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Intermediate-term outcome after PSMA-PET guided high-dose radiotherapy of recurrent high-risk prostate cancer patients

BackgroundBy the use of PSMA positron emission tomography (PET) detection of prostate cancer lesions with a high sensitivity and specificity combined with a favorable lesion to background contrast is feasible. Therefore, PSMA-PET is increasingly used for planning of radiotherapy treatment; however, any data on intermediate-term outcome is missing so far.MethodsPatients with high-risk or very high risk prostate cancer, referred for salvage radiotherapy (SRT, n = 22) between 2013 and 2015, underwent PSMA-PET prior to therapy. Irradiation was planned on PET data with boost to macroscopic tumors/metastases. Treatment related toxicity was measured using Common Terminology Criteria for Adverse Events (CTCAE, v4.0).ResultFindings in PSMA-PET led to treatment modifications in 77% of SRT patients compared to available CT information. One patient did not receive irradiation due to disseminated disease, the other patients received increased boost doses to macroscopic disease and/or inclusion of additional target volumes. Toxicity was low as only 2 patients reported toxicities > grade 1. With a Median follow-up time of 29 in patients that were not lost to follow-up, prolonged PSA responses below baseline were observed in the majority of patients (14 of 20). In hormone-naïve SRT patients (n = 11), radiotherapy led to prolonged PSA decrease in 8/11 patients, however with 3 of these 8 patients receiving repeated PSMA based irradiation of novel lesions during follow-up.ConclusionPSMA-PET guided planning of radiotherapy led to change of treatment in the majority of patients. Treatment related toxicity was well tolerated and promising results regarding intermediate-term PSA decrease were observed.Trial registrationNo trial registration was performed due to retrospective evaluation.

Long-term oncologic outcomes of localized high-risk prostate cancer undergoing brachytherapy combined with external-beam radiation therapy and maximal androgen blockade

Objective: To investigate the oncologic outcome and PSA kinetics of localized high-risk prostate cancer (PCa) patients treated with combination strategy of radiation therapy (RT) and maximal androgen blockade (MAB). Methods: We retrospectively reviewed the clinical data of 320 localized PCa patients undergoing RT+ MAB from 2001 to 2015. And radiation treatment protocol consisted of permanent prostate brachytherapy (PPB) at 110 Gy and EBRT at 45 Gy/23 fractions. Results: The median follow-up time was 90 (range: 12-186) months. And 117 (36.6%) cases underwent MAB + external-beam radiotherapy (EBRT), and other 203 (63.4%) cases received MAB+ EBRT+ PPB. Multivariate Cox regression analyses showed that PSA kinetics were positive indicators of oncologic outcomes. Furthermore, PSA kinetics were aberrantly improved by supplemental PPB to MAB+ EBRT as following, PSA nadir (1.3±0.7)μg/L vs(0.11±0.06)μg/L, time of PSA decrease to nadir (7.5±1.8)months vs (3.2±2.1)months, PSA doubling time (15.6±4.2)months vs (22.6±6.1)months, PSA decreasing amplitude (84.6±6.2)%vs(95.8±3.4)%. Additionally, the median time of several important oncologic events in MAB+ EBRT+ PPB group were also prolonged than that in MAB+ EBRT group as following, overall survival (12.3 years vs 9.1 years, P<0.001), biochemical recurrence-free survival (9.8 years vs 6.5 years, P<0.001), skeletal-related event (10.4years vs 8.2 years, P<0.001), and cytotoxic chemotherapy (11.6 years vs 8.8 years, P=0.007). Conclusion: MAB+ EBRT+ PPB is extremely effective combination strategy for localized high-risk PCa patients, and PPB plays the important synergistic role in improving PSA kinetics, which are independent predictor for oncologic outcomes.

Abstract CT103: A phase II study to evaluate outpatient magnetic resonance image-guided laser focal therapy for prostate cancer: A 20-year survival study (seven-year interim results)

Abstract Purpose: In the United States alone, new prostate cancer cases for 2016 were estimated at 180,890 and deaths at 26,120. Focal therapies for low risk and intermediate risk localized prostate cancer are increasingly being explored. Additionally, new treatments for patients with biochemical recurrence of prostate cancer are also under investigation. Our objective is to investigate the safety and feasibility of using outpatient MR-guided laser focal therapy for MR visible prostate cancer utilizing a transrectal approach for laser applicator placement and therapy delivery in an outpatient setting. Method and Materials: All MRI-guided therapy was delivered using a 1.5 Tesla MRI system for both image acquisition and real-time thermometry. Commercially available hardware and software were used for image analysis and interventional planning. Laser therapy was delivered using a 15W, 980 nm diode laser applicator with fiber-cooling catheter introduced transrectally using a commercially available MRI-compatible introducer system. Results: 80 men were treated. 112 cancer foci were treated. Total procedure time was between 1.5 and four hours MRI volume of coagulation necrosis ranged from 0.57 to 22.93 cc. No serious adverse events or morbidity were reported. 17 treatment regions were positive at six months biopsy, consistent with residual or recurrent cancer 26% of subjects 18% of treated regions.We observed a 40% decrease in mean PSA at 1 year post therapy and no statistically significant change in IPSS and SHIM scores at 6 months post-treatment. Conclusion: Our data indicate that outpatient, transrectally delivered MRI-guided laser focal therapy for prostate cancer is both safe and feasible. Clinical Relevance/Application: In the current climate of cost-reduction and emphasis on minimally-invasive treatment of cancer, focal treatment of prostate cancer may be an attractive option. The precise energy delivery under MRI-guidance may have favorable results for cost control and quality of life without eliminating the possibility of whole-gland treatment in the patient’s future. Citation Format: Bernadette Marie Greenwood, John F. Feller, Stuart T. May, Wes Jones, Axel Winkel. A phase II study to evaluate outpatient magnetic resonance image-guided laser focal therapy for prostate cancer: A 20-year survival study (seven-year interim results) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT103. doi:10.1158/1538-7445.AM2017-CT103

Salvage robotic SBRT for local prostate cancer recurrence after radiotherapy: preliminary results of the Oscar Lambret Center

BackgroundCurrently, there is no standard option for local salvage treatment for local prostate cancer recurrence after radiotherapy. Our objective was to investigate the feasibility and efficiency of Robotic Stereotactic Body Radiation Therapy (SBRT) in this clinical setting.Methods/materialsWe retrospectively reviewed patients who were treated at our institution with SBRT for local prostate cancer recurrence after External Beam Radiation Therapy (EBRT) or brachytherapy.Multidisciplinary staff approved the treatment, and recurrence was biopsy-proven when feasible. A dose of 36 Gy was prescribed in six fractions. Treatment was delivered every other day.ResultsBetween August 2011 and February 2014, 23 patients were treated with SBRT for intra-prostate cancer recurrence with a median follow up of 22 months (6 to 40).Twenty patients had biopsy-proven recurrence.For 19 patients, EBRT was the initial treatment and in four patients, brachytherapy was the initial treatment; the median relapse-time from initial treatment was 65 months (28 to 150).At relapse, 10 patients had an extra-capsular extension.Fourteen patients were treated with androgen deprivation that could be stopped after a median of 1 month after SBRT (range 0–24).A PSA decrease occurred in 82.6% of the patients after SBRT.The 2-year disease-free survival and overall survival rates were 54 and 100%, respectively.Disease progression was observed for nine patients (39.1%) (five local, three metastatic and one nodal progression) after a median of 20 months (7–40 months).The median nadir PSA was 0.35 ng/ml and was achieved after a median of 8 months (1 to 30) after treatment.We observed no grade 4 or 5 toxicity. Two patients presented with grade 3 toxicities (two Cystitis and one neuralgia). Other toxicities included urinary toxicities (five grade 2 and nine grade 1) and rectal toxicities (two grade 2 and two grade 1).ConclusionSBRT for local prostate cancer recurrence seems feasible and well tolerated with a short follow up. Prospective evaluation is needed.

Evaluating the impact of bone-targeted agents in the era of novel androgen targeted therapy for metastatic castration-resistant prostate cancer.

e16500 Background: Patients with metastatic castrate resistant prostate cancer (mCRPC) often develop bone metastases, resulting in a risk of symptomatic skeletal events (SSE). Bone-targeted agent (BTA) has been integrated into the overall treatment strategy, but its role in the era of novel androgen-targeted therapy (ATT) is still unclear. Methods: A retrospective analysis of real-world practice from 2010 to 2015 was conducted. Patients diagnosed with mCRPC and bone metastases who received systemic therapy (docetaxel/abiraterone/enzalutamide) with or without BTA (zoledronic acid/denosumab/alendronate) were included. Results: We obtained data from 299 patients with a median follow-up of 75.5 months. Compared with no BTA, concomitant BTA was associated with decreased incident of SSE (3.8% vs. 19.2%, p&lt; 0.001), especially in the need for bone radiation (1.9% vs. 15.8%, p&lt; 0.001). Compared to patients without SSE, patients with SSE were more likely to have previous fracture history (10.8% vs. 9.7%, p= 0.047), steroid use history (2.4% vs. 1.4%, p= 0.019), smoking history (53.0% vs. 38.9%, p= 0.009), diabetes (19.3% vs. 8.8%, p= 0.012) and reduced baseline mobility (9.6% vs. 4.2%, p= 0.002). Among those who received first-line novel ATT (n = 152), concurrent ATT+BTA significantly decreased the incident of SSE (2.8% vs. 27.3%, p= 0.004) and prolonged the time to SSE (24.3 vs. 3.2 mo, p&lt; 0.001), when compared to ATT alone. But there was no difference in overall survival between two groups (134.2 vs. 138.9 mo, p= 0.99). In patients who responded to systemic treatment with PSA declining, the SSE rate (2.4% vs. 14.3%, p= 0.037) was lower and the time to SSE was longer (49.6 vs. 32.3 mo, p= 0.026) than those who did not respond. Smoking history (adjusted HR = 1.46, p= 0.013) and PSA response (adjusted HR = 0.19, p&lt; 0.001) are independent risk factors for SSE. Conclusions: This real-world database suggests that concomitant BTA with novel ATT was associated with reducing SSEs. PSA decrease might be used as a predictive factor for those under BTA treatment. Further studies are warranted to validate the role of PSA response.

MP97-07 IMPACT OF REVERSE STAGE MIGRATION ON THE OUTCOME OF NODE POSITIVE PROSTATE CANCER PATIENTS TREATED WITH RADICAL PROSTATECTOMY: RESULTS OF A LARGE, TWO-CENTER EXPERIENCE

You have accessJournal of UrologyProstate Cancer: Localized: Surgical Therapy VIII1 Apr 2017MP97-07 IMPACT OF REVERSE STAGE MIGRATION ON THE OUTCOME OF NODE POSITIVE PROSTATE CANCER PATIENTS TREATED WITH RADICAL PROSTATECTOMY: RESULTS OF A LARGE, TWO-CENTER EXPERIENCE Paolo Dell'Oglio, Derya Tilki, Emanuele Zaffuto, Raisa S. Pompe, Giorgio Gandaglia, Nicola Fossati, Armando Stabile, Thomas Steuber, Nazareno Suardi, Francesco Montorsi, Markus Graefen, and Alberto Briganti Paolo Dell'OglioPaolo Dell'Oglio More articles by this author , Derya TilkiDerya Tilki More articles by this author , Emanuele ZaffutoEmanuele Zaffuto More articles by this author , Raisa S. PompeRaisa S. Pompe More articles by this author , Giorgio GandagliaGiorgio Gandaglia More articles by this author , Nicola FossatiNicola Fossati More articles by this author , Armando StabileArmando Stabile More articles by this author , Thomas SteuberThomas Steuber More articles by this author , Nazareno SuardiNazareno Suardi More articles by this author , Francesco MontorsiFrancesco Montorsi More articles by this author , Markus GraefenMarkus Graefen More articles by this author , and Alberto BrigantiAlberto Briganti More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.3051AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The aim of this study was to evaluate the impact of the year of surgery on clinical, pathological and oncological outcomes in N+ prostate cancer (PCa) patients who underwent radical prostatectomy (RP) and extended pelvic lymph node dissection (ePLND) METHODS 1,653 patients with N+ PCa treated with RP and ePLND at two tertiary care referral centres between 1998 and 2013. Lowess functions were used for graphical representation of the year-by-year trends in clinical, pathological characteristics and use of adjuvant treatments. Linear regression was used to test statistical significance of those temporal trends. Multivariable Cox regression analyses (MVA) were used to assess the relationship between year of surgery and oncological outcomes, namely biochemical recurrence-BCR and clinical recurrence-CR. Covariates consisted of patient age, preoperative PSA, pathological stage (pT2 vs. pT3a vs. ≥pT3b), positive surgical margins-PSM, pathological Gleason score (6 vs. 3+4 vs. 4+3 vs. ≥8) and year of surgery RESULTS Overall, 50.6 and 20.1% had BCR and CR, respectively. A significant decrease in the median PSA was observed over time (p=0.02). A similar trend was seen for clinical stage T3 (from 24.8% in 1998 to 6.7% in 2013; p<0.001). Conversely, biopsy Gleason ≥8 dramatically increased from 23% in 1998 to 53.1% in 2013 (p<0.001). We observed a considerable increase in the median number of lymph nodes removed (from 13.4 in 1998 to 20.5 in 2013; p=0.003), associated with an increased rate of patients with ≥3 positive lymph nodes (from 5.6% in 1998 to 30.9% in 2013; p=0.002). Pathological stage remained stable over time (all p?0.8). Conversely, the rate of pathological Gleason 4+3 and ≥8 increased significantly (from 17.6 to 43.1% and from 13.6 to 45.2% in 1998 and 2013, respectively; all p<0.001). The rate of PSM increased between 1998 and 2007, and remained stable thereafter. There was a trend towards lower use of adjuvant therapies (hormonal therapy-HT and radiotherapy with or without HT from 2004 to 2013; p<0.001), with increasing rates of men conservatively managed after RP (p<0.001). At MVA, year of surgery was associated with higher risk of BCR (HR: 1.08; p<0.001) and CR (HR: 1.09; p<0.001) CONCLUSIONS A trend towards more aggressive disease and worse cancer control was observed in more contemporary N+ PCa patients treated with RP which paralleled a lower rate of utilization of adjuvant therapies. These data should be taken into account when selecting the proper post-operative management of N+ PCa patients © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1305-e1306 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Paolo Dell'Oglio More articles by this author Derya Tilki More articles by this author Emanuele Zaffuto More articles by this author Raisa S. Pompe More articles by this author Giorgio Gandaglia More articles by this author Nicola Fossati More articles by this author Armando Stabile More articles by this author Thomas Steuber More articles by this author Nazareno Suardi More articles by this author Francesco Montorsi More articles by this author Markus Graefen More articles by this author Alberto Briganti More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

PD71-07 GAS6, KLK2, AND BMP7 DETECTED IN CIRCULATING TUMOR CELLS PREDICT RESISTANCE TO CHEMOTHERAPY IN MCRPC

You have accessJournal of UrologyProstate Cancer: Markers III1 Apr 2017PD71-07 GAS6, KLK2, AND BMP7 DETECTED IN CIRCULATING TUMOR CELLS PREDICT RESISTANCE TO CHEMOTHERAPY IN MCRPC Jae-Seung Chung, Yugang Wang, Henderson James, Udit Singhal, Yuanyuan Qiao, Alexander Zaslavsky, Dan Hovelson, Felix Feng, Ganesh Palapattu, Taichman Russell, Arul Chinnaiyan, Scott Tomlins, and Todd Morgan Jae-Seung ChungJae-Seung Chung More articles by this author , Yugang WangYugang Wang More articles by this author , Henderson JamesHenderson James More articles by this author , Udit SinghalUdit Singhal More articles by this author , Yuanyuan QiaoYuanyuan Qiao More articles by this author , Alexander ZaslavskyAlexander Zaslavsky More articles by this author , Dan HovelsonDan Hovelson More articles by this author , Felix FengFelix Feng More articles by this author , Ganesh PalapattuGanesh Palapattu More articles by this author , Taichman RussellTaichman Russell More articles by this author , Arul ChinnaiyanArul Chinnaiyan More articles by this author , Scott TomlinsScott Tomlins More articles by this author , and Todd MorganTodd Morgan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.3174AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Docetaxel or cabazitaxel-based chemotherapy continues to have a critical role in the treatment of men with metastatic castration-resistant prostate cancer (mCRPC). However, responses are heterogeneous and resistance to therapy is a pressing clinical problem. With the goal of developing liquid biomarkers to aid in treatment selection, we sought to identify genes associated with resistance to chemotherapy using a circulating tumor cell (CTC)-based approach. METHODS Whole blood (~5mL) was obtained from 25 patients with mCRPC starting docetaxel (n=21) or cabazitaxel (n=4). CTCs were isolated using anti-EpCAM-conjugated magnetic beads, and following cell lysis, mRNA was extracted followed by multiplex qRT-PCR for 44 prostate cancer-related genes plus internal controls. Gene expression was normalized to controls, and samples were considered CTC-positive based on a previously established set of epithelial markers (EpCAM, EGFR, DSG2, KRT8, KRT18 and KRT19). The primary endpoint was PSA progression-free survival (PFS), with PSA progression defined as an increase of 25% or more above the nadir. Univariable Cox regression analyses were performed to assess for genes associated with PFS at false discovery rate (FDR) < 0.20. RESULTS Among 25 patients with mCRPC, we identified 84% (21/25) with detectable CTCs. The median age of the cohort was 62 years (IQR 58-70). At a median (IQR) follow up of 5.4 (3.4-9.3) months, 47.6 % (10/21) of patients showed a PSA decrease of at least 30% following treatment initiation. 18/21 patients (85.7%) experienced PSA progression at a median of 2.8 months (IQR 1.7-4.8). In the Cox analysis, KLK2 (HR 2.54, 95%CI 1.24-5.21, p=0.011), GAS6 (HR 3.50, 95%CI 1.30-9.42, p=0.013), and BMP7 (HR 2.01, 95%CI 1.15-3.52; p=0.014) were associated with shorter PFS. CONCLUSIONS We have identified three genes associated with progression in mCRPC patients initiating chemotherapy. While these early results need further confirmation, they suggest that CTCs may be utilized to help guide precision-based treatment strategies in patients with mCRPC. Additionally, these results corroborate our recent in vitro and in vivo findings (Lee et al, J Cell Biochem, 2016) indicating that GAS6 protects prostate cancer cells from docetaxel-induced apoptosis. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1358 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Jae-Seung Chung More articles by this author Yugang Wang More articles by this author Henderson James More articles by this author Udit Singhal More articles by this author Yuanyuan Qiao More articles by this author Alexander Zaslavsky More articles by this author Dan Hovelson More articles by this author Felix Feng More articles by this author Ganesh Palapattu More articles by this author Taichman Russell More articles by this author Arul Chinnaiyan More articles by this author Scott Tomlins More articles by this author Todd Morgan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

PD23-06 THULIUM VAPOENUCLEATION OF THE PROSTATE VERSUS HOLMIUM LASER ENUCLEATION OF THE PROSTATE: 6-MONTH SAFETY AND EFFICACY RESULTS OF A PROSPECTIVE RANDOMIZED TRIAL

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Surgical Therapy & New Technology III1 Apr 2017PD23-06 THULIUM VAPOENUCLEATION OF THE PROSTATE VERSUS HOLMIUM LASER ENUCLEATION OF THE PROSTATE: 6-MONTH SAFETY AND EFFICACY RESULTS OF A PROSPECTIVE RANDOMIZED TRIAL Christopher Netsch, Benedikt Becker, Christian Tiburtius, Christina Moritz, Arcangelo Venneri Becci, Thomas Herrmann, and Andreas Gross Christopher NetschChristopher Netsch More articles by this author , Benedikt BeckerBenedikt Becker More articles by this author , Christian TiburtiusChristian Tiburtius More articles by this author , Christina MoritzChristina Moritz More articles by this author , Arcangelo Venneri BecciArcangelo Venneri Becci More articles by this author , Thomas HerrmannThomas Herrmann More articles by this author , and Andreas GrossAndreas Gross More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1070AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES To compare the 6-month outcomes of thulium vapoenucleation of the prostate (ThuVEP) with holmium laser enucleation of the prostate (HoLEP) for patients with symptomatic benign prostatic obstruction (BPO). METHODS A prospective randomized trial comparing ThuVEP with HoLEP was conducted from February 2015 to February 2016 at the Asklepios Klinik Barmbek. A total of 94 patients with symptomatic BPO were prospectively randomized to ThuVEP (n=48) or HoLEP (n=46). All patients were assessed preoperatively by International Prostate Symptom Score (IPSS), Quality of Life (QoL), maximum urinary flow rate (Qmax), post-void residual urine (PVR), PSA, and prostate volume measurement by transrectal ultrasound. The patients were reassessed with the same tests at 1-month and 6-month follow-up. The complications were noted and classified according to the modified Clavien classification system. Patient data were expressed as median (interquartile range) or numbers (%). RESULTS There were no statistically significant differences in any baseline characteristics between the groups. Median age at surgery was 73 (67-76) yrs. and median prostate volume was 80 (46.75-100) cc. 43 (45.7%) patients presented in urinary retention with an indwelling catheter. The median operative time was 60 (41-79) minutes without significant differences between the groups. There were no significant differences between the groups regarding catheter time (2 (2-2) days) and postoperative stay (2 (2-3) days). Clavien 1 (13.8%), 2 (3.2%), 3a (2.1%), and Clavien 3b (4.3%) complications occurred without significant differences between the groups. However, the occurrence of acute postoperative urinary retention was significantly higher after HoLEP compared to ThuVEP (15.2% vs. 2.1%, p≤0.022) at 4-week follow-up. At 6-month follow-up, median Qmax (10.7 vs. 25.9 ml/s), PVR (100 vs. 6.5 ml), IPSS (20 vs. 5), QoL (4 vs. 1), PSA (4.14 vs. 0.71 μg/l), and prostate volume (80 vs. 16 ml) had improved significantly (p<0.001) compared to baseline without differences between the groups. The median PSA decrease was 79.7% (58.8-90.6%) and the median prostate volume reduction was 74.5% (68.57-87.63%) without differences between the groups. The reoperation rate was zero at 6-month follow-up. CONCLUSIONS ThuVEP and HoLEP are both safe and effective procedures for the treatment of symptomatic BPO. Both procedures give equivalent and satisfactory micturition improvement with low morbidity and sufficient prostate volume reduction at 6-month follow-up. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e449 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Christopher Netsch More articles by this author Benedikt Becker More articles by this author Christian Tiburtius More articles by this author Christina Moritz More articles by this author Arcangelo Venneri Becci More articles by this author Thomas Herrmann More articles by this author Andreas Gross More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

V4-02 GOLD NANO-PARTICLE DIRECTED FOCAL LASER ABLATION FOR PROSTATE TUMORS USING US AND MR FUSION TECHNOLOGY

You have accessJournal of UrologyImaging/Uroradiology1 Apr 2017V4-02 GOLD NANO-PARTICLE DIRECTED FOCAL LASER ABLATION FOR PROSTATE TUMORS USING US AND MR FUSION TECHNOLOGY Jared S Winoker, Pratik A Shukla, Michael A Carrick, Harry Anastos, Cynthia J Knauer, Ashutosh K Tewari, Bachir M Taouli, Sara C Lewis, Jon A Schwartz, Joshua M Stern, Steven E. Canfield, and Ardeshir Rastinehad Jared S WinokerJared S Winoker More articles by this author , Pratik A ShuklaPratik A Shukla More articles by this author , Michael A CarrickMichael A Carrick More articles by this author , Harry AnastosHarry Anastos More articles by this author , Cynthia J KnauerCynthia J Knauer More articles by this author , Ashutosh K TewariAshutosh K Tewari More articles by this author , Bachir M TaouliBachir M Taouli More articles by this author , Sara C LewisSara C Lewis More articles by this author , Jon A SchwartzJon A Schwartz More articles by this author , Joshua M SternJoshua M Stern More articles by this author , Steven E. CanfieldSteven E. Canfield More articles by this author , and Ardeshir RastinehadArdeshir Rastinehad More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.901AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES : A growing collective proficiency in multiparametric magnetic resonance imaging (mpMRI) and targeted biopsies for prostate cancer (PCa) screening has given way to an increasing interest in the application of these technologies for targeted therapy. Various targeted therapies have been developed and evaluated; however, these treatments focus energy at a region of the prostate, as opposed to directly at the tumor. Gold nanoparticle (GNP) therapy is a novel treatment that results in tumor-specific ablation, sparing surrounding tissue and structures. Herein, we report the first two cases in the world using gold nanoparticle-directed focal laser ablation of prostate tumors targeted with ultrasound (US) and MR/US fusion technology. METHODS Patients were enrolled in a phase II trial, ′A Study of MRI/US Fusion Imaging and Biopsy in Combination with Nanoparticle Directed Focal Therapy for Ablation of Prostate Tissue.′ Treatment and follow up plan are as follows: intravenous infusion on day 0, which allows GNP deposition into the tumors with the goal of achieving a 15.2 µg/cc tumor concentration required for excitation/ablation. On day 1, the patient presents for focal laser excitation of the GNPs. Laser catheters are placed using a combination of US and a transperineal electromagnetic-tracked MR/US fusion device (Invivo, Gainesville, FL). 48 hours' post-ablation, the patient is imaged, fig 1, followed by re-imaging and MR/US fusion guided biopsy (FBx) at 3 months. All patient demographics, clinical variables, and complications were recorded. RESULTS To date, 2 patients have been enrolled in the trial, both with localized Gleason 7 PCa diagnosed using MR/US FBx. Mean age was 67 + 4.3 years and mean prostate specific antigen was 6.1 + 0.06 ng/ml. The mean tumor volume was 0.40 + 0.05 cc with a solitary lesion in each patient. The mean PSA decrease was 3.6 + 0.6 ng/ml, a 40.9% decrease at 1 month. No short-term complications were observed. The first patient underwent a follow up FBx at 3 months with no detectable cancer. CONCLUSIONS Increasing interest in image guidance technologies and focal therapies has sparked a new generation of PCa treatment modalities. We have demonstrated the first safe and effective use of ultra-focal therapy using MR/US fusion technology in concert with GNP directed therapy to treat prostate tumors. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e375-e376 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Jared S Winoker More articles by this author Pratik A Shukla More articles by this author Michael A Carrick More articles by this author Harry Anastos More articles by this author Cynthia J Knauer More articles by this author Ashutosh K Tewari More articles by this author Bachir M Taouli More articles by this author Sara C Lewis More articles by this author Jon A Schwartz More articles by this author Joshua M Stern More articles by this author Steven E. Canfield More articles by this author Ardeshir Rastinehad More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

ODM-204 a novel dual inhibitor of CYP17A1 and androgen receptor: Early results from phase I dose escalation in men with castration-resistant prostate cancer.

246 Background: Castration-resistant prostate cancer (CRPC) is characterized by high androgen receptor (AR) expression, various AR mutations and persistent activation of AR signaling axis by residual tissue androgens and other steroids. Inhibiting both the AR and androgen biosynthesis may be more effective than inhibiting either alone to treat CRPC. ODM-204 is a potent, orally administered investigational non-steroidal dual inhibitor of CYP17A1 and the AR that has shown activity in nonclinical tumor models. Methods: We report early data of the DUALIDES phase I dose escalation part (NCT02344017), in which patients with metastatic CRPC (mCRPC) were enrolled into ODM-204 dose levels of 50, 100, 200, 300, 500 mg twice daily. Data cut-off was Oct 14th2016. Results: In the trial 23 patients with progressive mCRPC received increasing doses of ODM-204. At baseline, the median age of patients was 70 yrs (57-84 yrs), and median PSA was 46.5 ng/mL (0.7-249.6 ng/mL). Median time on treatment was 11.6 weeks (0.3-60.4 wks). Nine (39%) patients continued treatment for more than 12 weeks, and 4 (17.4%) patients were still receiving treatment at the time of data cutoff. ODM-204 was generally well tolerated, and the most commonly reported adverse events (AEs) were fatigue (n = 6, 26%), nausea (n = 6, 26%), decreased appetite (n = 5, 22%,) diarrhea (n = 5, 22%), and vomiting (n = 5, 22%). Two patients discontinued treatment due to an AE. The AUCt and Cmax values of ODM-204 in plasma increased with dose up to 300 mg after a single dose. Steady state values on day 8 were unexpectedly decreased in most patients, especially at higher doses, contrary to what was observed in the nonclinical monkey studies. Further, decreased predose concentrations were observed on day 29. PSA decreases were seen in 7 (30%) patients, and the median decrease was 47% (2-99%). At 12 weeks, 3 (13%) patients had a PSA response ( ≥ 50% reduction from baseline). Conclusions: Although evidence of anticancer activity was provided with ODM-204 in mCRPC, decreasing steady state concentration was observed. Clinical trial information: NCT02344017.

A drug-drug interaction study on the combination of cabazitaxel with enzalutamide in patients with metastatic castration-resistant prostate cancer.

188 Background: Cabazitaxel and enzalutamide are effective single agent treatment options for metastatic castration resistant prostate cancer (mCRPC). Preclinical studies suggest enhanced efficacy of the combination of a taxane with enzalutamide. Recently, Morris et al. (CCR 2016) reported on an interaction study between docetaxel and enzalutamide: docetaxel mean exposure decreased by 12% during a short period of co-treatment with enzalutamide, probably due to enzyme (CYP3A4) induction. Since cabazitaxel is a CYP3A4 substrate, we investigated the influence of enzalutamide on cabazitaxel pharmacokinetics (PK) and toxicity during 3 chemotherapy cycles. Methods: We performed a cross-over study in 14 evaluable mCRPC patients who were treated with i.v. cabazitaxel Q3W (25 mg/m2). PK-sampling (over 24h) was conducted on day 1 of each cycle during 3 consecutive cabazitaxel cycles. From day 8 (±1) of the first cycle until day 8 (±1) of the third cycle, enzalutamide (160 mg/day) was administered concomitantly. Primary endpoint was the difference in geometric mean area under the curve (AUC0-24h) between the first and third cycle. Secondary endpoints included safety parameters and PSA response. Results: The AUC was 22% (95%CI 9-34%) lower during the third cycle (181 ng*h/mL, 95%CI 150-219 ng*h/mL) than during the first cycle (234 ng*h/mL, 95%CI 209-261 ng*h/mL; p = 0.005). No relevant adverse events occurred due to the drug combination. Nine patients (64%) received the full dose of cabazitaxel during the 3 study cycles. No enzalutamide dose reductions took place, and the combination was well tolerated. PSA response ( ≥ 50% decrease of baseline PSA ) was observed in 10 patients (71%). Conclusions: Cabazitaxel exposure is both statistically and clinically significantly reduced by concomitant enzalutamide use. Since the PROSELICA study (De Bono et al, ASCO 2016) may lead to an adapted standard cabazitaxel dose of 20 mg/m2, the clinical relevance of this interaction may be extensive, since it is likely to result in suboptimal exposures. We stimulate clinical studies with this combination, but these should include monitoring of the PK of cabazitaxel, and appropriate dose adaptations. Clinical trial information: NTR5164.

First Line Androgen Deprivation Therapy Duration Is Associated with the Efficacy of Abiraterone Acetate Treated Metastatic Castration-Resistant Prostate Cancer after Docetaxel.

Introduction: We performed a chart review study in our castration-resistant prostate cancer (CRPC) patients who received Abiraterone acetate (AA) treatment after docetaxel and identified clinical markers which can predict treatment outcome.Materials and Methods: From 2012 to 2016, 64 patients who received docetaxel after CRPC followed by AA treatment were included. Clinical parameters were recorded and analysis was performed to identify associations between pre-treatment variables and treatment outcome.Results: Thirty three patients (51.6%) achieved a decrease in PSA of 50%. The median PSA progression-free survival and overall survival in the total cohort of 64 patients were 6.6 and 24 months, respectively. Adverse events (AEs) in all grades developed in 35.9% (23/64) patients and mostly were grade 1 or 2. The most common AEs were gastric upset, hypokalemia and elevated liver function tests. Of the eight variables analyzed, first line androgen deprivation therapy (ADT) duration showed positive association to progression free survival (HR 0.98, 95% CI [0.96–0.99], p = 0.012) and overall survival (HR 0.97, 95% CI [0.94–0.99], p = 0.019). Pre-AA PSA and PSA progression ratio showed negative association only to progression free survival (HR 1.0, 95% CI [1.000–1.002], p = 0.025, HR 1.01, 95% CI [1.00–1.01], p < 0.001, respectively).Conclusion: First line ADT duration was positively associated with AA treatment efficacy in progression free survival and overall survival. It can be used as a pre-treatment predictor.

Assessment of a prognostic model, PSA metrics and toxicities in metastatic castrate resistant prostate cancer using data from Project Data Sphere (PDS).

BackgroundPrognostic models in metastatic castrate resistant prostate cancer (mCRPC) may have clinical utility. Using data from PDS, we aimed to 1) validate a contemporary prognostic model (Templeton et al., 2014) 2) evaluate prognostic impact of concomitant medications and PSA decrease 3) evaluate factors associated with docetaxel toxicity.MethodsWe accessed data on 2,449 mCRPC patients in PDS. The existing model was validated with a continuous risk score, time-dependent receiver operating characteristic (ROC) curves, and corresponding time-dependent Area under the Curve (tAUC). The prognostic effects of concomitant medications and PSA response were assessed by Cox proportional hazards models. One year tAUC was calculated for multivariable prognostic model optimized to our data. Conditional logistic regression models were used to assess associations with grade 3/4 adverse events (G3/4 AE) at baseline and after cycle 1 of treatment.ResultsDespite limitations of the PDS data set, the existing model was validated; one year AUC, was 0.68 (95% CI 95% CI, .66 to .71) to 0.78 (95%CI, .74 to .81) depending on the subset of datasets used. A new model was constructed with an AUC of .74 (.72 to .77). Concomitant medications low molecular weight heparin and warfarin were associated with poorer survival, Metformin and Cox2 inhibitors were associated with better outcome. PSA response was associated with survival, the effect of which was greatest early in follow-up. Age was associated with baseline risk of G3/4 AE. The odds of experiencing G3/4 AE later on in treatment were significantly greater for subjects who experienced a G3/4 AE in their first cycle (OR 3.53, 95% CI 2.53–4.91, p < .0001).ConclusionDespite heterogeneous data collection protocols, PDS provides access to large datasets for novel outcomes analysis. In this paper, we demonstrate its utility for validating existing models and novel model generation including the utility of concomitant medications in outcome analyses, as well as the effect of PSA response on survival and toxicity prediction.

CLINICAL STUDY OF SEQUENTIAL THERAPY WITH ABIRATERONE AND ENZALUTAMIDE FOLLOWING DOCETAXEL THERAPY FOR CASTRATION-RESISTANT PROSTATE CANCER

(Purpose) This study is to evaluate the efficacy and safety of sequential therapy with two novel drugs, abiraterone and enzalutamide after docetaxel (DOC) therapy for castration-resistant prostate cancer (CRPC). (Material and methods) Twenty-one patients were identified received sequential therapy with abiraterone and enzalutamide after DOC therapy at our institution. We investigated PSA response (decrease of 50% or more) to prior administered drug as primary endpoint, and overall survival rate and occurrence of adverse events as secondary endpoint. (Results) There were 12 patients in the group preliminarily administered enzalutamide (Group E) and 9 patients in the group preliminarily administered abiraterone (Group A). The novel drugs were administered immediately following DOC therapy in nearly all cases. Of the 9 patients in Group A, only one patient (11%) and of the 12 patients in Group E, only one patient (9%) achieved PSA decrease of 50% or more, thus resulting in a poor response rate. There was not significantly difference in both groups. The overall survival rates of Group A and E were not significantly difference. There were three adverse events which required change drug. Those were two cases (appetite loss and general fatigue) on enzalutamide and one case (edema) on abiraterone. (Conclusion) This study suggested that sequential therapy with abiraterone and enzalutamide after DOC therapy had poor clinical benefit regardless of the order of administration of both drugs.

Predictive factors of 18F-choline PET/CT positivity in patients with prostate cancer recurrence after radiation therapy: is the impact of PSA nadir underestimated?

BackgroundThe objective of this study is to explore the impact of PSA nadirs on detection rates of prostate cancer (PCa) recurrence with 18F-choline (CH) PET/CT after external beam radiation therapy (EBRT).MethodsIn this retrospective study, data were collected from 54 patients with suspicion of PCa biochemical recurrence after EBRT (28 patients treated initially with EBRT and 26 as salvage therapy in the absence of PSA decrease after initial treatment), who underwent 18F-CH PET/CT between 2010 and 2015. PSA nadir and trigger PSA were collected from patient files. Relative PSA was calculated by subtracting the nadir from the trigger PSA.ResultsMedian PSA nadir was 0.31 (0.01–13.31) ng/mL, trigger PSA was 7.85 (0.47–111.60) ng/mL, and relative PSA was 6.05 (0.24–104.59) ng/mL. Overall, 40 (74%) PET/CT scans were positive: recurrence was local and/or regional in 29 patients, distant in 15 and combined both in four, with no association between PSA values and sites of recurrence.In univariate analysis, trigger (p = 0.015) and relative (p = 0.0005) PSA values and PSA velocity (p = 0.01) were significantly linked to positive PET/CT, but PSA nadir was not. In subgroup analysis, these significant differences were only found in the salvage EBRT group. Akaike Information Criterion multivariate model comparison found that relative PSA was a better predictor of positive PET/CT than trigger PSA (PSAt). 18F-CH PET/CT detection rates increased with trigger and relative PSA: 0% (0/4 patients), 71% (5/7 patients), and 81% (35/43 patients) for PSAt <2 ng/mL, 2≤ PSAt ≤4 ng/mL, and PSAt >4 ng/mL, respectively, and 14% (1/7 patients), 50% (5/10 patients), and 92% (34/37 patients) when relative PSA was taken into account instead of trigger PSA, with seven (13%) patients changing subgroups.ConclusionsWe found a high overall detection rate and an increase in detection rates proportional to trigger and relative PSAs. Although relative PSA, taking into account PSA nadir, was a better predictive factor of PET/CT positivity in univariate analysis, this was most noticeable for high PSAs. For low PSAs, trigger PSA remains most relevant. Larger series with intermediate PSA values need to be studied to fully apprehend nadir impact.

Abstract 3074: Addition of ARN509 and docetaxel, alone or in combination, to castration demonstrates improved efficacy and heterogeneity of molecular response in prostate cancer patient-derived xenografts

Abstract Results from clinical and preclinical investigations suggest potential survival benefits from more aggressive early treatment of some patients. Our objective was to evaluate in vivo the efficacy of adding docetaxel (DOC) or ARN509, alone or in combination, to primary androgen ablation and to investigate the associated molecular response and resistance. We used hormone-sensitive LuCaP patient-derived prostate cancer xenografts (PDXs) models 35, 77, and 147 that all express AR but differ significantly in responses to castration (CX) and exhibit diverse molecular characteristics. Tumors were grown in intact mice and when established, mice were randomized for CX alone or CX with DOC or ARN-509, or their combination. Tumor volume (TV), and serum PSA responses were monitored. Tumors were harvested 5 days post-treatment (d5) and at end of study (EOS) for analyses. Our results show differential efficacy of the treatments, mimicking the heterogeneity of clinical response. LuCaP 77 progression was inhibited by CX and the additional treatments (TXs) further inhibited TV, with the most decreased TV and PSA detected in the combination group. When compared to CX, CX combined with ARN509 demonstrated the most significantly improved survival benefit (10w vs 16.5w median survival; HR = 0.2, p&amp;lt;0.001), while CX combined with DOC resulted in a smaller survival benefit (10w vs 12.5w, median survival HR = 0.5 p = 0.036). The combination TX did not result in improved survival due to negative health side effects that resulted in early sacrifice. LuCaP 147 exhibited similar responses to CX as LuCaP 77 but only small additional inhibition of TV with the combination TXs and no significant survival improvements over CX alone. LuCaP 35 was the most responsive to CX and the additional treatments did not enhance the TV inhibition, decreases in serum PSA or survival. Preliminary IHC analyses of the early response (d5 tumors) did not show significant decrease in AR or GR in any of the PDXs but decrease in PSA indicated the efficacy of androgen suppression. Decreased proliferation (Ki67) was detected in LuCaP 77 and LuCaP 147 after CX and more pronounced decreases in the combination vs CX groups in LuCaP 77 and ARN509 and the combination vs CX in LuCaP 147 with no difference detected in LuCaP 35. Analyses of early gene expression responses at d5 by qPCR revealed changes specifically associated with single and combination treatment with ARN509 in LuCaP 77 for both AR-regulated genes (FKBP5, PCNA, and AKR1C3) and proliferation-associated genes (UBE2C3 and NUSAP1). Further analyses of the responses and alteration of genes and proteins associated with AR signaling, proliferation and drug resistance at d5 and EOS are ongoing. Citation Format: Ryan McMullin, Himanshu Gupta, Yashoda Rajpurohit, Holly Nguyen, Lisha Brown, Daniel Sondheim, Gormley Michael, Deborah Ricci, Shibu Thomas, Corey Eva. Addition of ARN509 and docetaxel, alone or in combination, to castration demonstrates improved efficacy and heterogeneity of molecular response in prostate cancer patient-derived xenografts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3074.

Early assessment of PSA response in CRPC patients treated with enzalutamide (Enza) or abiraterone (Abi).

249 Background: Abi and Enza are used in treating metastatic CRPC. Primary resistance is well described but little data exists for early treatment responders. Further characterization of patients with early PSA declines was the goal of this study. Methods: Single institution, retrospective reviews were performed on 84 CRPC patients (pts) treated with Abi or Enza. PSAs were recorded for the duration of treatment. The primary end point was to describe receiver operating characteristics (ROC) of early PSA changes, including sensitivities and specificities, as a predictor of later treatment response (defined as ≥ 50% decrease in PSA from baseline). 12 additional clinical covariates were also evaluated as treatment response predictors. Results: 30/63 pts in the Abi treatment group and 12/44 pts in the Enza treated group had a PSA treatment response at some point. Among the “eventual” Abi responders, some achieved a response early; 16/30 at 4 weeks and 22/30 at 8 weeks. Of Enza “eventual” responders, 7/12 achieved response at 4 weeks. For early responders (either 4 or 8 weeks), Abi pts median treatment time was 336 days. Enza early responders median treatment was time 303 days. For ROC analysis of PSA changes at 4 &amp; 8 weeks, in terms of predicting ‘eventual’ responders, the Abi group had an area under the curve (AUC) of 0.86 ± 0.07 and 0.93 ± 0.08, respectively. Enza ROC analysis of PSA change at 4 weeks had an AUC of 0.97 ± 0.03. Sensitivities and specificities were also described for various PSA change thresholds in each group. Ideal cut-off points for Abi at 4 weeks was a 37% decrease in PSA (sensitivity: 0.74, specificity: 0.97) and at 8 weeks was a 33% decrease (0.82, 0.97). For Enza ideal cut-off at 4 weeks was a 31% PSA decrease (0.82, 0.93). Covariate analysis of the Abi pts indicated that metastasis at diagnosis (P = 0.048) and prior taxanes predicted resistance to treatment (P = 0.019), as measured by &lt; 50% decline in PSA. All covariates in the Enza pts failed to reach significance. Conclusions: Results suggest that early PSA changes for both Enza and Abi may be a reliable way for clinicians to predict long-term PSA response. This may allow for earlier modifications to be made in patient management for those not achieving an early PSA response.

Prospective evaluation of the response to prednisone-dexamethasone switch in castration-resistant prostate cancer patients treated with abiraterone pre- and post-docetaxel.

327 Background: Abiraterone acetate (AA) administered with prednisone (P) to reduce mineralocorticoid-related adverse events improves survival in CRPC with a favourable tolerance profile. However, in the phase I/II of AA without steroids, dexamethasone 0,5mg/day was added after biochemical progression reaching a 25% of PSA decline. Lorente et al (BJC, 2014) showed durable biochemical responses in 40% of cases treated with AA and steroid switch in the post-docetaxel setting. We hypothesize that P to D switch in patients with biochemical progression to AA+P would lead to secondary responses also in the pre-docetaxel setting. Methods: Change of P 5mg/12h to D 0.5mg/24h was prospectively tested in clinically stable CRPC with biochemical progression ( &gt; 25% PSA rise over nadir, confirmed in a second determination) and/or limited radiological progression ( &lt; 3 new bone/lymphatic metastasis, non-bulky), after ³12 weeks of AA+P. PSA was monitored q4wks. CT- &amp; bone-scans were performed every 12-16 weeks. Biochemical and radiological responses were evaluated by PSAWG2 and RECIST criteria. Survival outcomes were calculated using Kaplan-Meier method. Results: 18 patients were included (11 pre- &amp; 7 post-docetaxel). Median age 72 (60-85); visceral, bone and/or lymph metastasis were present in 17%, 83% and 50% of patients. Median PSA at AA+P and AA+D commencement was 81 ng/ml and 100ng/ml, respectively. Biochemical response was observed in 83% of patients: 56% with a PSA decrease ≥ 30%, and 28% with PSA decrease ≥ 50%. Median biochemical progression-free survival (bPFS) with AA+P was 5.7 months (CI95% 2.9-9.1) and 3.8m (CI95% 1.4-6.5) in the pre- and post-docetaxel setting, respectively. Median bPFS with AA+D was 5.4m (1.2-8.8) and 2.5 (CI95% 1.1-2.9) in the pre- and post-docetaxel settings. Two radiological partial responses were observed with AA+D. Conclusions: Clinically stable patients with limited disease progression after AA+P may benefit from steroid switch in both the pre- and post-docetaxel settings.

A phase II open-label trial of GTx-758 in men with castration-resistant prostate cancer: Final analysis of the primary endpoint.

185 Background: Recently approved agents that target the androgen receptor pathway emphasize the importance of the persistent activity of the androgen receptor pathway in castration-resistant prostate cancer (CRPC). This raises the possibility that agents with distinct mechanisms of action may add value. GTx-758 is a selective ERα agonist that can increase SHBG and therefore reduce biologically active testosterone (T) levels. Reported here are the results, including the final primary endpoint analysis, from the 250 mg daily GTx-758 cohort of a phase II clinical trial in men on LHRH agonists that developed CRPC. Methods: This phase II open label trial (G200712, NCT01615120) treated men with high risk nmCRPC or mCRPC with T levels &lt; 50 ng/dL who continued to receive their current form of ADT along with either 125 mg or 250 mg of GTx-758 daily, for at least 90 days. The primary endpoint was the proportion of men with a PSA decline ≥ 50% by day 90, while secondary endpoints included serum total and free T, sex hormone binding globulin (SHBG), bone turnover markers and hot flashes. Results: The 250 mg cohort (n = 39) has completed the time period for assessment of the primary endpoint. Ten of the 39 (26%) subjects exhibited a ≥ 50% decrease in PSA by Day 90, with 11/39 (28%) by Day 120, while 18/39 (46%) had PSA declines of ≥ 30%. Median SHBG levels increased 301% of baseline, confirming the principal mechanism of drug action. While on study, median free T decreases of 44% were observed across all subjects and 20/26 (77%) of the subjects with baseline serum free T levels &gt; 0.7 pg/ml fell below this level. Therefore, 250 mg GTx-758 decreased free testosterone levels in an additive fashion to their existing LHRH therapy. The bone turnover biomarker, C-telopeptide, decreased in 79% of the subjects. 250 mg of GTx-758 has been generally well tolerated with two reported possibly drug related SAEs (VTE and MI). Conclusions: In this phase II trial, 250 mg daily GTx-758 has activity, likely mediated by lowering free T levels in patients with CRPC on LHRH therapy, and may provide amelioration of estrogen deficiency side effects associated with ADT. Clinical trial information: NCT01615120.

A phase I/II study of the investigational drug alisertib in combination with abiraterone and prednisone (AP) for patients with metastatic castration-resistant prostate cancer (mCRPC) progressing on abiraterone.

311 Background: Aurora A kinase (AK) phosphorylates and interacts with androgen receptor (AR) and enhances AR DNA binding activity. We hypothesized that AK contributes to castration resistance in PCa, and targeting AK can inhibit AR function and re-sensitize PCa cells to AR signaling inhibitors such as abiraterone. Methods: Aphase I/II, open label, single institution trial to determine the safety and efficacy of AK inhibitor alisertib when given in combination with abiraterone plus prednisone (AP) was planned. Eligible subjects had mCRPC with disease progression on abiraterone. Androgen deprivation plus abiraterone and prednisone were maintained through the trial. Subjects were treated with dose escalation per standard 3+3 design. Planned 3 dose cohorts of alisertib were 30, 40, 50 mg PO BID D 1-7 every 21 D. Correlative studies included kinetics of neuroendocrine tumor markers, enumeration and AK gene amplification of CTCs. Results: Nine of 43 planned subjects were enrolled, 3 in cohort 1 without DLT. Two DLTs developed in cohort 2, thus 3 more patients were enrolled into cohort 1, and 2 developed DLT (total 2/6) in this cohort. The grade 3/4 toxicities (4/9) include neutropenic fever (1/9), neutropenia (1/9), fatigue with memory impairment (1/9), and mucositis (diarrhea and mouth sores, 1/9). Pharmacodynamically, adding alisertib did not affect circulating total testosterone and DHEA levels. Only one patient had decreased Chromogranin A level lasted for 4 months when compared to baseline. Four (4/9) patients had ≥ 5 CTCs at baseline but no conversion ( to &lt; 5) was observed. No PSA decrease was observed during the study. Mean duration of study was 2.5 months. The toxicity / efficacy ratio did not warrant further dose expansion and the trial was terminated early after discussion with sponsor. Conclusions: A tolerable dose of alisertib in combination with AP in mCRPC was not established in this study. There was no clear signal indicating that alisertib might be beneficial for patients with mCRPC progressing on abiraterone. Clinical trial information: NCT01848067.