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74 Background: Understanding the lethal nature of high risk prostate cancer, there is a need for the development of multimodal therapies. Prior studies have confirmed a survival benefit with the addition of docetaxel to androgen deprivation therapy (ADT) in men with metastatic hormone-sensitive prostate cancer (HSPC). We conducted a Phase II trial enrolling men with very high risk localized, locally advanced or oligometastatic prostate cancer (PC) to examine resistance and response to neoadjuvant chemohormonal therapy. This analysis aims to identify the preoperative predictors of biochemical recurrence (BCR). Methods: UW17009 is an IRB-approved open-label, single-arm trial that recruited 26 men with newly diagnosed advanced PC. Patients received ADT and docetaxel for 3 months followed by prostatectomy. The primary endpoint was pathologic complete response rate. A secondary clinical objective was the rate of PSA recurrence 12 months after surgery. The pre-trial PSAs, age, cancer grade, stage, percent tumor involvement of the initial biopsy, metastatic disease on conventional and 18F-DCFPyL PSMA (DCFPyL) PET/CT and MRI imaging, completion of chemohormonal therapy and PSA nadirs following chemohormonal therapy were assessed in relationship to biochemical recurrence. One way ANOVA was used to evaluate differences among continuous values: age, PSA at diagnosis, percent tumor involvement, and PSA nadir after chemo ADT. Fisher’s exact tests were used to evaluate the differences among categorical variables: stage at diagnosis, positive bone scan, and positive PSMA PET. Results: 26 patients were enrolled and underwent neoadjuvant treatment, radical prostatectomy (RP) and lymph node dissection. The median age was 62 (IQR 58-66), mean PSA at diagnosis was 32.8 ng/dl and 88.4% had Gleason 9 cancer. At study initiation, 12/26 patients had metastatic disease detected by DCFPyL-based PSMA PET. Final pathology demonstrated 81%(21/26) had ≥ pT3 and 73%(19/26) patients had negative margins. Positive lymph nodes were found in 10/26(38.5%) patients on final pathology. At week 6 after surgery, 91%(24/26) had undetectable PSA. At a mean follow up of 12.1 months(5.2-21.4), the biochemical recurrence rate is 58%(15/26). Features associated with BCR include stage, % tumor involvement, and positive PSMA PET scan. All patients with positive margins and 9/10 patients with positive nodes at final pathology developed BCR at a mean follow up of 12 months. Conclusions: In this neoadjuvant cohort, stage T2c, elevated PSA, positive pre-operative PSMA PET/CT, and PSA nadir > 1 following chemohormonal therapy predict biochemical recurrence. Clinically, and in the short term, neoadjuvant chemohormonal therapy prior to definitive surgery for very high risk localized and/or oligometastatic PC generates local tumor control with a high rate of negative surgical margins.

285 Background: Due to its high prevalence and often indolent natural history, prostate cancer(PC) active surveillance(AS) is an ideal setting for chemoprevention. Studies assessing pomegranate and its extracts have shown promising anti-proliferative and pro-apoptotic effects in cell lines and animal models and a single-arm clinical trial of pomegranate fruit extract(PFE) reported an increase in PSA doubling time(PSADT) during AS. The primary objective of this trial was to assess the effect of PFE supplementation on plasma levels of Insulin-like Growth Factor-1(IGF-1). Secondary objectives addressed PSA doubling time(PSADT), tumor volume on end-of-study(EOS) biopsy and plasma and prostate tissue biomarkers. Methods: Men with organ-confined favorable-risk PC on AS were randomly assigned to receive PFE 1,000 mg(n=15) or placebo(n=15) once daily for twelve months. Prostate biopsies were performed at study entry and upon completion of the one-year intervention. Tissue biomarkers were assessed by immunohistochemistry(IHC) with automated quantitation. Results: PFE was well-tolerated with no significant toxicities. One patient withdrew before study initiation and 29 completed the one-year intervention. No differences in plasma IGF-1 levels(p=0.5), PSADT, or tissue biomarkers of apoptosis or proliferation were observed. A significant increase in urolithin A(a urinary metabolite of pomegranate) was observed in the PFE arm. IHC analyses of both tumor (Table) and normal-appearing tissue adjacent to tumor showed reductions from baseline in IGF-1, 8-OHdG(DNA damage marker), and androgen receptor expression associated with PFE treatment. A trend towards a reduction in the maximum percent of biopsy core tumor involvement was observed(p=0.06) in PFE. Conclusions: PFE administration for 12-months was not associated with a decrease in plasma IGF-1 levels nor an increase in PSADT. However, exploratory analyses suggest that PFE may contain bioactive compounds capable of altering biomarkers in PC and normal-appearing adjacent tissue providing a rationale for further investigation of PFE in the active surveillance population.

334 Background: Previous studies have shown that addition of docetaxel to androgen deprivation therapy (ADT) significantly improves progression-free survival (PFS) and overall survival (OS) in men with metastatic hormone-sensitive PC. Removal of the primary may also improve outcomes by reducing tumor self-seeding. We are conducting a phase II trial in men with PC to examine the feasibility of NAC, response using PSMA PET/MRI imaging and molecular mechanisms of resistance. Methods: This is an open-label, single-arm trial. Thirty patients with newly diagnosed very high risk localized, locally advanced or oligometastatic PC will receive ADT/docetaxel for three cycles before prostatectomy. The primary endpoint is rate of complete pathologic response. Key secondary objectives include PSA recurrence at month 12 after surgery. Exploratory objectives include tumor response and response heterogeneity in primary and metastatic tumors before and after treatment assessed by PSMA PET/MRI and evaluation of gene expression signatures in cancer cells, prostate stroma, bone marrow microenvironment and circulating tumor cells. Results: To date, 26 of 30 patients have enrolled and completed treatment. Mean age was 61 and mean PSA at time of diagnosis was 32.1 ng/dl. All patients had multi-focal prostate cancer with 23/26 patients with Gleason Grade Group 5. Metastatic disease by conventional imaging was identified in 6/26 patients (5 in lymph nodes [LN] and bone, 1 in LN only). Treatment was overall well tolerated. All patients had multi-focal primary prostate cancer detected on PSMA PET/MRI. All patients had a decline in PSMA PET SUVmax in at least one intraprostatic lesion. Two patients had an increase in SUVmax in at least one intraprostatic lesion that correlated with a resistant tumor focus on histopathology. Conclusions: NAC prior to surgery generates high rates of local tumor control with a heterogeneous response between foci. Primary resistance, identified by increasing PSMA PET SUVmax, is uncommon, however incomplete responses were observed in nearly all patients, suggesting that more cycles of treatment would improve response. PSMA PET/MRI can be used to monitor response and resistance in PC. Clinical trial information: NCT03358563.

5020 Background: The HSD3B1(1245A > C) variant allele, whose frequency varies by race, encodes a missense sequence that stabilizes the rate-limiting enzyme responsible for extragonadal androgen synthesis, thus enhancing intratumoral dihydrotestosterone (DHT) synthesis. Multiple retrospective studies have found that men inheriting the HSD3B1(1245C) variant allele exhibit early resistance to ADT. We sought to validate these findings with prospective data from the Chemohormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED). Methods: Men with newly metastatic PCa were randomized to receive either ADT plus docetaxel at a dose of 75 mg/m2 every 3 weeks for 6 cycles (arm A) or ADT alone (arm B). We determined germline HSD3B1 genotype in the subset of men with LV disease ( < 4 bone metastases, no visceral metastases). We analyzed freedom from castration-resistant prostate cancer (CRPC) and OS according to HSD3B1 genotype using Cox and Kaplan-Meier methods. Results: 197 patients with LV disease had blood samples available and were genotyped, including 97 in arm A and 100 in arm B. Docetaxel did not improve OS of LV men. Of the 197 men, 47% were homozygous wild-type (WT), 43% were heterozygous, and 10% were homozygous variant. When all 197 men were analyzed as one goup, the median time to CRPC was 39.7 mos. in homozygous WT men vs. 25.0 mos. in men with one or more copies of the variant allele (HR 1.27, 95% CI 0.89 to 1.82; p = 0.187). Although OS data are still maturing, at 52 months OS was 83% (95% CI 75% to 91%) in homozygous WT men vs. 64% (95% CI 55% to 74%) in men with one or more variant alleles. There was a suggestion that docetaxel delayed development of CRPC among men with at least 1 variant allele (20.3 vs. 40.7 mos.; HR 0.66, 95% CI 0.40 to 1.04; p = 0.08). Benefit for men with high-volume disease was not evident. Conclusions: Inheritance of the HSD3B1(1245C) allele that augments DHT synthesis may be associated with lower OS in men treated with ADT with or without docetaxel for LV newly metastatic PCa. Additional study is warranted in patients with LV disease. Clinical trial information: NCT00309985.

5046Background: Recent data has highlighted the high frequency with which metastatic prostate cancer can progress either radiographically or symptomatically without a rise in PSA, so called PSA-Cli...

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

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

5004Background: Androgen deprivation therapy plus docetaxel (ADT+D) for metastatic hormone sensitive prostate cancer (mHSPC) improves overall survival over ADT. However, docetaxel’s adverse event p...

286 Background: Docetaxel concurrent with androgen deprivation (ADT) for metastatic hormone sensitive prostate cancer (mHSPC) improves overall survival over ADT alone. However, docetaxel as a cytotoxic has an adverse event profile that can diminish QOL. Methods: Patients were randomized to ADT plus 6 cycles of docetaxel every 3 weeks (Arm A, N = 397) or ADT alone (Arm B, N = 393). Validated QOL instruments for PrCa and docetaxel including Functional Assessment of Cancer Therapy (FACT)–Prostate were administered at baseline and 3, 6, 9 and 12 months (mos.) after randomization. Paired t-tests were used to examine QOL changes over time. A mixed effect model compared QOL between arms at each time point (Table). Results: 790 patients were randomized and QOL completed for Arm A and B (91% and 88%, baseline; 87% and 80%, 3 mos.; and 70% and 67%, 12 mos.). Patients in Arm A (ADT + docetaxel) reported -2.7 [Standard Error (SE) 0.9] decline in FACT-P at 3 mos. (p = 0.003), but did not differ significantly from baseline at 12 mos. (-0.7, SE 1.1). In contrast, patients in Arm B (ADT alone), did not differ significantly at 3 mos. [-1.1 (SE: 1.0)], but reported a significant decline [-4.2 (SE: 1.1); p = 0.0001] from baseline to 12 mos. FACT-P scores differed significantly between Arm A and B at 3 mos. (p = 0.02) and 12 mos. (0.04), with Arm A lower at 3 mos. and higher at 12 mos. Conclusions: Docetaxel is associated with decreased QOL on treatment (at 3 mos.) not seen with ADT alone. However, 12 mos. QOL was better for the patients who had docetaxel versus ADT alone, returning to baseline. This suggests that docetaxel + ADT does not confer long-term negative impact on QOL for mHSPC. Clinical trial information: NCT00309985. [Table: see text]