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BACKGROUND: It is hypothesised that cotargeting the androgen receptor (AR) and paracrine androgen biosynthesis with enzalutamide and abiraterone acetate in metastatic castration-resistant prostate cancer (mCRPC) will dissipate adaptive feedback loops observed with either agent alone. OBJECTIVE: To assess the safety, efficacy, androgen signalling/metabolome, and drug-drug interactions (DDIs) of enzalutamide with abiraterone acetate in progressive bone mCRPC (bmCRPC). DESIGN, SETTING, AND PARTICIPANTS: This open-label, single-centre interventional study was conducted in bmCRPC patients. INTERVENTION: Enzalutamide 160 mg and abiraterone acetate 1000 mg once daily; prednisone 5 mg twice daily. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Adverse events (AEs), prostate-specific antigen (PSA) response, progression-free survival (PFS), tumour biomarker/metabolite expression, and C(min) plasma concentrations were evaluated. RESULTS AND LIMITATIONS: Sixty patients were enrolled. Common AEs independent of grade/causality included fatigue (72%), hyperglycaemia (67%), alkaline phosphatase (ALP) elevation (53%), and hot flush (43%). Grade 3 AEs included hypertension (17%), alanine aminotransferase elevation (12%), ALP elevation (5%), and arthralgia (5%). No treatment-related grade 4 AEs or deaths were reported. Median treatment-discontinuation time was 312 d (95% confidence interval [CI] 196.0–483.0). Maximal PSA decline ≥50% and ≥90% occurred in 46 (77%) and 29 (48%) patients, respectively. Median PFS was 251 d (95% CI 147–337). At week 9, median tumour microenvironment androgens, precursors, and nuclear AR expression decreased (p < 0.001). The baseline tumour AR C/N terminal ratio of ≥80% was associated with treatment benefit. At enzalutamide steady state, abiraterone acetate C(min) was ~23% lower (range 14.05–200.5 ng/ml) than when given alone. CONCLUSIONS: Enzalutamide combined with abiraterone acetate has a manageable safety profile, without a meaningful DDI. Both agents are pharmacodynamically active with no feedback. Efficacy findings do not support significant benefit of combined treatment for unselected bmCRPC. PATIENT SUMMARY: This is the first study combining enzalutamide plus abiraterone in bone metastatic castration-resistant prostate cancer. Results show that this combination is safe.

To evaluate the pathologic features after radical prostatectomy to determine if the length of positive surgical margin (PSM) and the highest Gleason grade within the tumor at the PSM could risk stratify patients for biochemical recurrence (BCR). We performed a retrospective, matched, cohort study to identify patients with pathologically organ-confined (pT2) tumors and negative nodes (pN0/Nx), receiving no adjuvant therapy. Specimens underwent single pathologist review. BCR-free survival was estimated using the Kaplan–Meier method and compared between subgroups using two-sided log-rank test. Using Classification and Regression Tree analysis (CART), we identified an optimal cutoff for the PSM length which differentiated risk for BCR. Cox proportional hazards regression models were fit to assess the association between variables and BCR-free survival. Two-hundred PSM patients were matched to 200 patients with negative surgical margins (NSM). Median follow-up was 64 months. 5 year BCR-free survival was 90% (95% CI 84–97%) in the NSM group and 70% (95% CI 63–79%) in the PSM group. There was an increased risk of BCR with any PSM. Multivariable analysis demonstrated an association with length of PSM ( > 1 mm vs. ≤ 1 mm, HR 2.29; 95% CI 1.2–4.5) and having a highest Gleason grade of the cancer focus at the margin ≥ 4 (HR 6.8; 95% CI 1.6–29). We demonstrated that patients with pathologic T2 tumors with PSM > 1 mm or a Gleason grade of tumor focus at the margin ≥ 4 are at elevated risk for BCR. However, this study suggests that patients with pT2 tumors with positive surgical margins have a relatively low risk of biochemical recurrence and adjuvant radiation may be over treating this sub population. The subsets at greatest risk for BCR may benefit from more frequent PSA monitoring to direct salvage therapies.

The Puerto Rican (PR) population is a racially admixed population that has a high prostate cancer (PCa) mortality rate. We hypothesized in this pilot study that West African Ancestry (WAA) was associated with PCa in this heterogeneous (PR) population.A case/case and case/control study was performed. Controls, 207 African American (AA) and 133 PR were defined as men with no PCa, a serum PSA 2.5 ng/mL and a negative rectal examination. Cases were patients with pathological specimens from radical prostatectomies (RP) (291 PR and 200 AA). DNA was extracted from whole blood of controls and from paraffin embedded normal seminal vesicle from the RPs. We assessed the association of PCa and aggressiveness with genetic ancestry using an ancestry informative marker panel (AIMs) and Wilcoxon rank-sum test and the association of PCa and aggressiveness with 15 previously PCa associated SNPs using Chi square test. Gleason Score (GS) and tumor stage (TS) were used to define low risk (GS ≤ 7[3 + 4]), TS ≤ pT2) and high risk (GS≥ 7[4 + 3], TS pT2) PCa. Statistical analyses were done using SAS.No difference in overall percent WAA was found between PR cases and controls. Among PR or AA cases WAA was not associated with disease severity based upon risk group, Gleason score or stage. Among AA controls WAA was significantly higher than in cases. The SNP rs7824364 (chromosome 8q24) PCa risk allele was significantly increased among cases versus controls for both AA (P 0.0001) and PR (P = 0.0001) men. PR men with ≥1 risk allele exhibited a higher percent of WAA (39% vs 29%, P = 0.034).The SNP rs7824364, a local marker of WAA in the 8q24 region was associated with PCa among both AA and PR men and with increased WAA among PR men. This novel relationship of PCA risk loci, WAA with PCa and its phenotype among PR men deserves further study.

Background In the Prostate Cancer Prevention Trial, finasteride selectively suppressed low-grade prostate cancer and significantly reduced the incidence of prostate cancer in men treated with finasteride compared with placebo. However, an apparent increase in high-grade disease was also observed among men randomized to finasteride. We aimed to determine why and hypothesized that there is a grade-dependent response to finasteride. Methods From 2007 to 2012, we randomized dynamically by intranet-accessible software 183 men with localized prostate cancer to receive 5 mg finasteride or placebo daily in a double-blind study during the 4–6 weeks preceding prostatectomy. As the primary end point, the expression of a predefined molecular signature (ERβ, UBE2C, SRD5A2, and VEGF) differentiating high- and low-grade tumors in Gleason grade (GG) 3 areas of finasteride-exposed tumors from those in GG3 areas of placebo-exposed tumors, adjusted for Gleason score (GS) at prostatectomy, was compared. We also determined androgen receptor (AR) levels, Ki-67, and cleaved caspase 3 to evaluate the effects of finasteride on the expression of its downstream target, cell proliferation, and apoptosis, respectively. The expression of these markers was also compared across grades between and within treatment groups. Logistic regression was used to assess the expression of markers. Findings We found that the predetermined molecular signature did not distinguish GG3 from GG4 areas in the placebo group. However, AR expression was significantly lower in the GG4 areas of the finasteride group than in those of the placebo group. Within the finasteride group, AR expression was also lower in GG4 than in GG3 areas, but not significantly. Expression of cleaved caspase 3 was significantly increased in both GG3 and GG4 areas in the finasteride group compared to the placebo group, although it was lower in GG4 than in GG3 areas in both groups. Interpretation We showed that finasteride's effect on apoptosis and AR expression is tumor grade dependent after short-term intervention. This may explain finasteride's selective suppression of low-grade tumors observed in the PCPT., Highlights • We studied 183 men with early prostate cancer receiving 5 mg finasteride or placebo daily for 4–6 weeks preprostatectomy. • Expression of androgen receptor and cleaved caspase 3 was dependent on tumor grade. • Finasteride's demonstrated effects in tissue may explain earlier seminal findings in the Prostate Cancer Prevention Trial. This study advances the fields of prostate cancer biology and prostate cancer treatment because it demonstrates effects of finasteride in prostatectomy tissues that offer an explanation for the mixed results of the 18,882-subject randomized and controlled Prostate Cancer Prevention Trial (PCPT). Initial results showing a 25% reduction in prevalence in prostate cancer in men in the finasteride group while revealing an apparent increase in high-grade disease among those in the same group suggested a grade-associated response to finasteride. The results of this present study indicate finasteride's effects are grade dependent, which may explain the split findings of the PCPT.

The arachidonic acid pathway is important in the development and progression of numerous malignant diseases, including prostate cancer. To more fully evaluate the role of individual cyclooxygenases (COXs), lipoxygenases (LOXs) and their metabolites in prostate cancer, we measured mRNA and protein levels of COXs and LOXs and their arachidonate metabolites in androgen-dependent (LNCaP) and androgen-independent (PC-3 and DU145) prostate cancer cell lines, bone metastasis-derived MDA PCa 2a and MDA PCa 2b cell lines and their corresponding xenograft models, as well as core biopsy specimens of primary prostate cancer and nonneoplastic prostate tissue taken ex vivo after prostatectomy. Relatively high levels of COX-2 mRNA and its product PGE2 were observed only in PC-3 cells and their xenografts. By contrast, levels of the exogenous 12-LOX product 12-HETE were consistently higher in MDA PCa 2b and PC-3 cells and their corresponding xenograft tissues than were those in LNCaP cells. More strikingly, the mean endogenous level of 12-HETE was significantly higher in the primary prostate cancers than in the nonneoplastic prostate tissue (0.094 vs. 0.010 ng/mg protein, respectively; p=0.019). Our results suggest that LOX metabolites such as 12-HETE are critical in prostate cancer progression and that the LOX pathway may be a target for treating and preventing prostate cancer.

5065 Background: Tumor mutational load and neoantigens have been associated with responses to immune checkpoint therapies in patients (pts) with melanoma and lung cancer. We designed a clinical trial (NCT02113657) in advanced PCa to determine whether the induction of antitumor responses by IPI correlate with T cell responses to PCa neoantigens. Methods: All advanced PCa pts enrolled into this study had sufficient DNA/RNA from tumor tissue obtained prior to receiving IPI (3 mg/kg every 21 days for up to 4 doses) for whole-exosome sequencing (WES) and RNA-seq. Results: Twenty-one of 30 pts have been enrolled. Nine (43%) have received all 4 doses of IPI. IPI was discontinued prematurely in 9 pts (43%) due to drug-related toxicities and in 3 (14%) due to disease progression. All 3 of the latter had liver metastases. To date, tumors from 13 pts have been comprehensively analyzed by WES and RNA-seq. The median time from IPI #1 to the next systemic therapy for these pts was 24 weeks (IQR, 18.3 – 54.3). Responders (R) were defined as pts whose time to next systemic therapy was > 24 weeks. The median time to next systemic therapy for R (n = 7, 54%) is 55 weeks (IQR, 52.0 – 89.0; 2 pts with ongoing responses) versus 18 weeks (IQR, 10.5 – 23.0) for non-responders (NR; n = 6, 46%). In an analysis of all 13 pts, including those with liver metastases, tumor mutational load and frequency of expressed non-synonymous mutations were similar for R and NR pts. However, a subset analysis, excluding pts with liver metastases, revealed > 100 total mutations and/or > 10 expressed non-synonymous mutations in 7/7 R versus 1/4 NR. Conclusions: For advanced PCa pts without liver metastases, tumor mutational load may be associated with responses to IPI. Identification of immunodominant neoantigens may lead to the development of personalized vaccines to be combined with immune checkpoint therapies for the effective treatment of pts with PCa. Clinical trial information: NCT02113657.

Focal therapy is currently under investigation as an alternative to salvage radical prostatectomy for locally recurrent prostate cancer after primary radiation therapy. If patients can be selected properly, focal therapy could enable tumor eradication without the morbidity associated with salvage radical prostatectomy. We describe the pathological features of recurrent prostate cancer in salvage radical prostatectomy specimens and the implications of these results for focal therapy.We gathered data on 50 consecutive patients who had recurrence after primary radiation therapy and underwent salvage radical prostatectomy between 1993 and 2008. Preoperatively prostate specific antigen was less than 10 ng/ml in 49 patients (98%) and biopsy Gleason score was 7 or less in 18 (36%). Salvage radical prostatectomy specimens were analyzed for tumor zonal origin, site and volume, Gleason score and pathological stage.Median preoperative prostate specific antigen was 3.4 ng/ml. Pathological stage was T2 in 23 patients (46%). The salvage radical prostatectomy Gleason score was 7 or less in 17 patients (34%) and surgical margins were negative in 43 (86%). A single cancer focus was found in 33 cases (66%) while there was bilateral involvement in 37 (74%). The base and apex were involved in 23 cases (46%) and 37 tumors (74%) were located within 5.0 mm of the urethra. Median tumor volume was 1.27 cm(3) (range 0.05 to 12.96).Prostate cancer recurrence after radiation therapy is often bilateral and involves multiple zones. It is often high grade, bulky and close to the urethra. These findings suggest that planning salvage focal therapy after radiation failure will be difficult.

The objective of this work was to compare the amount of residual periprostatic tissue for radical prostatectomy performed by the partial NS (PNS) technique with that performed by the nerve-sparing (NS) or wide-resection (WR) techniques. Retrospective histomorphologic evaluation of radical prostatectomy specimens (RPSs) from patients undergoing laparoscopic radical prostatectomy (LRP) or robot-assisted radical prostatectomy (RARP) was performed. The posterolateral regions corresponding to the neurovascular bundle in RPSs from 48 patients who had undergone NS, PNS, or WR during LRP (n = 30) or RARP (n = 18) were examined by two pathologists unaware of the technique used. The RPSs were evaluated at the base, mid-gland, and apex. The amount of periprostatic tissue at each site was recorded. Measurements were analyzed by use of a linear mixed model. For both LRP and RARP, each gradation of nerve-preservation was associated with periprostatic tissue, except PNS and WR did not differ for LRP at the apex and base or for RARP at the apex, mid-gland, and base. For LRP, a greater amount of tissue was on the left side of the prostate than on the right at the mid-gland level (P = 0.004) whereas for RARP the opposite was found (P = 0.024). Of 18 separate analyses, 13 were significantly associated. The study is limited by its retrospective design. The amount of periprostatic tissue in the neurovascular bundle area correlates well with the nerve-preservation approach used during LRP and RARP, providing anatomic evidence supporting the PNS approach. We also describe a novel finding of laterality bias at the mid-gland level in LRP and RARP specimens.

103 Background: While three prospective trials have demonstrated benefit from adjuvant radiation (XRT) after radical prostatectomy (RP) in patients with positive surgical margins (PSM), its use varies amongst physicians. Many rely on clinical acumen to determine the optimal strategy for application of XRT post RP. We aim to determine if the length of PSM and highest Gleason grade (GG) of tumor at the PSM (hGGPSM) can be used to identify patients at greatest risk of biochemical failure (BCF) post RP. Methods: A retrospective review of all RP patients at The University of Texas MD Anderson Cancer Center from 2002 to 2010 was performed. After a single pathologist review, patients with organ confined disease (pT2), pathologic N0/Nx and a PSM were included. BCF was defined as 2 sequential PSA values of ≥0.2 or any detectable PSA prompting XRT. Patients receiving adjuvant XRT or with 1, p=0.02). When accounting for hGGPSM, Gl 3 tumors were less likely to experience BF (5 yr BCFFS-96%) regardless of PSM length, while BCFFS for Gl >3 tumors were significantly lower dependent upon length of PSM ( ≤1mm vs >1mm, p=0.03). On multivariable analysis length of PSM (p=0.05) and hGGPSM (p=0.007) remained independent predictors of BCF (Table). Conclusions: Length of PSM and hGGPSM are independent predictors of BCF. These should be considered when evaluating patients for adjuvant XRT and in risk stratifying patients in prospective clinical trials. [Table: see text]