 men who met the inclusion criteria, we included those with data on baseline biopsy prostate inflammation, acute/chronic or none, determined by central pathology. Logistic regression was used to compare prostate inflammation by race, and models were adjusted for demographic and clinical features. Results: Of the 8,046 men, 7,326 were white (91.1%), 184 (2.3%) black, 132 (1.6%) Asian, 323 (4.0%) Hispanic, and 81(1%) unknown. Seventy eight percent of men had chronic and 15% had acute prostate inflammation. Men with chronic inflammation were older (p<0.001), while men with acute inflammation were younger (p<0.001) compared to men with none prostate inflammation. Both acute and chronic inflammation was associated with lower PSA (all p≤0.0001), smaller prostate volume (all p≤0.0001) and geographic region (all p≤0.006). On crude analysis, compared to whites, Asian men were two times more likely to have acute prostate inflammation (OR=1.92, 95%CI: 1.29-2.85, p=0.001), whereas the associations with Hispanic and black race were not significant (all p≥0.39). However, on multivariable analysis, black men were 36% less likely to have acute prostate inflammation (OR=0.64, 95%CI: 0.41-0.99, p=0.04), whereas the likelihood of having acute prostate inflammation remained high in Asians (OR=1.85, 95%CI: 1.25-2.85, p=0.004). No associations by race were found with chronic prostate inflammation. Conclusions: Given that at the population level, black race is a high risk factor for PC and Asian men have lower risk of PC, these data indicate that the presence of acute inflammation in a negative prostate biopsy could be an indication of future PC risk. Further studies to confirm these findings are needed. Clinical trial information: NCT00056407.