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168 Abstracts

  • Introduction & Objectives

    EPI-506 is a first-in-class, highly specific small molecule inhibitor of the Androgen Receptor (AR) N-Terminal Domain (NTD). Preclinical studies have shown significant activity against both full length AR as well as resistance-related AR species such as AR splice variants, including AR-V7 (associated with resistance to abiraterone and enzalutamide). EPI-506 is expected to be effective in mCRPC driven by canonical and aberrant AR signaling by inhibiting the transcriptional activity of the NTD. Initial clinical development of EPI-506 will target mCRPC with progression after prior enzalutamide and abiraterone. A phase 1/2 trial of EPI-506 is ongoing and represents the first investigation of an AR NTD inhibitor.

    Material & Methods

    This is an ongoing open-label, single-arm, phase 1/2 study evaluating the benefit of EPI-506 at once-daily dosing. The phase 1 portion will establish the safety, Pharmacokinetics (PK) and Maximum Tolerated Dose (MTD) of EPI-506. PSA response at week 12, defined as a ≥ 50% PSA decrease from baseline, and time to PSA progression will also be evaluated. The phase 2 portion of the study will evaluate activity in 3 patient populations: post-enzalutamide mCRPC, post-abiraterone mCRPC, and post -abiraterone and -enzalutamide mCRPC. Inclusion criteria include mCRPC with progression after one or more lines of hormonal therapy, and progression on enzalutamide or abiraterone. Exclusion criteria include hematologic, hepatic or renal insufficiency. Plasma concentrations were measured over 48 hours to assess PK in fasted and fed states. Exploratory endpoints include evaluation of AR splice variants and AR mutations from CTC-based and cfDNA-based methodologies.

    Results

    Data to address the phase 1 primary endpoint of safety and tolerability, as well as secondary endpoints, including PK and PSA response, are currently being collected in this ongoing trial (trial in progress).

    Conclusions

    This clinical study will be the first to evaluate the novel AR NTD inhibitor EPI-506 in men with enzalutamide- and/or abiraterone-resistant mCRPC, and is the first agent with the potential to inhibit both canonical and variant-mediated AR signaling. Clinical trial information: NCT02606123

  • Introduction & Objectives

    The optimal management of pelvic or retroperitoneal nodal Prostate Cancer (PCa) recurrences after primary treatment remains largely undefined. These patients are usually treated in the same way as those with distant metastases by means of Androgen Deprivation Therapy (ADT). We want to report the outcome of Stereotactic Body Radiotherapy (SBRT) for oligorecurrent nodal PCa.

    Material & Methods

    This was a retrospective multicentre analysis of patients diagnosed with 3 metachronous nodal recurrences treated with SBRT. SBRT was defined as a radiotherapy dose of at least 5 Gy per fraction to a Biological Effective Dose (BED) of at least 80 Gy to all metastatic sites. The study was approved by the central ethics committee (EC2014/ 0199). Inclusion criteria were as follows: histologically proven diagnosis of PCa, biochemical relapse of PCa after radical local prostate treatment and the detection of up to three N1 or M1a lesions. Patients were excluded in the case of M1b or M1c lesions, serum testosterone levels 12 months with SBRT, previous pelvic radiotherapy, biochemical relapse while on active treatment with a systmemic agent for PCa.  
    The primary endpoint was Distant Progression-Free Survival (DPFS), defined as the time interval between the first day of SBRT and appearance of new metastatic lesions, outside the high-dose region. Secondary endpoints were local control, time to start of palliative ADT and toxicity scored using the Common Terminology Criteria for Adverse Events v4.0.

    Results

    Overall, 171 metastases were detected (84% with choline PET-CT) and treated with SBRT in 134 patients. The median follow-up from SBRT was 29 mo (IQR: 13-47). Adjuvant ADT was given in 33% of patients for a median duration of 6 mo (IQR: 1-8 mo). The median DPFS was 21 mo (95% CI: 18-24 mo) with 80% of patients having ≤3 metastases at time of progression. The 3-year local progression rate was 41% for patients treated with a BED 100Gy (p<0.001). The median time from first SBRT to the start of palliative ADT was 25 mo (95% CI: 18 – 32). Late grade I and II toxicity was observed in 10% (N=13) and 4% of patients (N=6). No grade 3 toxicity was observed.

    Conclusions

    SBRT for oligometastatic PCa nodal recurrence is safe. The majority of subsequent relapses remain nodal and oligometastatic.

  • Introduction & Objectives

    Radical Prostatectomy (RP) is one major treatment option in prostate cancer. Depending on risk factors, 50-80% of the patients experienced biochemical recurrence (data from the ARO 96-02 trial). After recurrence, Salvage Radiotherapy (SRT) offers a second chance of cure: Around 60% of the patients can re-achieve an undetectable PSA after SRT and approximately 80% of these men are free from recurrence, 5 years later on. European guidelines (EAU) recommend SRT at a PSA <0.5 ng/ml. We analyse the efficacy of SRT given according to this recommendation and investigate the predictive power of the post-SRT PSA nadir.

    Material & Methods

    Between 1998 and 2013, 301 patients of two university hospitals received SRT for post-RP (N0) recurrent prostate cancer at a PSA <0.5 ng/ml. All had 3D-conformal RT (median 66.6 Gy) including 40 cases with IMRT. The median follow-up in this retrospective analysis was 5.9 years (max 13.3). Progression as defined by Stephenson et al. (JCO 2007) and overall survival were the endpoints.

    Results

    After RP, 260 patients achieved a PSA in the undetectable range (<0.1 ng/ml), 41 had a persistent or rising PSA. First recurrence was stated in median 0.9 years after RP (IQR 0.3-1.9). The median time from RP to SRT was 1.6 years (IQR 0.7-2.3). After SRT, 252 patients re-achieved an undetectable PSA, 49 retained higher values. There were 92 second recurrences and 17 patients died. In univariate analysis, the following parameters correlated unfavorably with post-SRT progression: pre-RP PSA ≥10 ng/ml, pT3-4, Gleason score (GLS) 7-10 or 8-10, negative surgical margins (R0), post-RP PSA ≥0.1 ng/ml, pre-SRT PSA ≥0.2 ng/ml and post-SRT PSA nadir ≥0.1 ng/ml. There was no subgroup that did not benefit from SRT at PSA <0.2 ng/ml. In backward excluding Cox regression analysis, pT3-4 (Hazard ration HR=2.29), GLS 7-10 (HR=2.52), negative margins (HR=1.68) and a pre-SRT PSA ≥0.2 ng/ml (HR=1.71) were significant risk factors. If the post-SRT PSA was added to that model, it dominated the outcome (HR=9.00). Of the patients with a pre-SRT PSA <0.2 ng/ml, only 9% failed re-achieving an undetectable PSA; with a higher pre-SRT PSA, 24% did so. This difference also had an impact on overall survival which was 98% vs. 91% after 5.9 years (Logrank p=0.004) favoring men with a post-SRT PSA <0.1 ng/ml.

    Conclusions

    SRT at a PSA <0.2 ng/ml correlates significantly with achieving a post-SRT undetectable PSA (<0.1 ng/ml) and subsequently with improved freedom from progression. In patients who had SRT at a PSA <0.5 ng/ml, an undetectable post-SRT PSA-nadir was the strongest predictor of freedom from progression and overall survival. The nadir may help to identify patients, who can benefit from additional systemic treatment. The recommended PSA cut-off for SRT should be reconsidered.

  • Introduction & Objectives

    71-85% Castrate Resistant Prostate Cancer (CRPC) patients revealed Neuroendocrine Differentiation (NED) of tumor tissue. The most valuable serum NED marker is Chromogranin A (CgA), the sensitivity of which reaches 60-70%. According to our data 34% of CRPC patients revealed increase in CgA serum level (more than 3 nmol/l), which is probably caused by NED development on the background of a long-term hormonal treatment. Based on these data, the evaluation study of CgA serum prognostic role in pathogenetically based somatostatin analogues (octreotide depo) CRPC patients treatment looks promising.

    Material & Methods

    The study includes 49 men with CRPC (T3-4N0-1M1), who were divided in 2 groups. Group I included 21 patients with elevated level of CgA › 3 nmol/l, Group II – 28 patients with normal CgA level. Combination therapy included octreotide depo 20-30 mg once every 28 days with dexamethasone in a dose of 4 mg per day for one month. Further on dexamethasone was administered in a dose of 2 mg per day for 2 weeks, after which the dose was reduced to 1 mg per day (maintenance dose). All patients were also prescribed with GnRH analogues, except those after surgical castration. In course of treatment all patients were CgA and PSA tested.

    Results

    Significant difference was revealed between the groups with number of patients in PSA decrease > 25% and > 50%. In Group I PSA progression was detected in 6 (29%) patients, and median time to PSA progression made 6 months. In Group II PSA progression was detected in 18 patients (64%), median time to PSA progression was 3.5 months (figure below). The difference between groups is statistically significant (p<0.05).

    Groups Number of patients Initial CgA level(nmol/l) in groups PSA Median time to PSA progression (TTPP) in groups (months)
    ↓PSA ≥25% ↓PSA≥50% PSA↑
    I (CgA↑) 21 5,9 15(71%) 11(52%) 6(29%) 6,0 (p<0,05)
    II
    (CgA N)
    28 1,6 10(36%) 4(14%) 18(64%) 3,5

    Conclusions

    CgA level is a valuable factor for effectiveness prognosis of somatostatin analogues  treatment in CRPC patients. The elevating initial CgA level showed decrease PSA >25% in 71% of octreotide depo treatments. This work was initiated and carried out by its authors without any sponsorship.

  • Introduction & Objectives

    Non-Muscle Invasive Bladder Cancer (NMIBC) accounts for 75% of all bladder cancer cases and it’s treated by Transurethral Resection of Bladder Tumor (TUR-BT) and intravesical treatments. However, the exact surveillance protocol and treatment regime vary among countries. Major guidelines support the role of repeat resection within 4–6 weeks after initial resection in cases of incomplete resection and in cases of high grade pTa and pT1 bladder tumor where detrusor muscle was not present. The tumor is often understaged by primary resection. The likelihood that muscle invasive disease is found by second resection of initially T1 tumour varies between 4% and 25%, and it rises to 45% if there is no muscle included in the initial resection. It has been seen that a repeat TUR-BT(Re-TUR) can increase recurrence-free survival, improve outcomes after BCG treatment, and provide prognostic information. Purpose: In this retrospective study, it is aimed to indicate the necessity of repeat transuretral resection of bladder in non-muscle invasive bladder cancer.

    Material & Methods

    51 patients with non-muscle invasive bladder tumor (Ta-T1) undergoing TUR-BT and second TUR-BT 4-6 weeks after the initial resection were included in the study. Re-TUR was performed to the scar of the first resection and other suspicious lesions in the bladder.

    Results

    From January 2012 to June 2016, 51 patients were included in the study. Operations were performed by 5 urologists who work in the same clinic. Mean age was 65. At the first TUR-BT, 15 (29%) patients had multiple lesions and 36 (71%) had a solitary tumor. 28 (54%) of initial TUR-B’s were radiologically bigger than 3 cm whereas 23 (46%) of them were smaller than 3 cm. Re-TUR revealed histological residual tumors in 22 (43%) patients. Residual tumor ratio was 46% in patients with a tumor bigger than 3 cm in initial TUR-BT while the ratio was 39% in patients with a smaller tumor. While T1 bladder cancer was found in 34 of patients who underwent initial TUR-BT, residual tumor was detected in 17 (50%) of them in Re-TUR. This ratio was 29% in patients who had Ta bladder cancer in initial TUR and underwent Re-TUR. T2 bladder cancer was found in Re-TUR operations of 4 (11%) of 24 patients who were diagnosed with T1 bladder ca in initial TUR-BT and this indicates the importance of Re-TUR.

    Conclusions

    Residual tumor may remain after initial TUR-BT performed to Ta High grade and T1 bladder cancer patients and this indicates the need for  Re-TUR. As it is demonstrated in our study of 51 patients  the need of Re-TUR for patients with T1 grade in initial TUR-BT is more significant. Muscle invasive bladder cancer after Re-TUR is seen in 11% of patients who have T1 bladder cancer in initial TUR-BT. Downstaging is seen in initial TUR-BT and this shows the significance of Re-TUR.

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