bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship of phosphodiesterase type 5 inhibitor to biochemical recurrence after definitive therapy for prostate cancer.
Authors: Leapman Michael S. , Cowan Janet E. , Nguyen Hao Gia , Porten Sima P. , Cooperberg Matthew R. , Carroll Peter
Published: February 2017

119

Background: Phosphodiesterase type 5 inhibitors (PDE5i) are commonly utilized among men receiving definitive treatment for prostate cancer (PCa). Recently, contradictory clinical evidence regarding the association between biochemical recurrence (BCR) and receipt of PDE5i has been reported. We aimed to clarify this question among a multi-center, cohort of men with PCa. Methods: Participants enrolled in Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) at diagnosis and received radical prostatectomy, RP, or radiation therapy, RT (external beam radiation therapy or brachytherapy) without androgen deprivation therapy ≤ 6 months. We examined associations between clinical, Prostate Cancer Index Sexual Function score, SF (0-100 (best)), and pathological characteristics as well as baseline, time-dependent and ever-use of PDE5i (patient or physician reported) with risk of BCR using descriptive analyses, Kaplan-Meier method, and multivariate Cox proportional hazards models. Results: A total of 4,844 men were identified (3,847 RP, 997 RT.) Men received RP at median age 61 years (IQR 56-66), had a mean baseline SF score 62.4 (SD 26.7), were followed for a median of 77 months (IQR 36-117), and 3,089 (80%) were prescribed or reported use of PDE5i post-operatively. Patients treated with RT were older with a median age 69 years (IQR 63-74) and mean baseline SF score 46.6 (SD 29.5), were followed for a median of 91 months (IQR 53-125), and had lower rates of reported PDE5i usage (421 men, 42%). In Cox regression models baseline use (HR = 0.9 (95% CI 0.3-2.4) p = 0.83) and ever-usage (HR = 0.7 (0.5-1.1) p = 0.73) of PDE5i were not independently associated with BCR after RP. Time-dependent use (HR 1.3 (0.6, 2.7) p = 0.45) also was not associated with BCR after RP among men taking PDE5i medications. Baseline (HR = 4.6 (0.6-37.3) p = 0.14) and ever-usage (HR 0.6 (0.3-1.5) p = 0.30) also were not associated with BCR after RT. This study was limited by incomplete data on prescription compliance. Conclusions: PDE5i usage following RP or RT for PCa was not associated with BCR. PDE5i therapy should not be withheld due to concerns that it increases the risk of disease recurrence.
Inflammatory bowel disease in patients with prostate cancer treated with radiation.
Authors: Gestaut Matthew Maxwell , Swanson Gregory P.
Published: February 2017

15

Background: Inflammatory bowel disease (IBD) has long been considered a risk factor for increased bowel toxicity from radiation therapy (RT); however, minimal evidence exists for patients with prostate cancer (PC) and IBD. Methods: The tumor registry was queried for patients with both IBD and PC from 2000-2010. A chart review was conducted for patients who received RT for PC. All patients carried the diagnosis IBD as defined by either Crohn’s disease or ulcerative colitis. RT specifics and radiation toxicity (acute and late) data were collected. Results: Eighteen patients met the inclusion criteria for PC and IBD diagnoses with radiation therapy treatment. Twelve were treated with external beam radiation therapy (EBRT), and 6 were treated with low dose rate (LDR) brachytherapy. Average length of follow-up was 12 years (median 9.54, range 0.42-19.9). Most patients had well controlled baseline bowel function on medical management. Twenty-two percent were in remission from IBD without any form of treatment; 56% were actively taking 5-ASA; 17% were prescribed prednisone; and 6% were taking Remicade. Sixty percent of patients (9/15) reported grade 0 (G0) diarrhea at baseline prior to radiation therapy. Forty percent (6/15) suffered grade 1 (G1) diarrhea at baseline. No baseline proctitis existed. Two patients reported ostomy prior to radiation. Following radiation treatment, 78% (14/18) of patients experienced G0 diarrhea while 22% (4/18) reported G1 diarrhea. No patients suffered from greater than G1 diarrhea. Sixty-seven percent (12/18), 17% (3/18) and 17% (3/18) of patients experienced G0, G1, and G2 proctitis, respectively. No patients suffered post-radiation stricture formation. All patients with G2 proctitis following RT received 3dCRT. Conclusions: No available published data explores RT for patients with PC and IBD. This retrospective review offers valuable insight into appropriate counseling for a rare patient subset. EBRT was associated with improvement in late G1 diarrhea rates. Grade 2 proctitis was only encountered among 3dCRT patients. No post-radiation stricture or ostomy placements occurred. Our findings suggest that IBD patients experience minimal toxicity with IMRT-based radiation therapy.
Digital health application for real-time patient-reported outcomes during prostate radiotherapy.
Authors: Yang Daniel Xiao , Thea Jackson , An Yi , Yu James B.
Published: February 2017

157

Background: The use of digital health technology, including mobile applications, in the clinical setting is becoming increasingly more prevalent. Such technology is currently being explored as clinical research tools. While the side effects of prostate radiotherapy are well documented after treatment, there remains a paucity of data on patient-reported outcomes and changes in quality of life (QOL) during the treatment period. Therefore, mobile applications represent a practical platform to enable patient reporting in real-time during prostate radiotherapy. Methods: Using an existing open source code framework (Apple ResearchKit), we developed a novel mobile application that enables prostate cancer patients to report, either during or immediately following daily radiation treatment, changes in urinary, bowel, sexual, and hormonal QOL domains. The mobile application utilizes validated questions from the Expanded Prostate Index Composite for Clinical Practice (EPIC-CP) Survey, and allows for survey responses to be tracked over time throughout the treatment period and at routine follow up. Results: For the initial phase of our study, we are currently piloting the mobile application at a single institution with a goal of accruing 50 patients. Study results will be compared to data from traditional surveys, which are available at follow-up but impracticable for real-time symptom reporting. By ASCO 2016 Genitourinary Cancers Symposium, we plan to begin the second phase of our study where any patient can enroll online through a mobile software distribution platform (Apple App Store). Conclusions: We demonstrate the feasibility of using a mobile application to enable patients to report quality of life changes in real-time during prostate radiotherapy. Moreover, our application facilitates clinical trials where patient data collection can be automated and completed at scale. Future prospective studies are planned to evaluate validity of clinical trial data gathered through such methodology.
Biallelic inactivation of BRCA2 in metastatic castration-resistant prostate cancer and platinum sensitivity.
Authors: Cheng Heather H. , Pritchard Colin C. , Nelson Peter , Montgomery Robert B.
Published: February 2017

164

Background: Predictive biomarkers are urgently needed in the treatment of metastatic castration-resistant prostate cancer (mCRPC), and the promise of precision medicine depends on understanding the molecular underpinnings of sensitivity to specific therapies. Methods: We identified three patients with mCRPC who achieved exceptional response to platinum chemotherapy after failing prior standard therapies. To identify associated molecular lesions, we retrospectively performed clinical targeted next generation sequencing (UW-OncoPlex) on metastatic and/or primary tumors. Results: Three of three patients were identified to have biallelic inactivation of BRCA2 (breast cancer 2, early onset), a tumor suppressor gene critical for homologous DNA repair and mutations of which are associated with hereditary breast and ovarian cancers. Two patients were subsequently confirmed to carry deleterious germline mutations in BRCA2, including one patient who was diagnosed at age 66 and lacked a significant family history of cancer. The third patient had somatic BRCA2 homozygous copy loss. Conclusions: Biallelic BRCA2 inactivation in mCRPC warrants further study as a predictive biomarker for sensitivity to platinum chemotherapy.
A phase II open-label trial of GTx-758 in men with castration-resistant prostate cancer: Final analysis of the primary endpoint.
Authors: Yu Evan Y. , Hancock Michael L. , Babicz Tamas , Tutrone Ronald F. , Ng Christopher , Belkoff Laurence H. , Aronson William J. , Papai Zsuzsanna , Geczi Lajos , Getzenberg Robert H.
Published: February 2017

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 < 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 > 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.
Radium-223 (Ra-223) re-treatment (Re-tx): First experience from an international, multicenter, prospective study in patients (Pts) with castration-resistant prostate cancer and bone metastases (mCRPC).
Authors: Sartor A. Oliver , Heinrich Daniel , Mariados Neil , Méndez-Vidal María José , Keizman Daniel , Thellenberg-Karlsson Camilla , Peer Avivit , Procopio Giuseppe , Frank Stephen Jay , Pulkkanen Kalevi , Severi Stefano , Trigo Perez Jose Manuel , Schwarzenberger Paul , Li Rui , Nordquist Luke T.
Published: February 2017

197

Background: Ra-223 tx for up to 6 injections (inj) is indicated for pts with symptomatic bone metastases. Ra-223 tx beyond 6 inj has not been previously reported. Herein we report the first safety and efficacy findings of Ra-223 re-tx from an international prospective trial in mCRPC pts. Methods: Pts with CRPC with ≥ 2 bone mets who completed 6 initial Ra-223 inj with no disease progression in bone and progressed after initial tx were potentially eligible for Ra-223 re-tx, provided that hematologic (heme) parameters were adequate. No concomitant cytotoxic agents were allowed; other agents were allowed at investigator discretion. Primary objective was safety. Exploratory objectives were time to radiographic bone progression, time to ALP progression, and radiographic progression-free survival (rPFS) based on MRI/CT and bone scans performed q 3 mo. Results: 44 pts had Ra-223 re-tx, 29 (66%) completed tx with all 6 inj; median (med) number inj = 6. Med time from initial Ra-223 tx = 6 mo. Besides prior Ra-223, all pts had ≥ 2 hormonal regimens; 45% had ≥ 1 chemotherapy regimen. 32 (73%) failed novel hormonal agents, eg, abiraterone and enzalutamide. Baseline characteristics were comparable to ALSYMPCA (Table). No new safety concerns were noted; incidence of tx-emergent adverse events (TEAEs) in re-tx pts was comparable to or lower than ALSYMPCA (Table). Only 2 re-tx pts had grade 3 heme TEAEs. Only 1 pt had radiographic bone progression; med time to ALP progression was not reached. Med rPFS = 9.9 mo. Conclusions: Ra-223 re-tx was well tolerated in this highly selected population, with minimal heme toxicity, and provided continued control of disease progression in bone. Clinical trial information: NCT01934790. [Table: see text] [Table: see text]
Second interim analysis (IA2) results from a phase II trial of TAK-385, an oral GnRH antagonist, in prostate cancer patients (pts).
Authors: Saad Fred , Bailen James L. , Pieczonka Christopher Michael , Saltzstein Daniel R. , Sieber Paul R. , Maclean David B. , Shi Hongliang , Faessel Helene M. , Shore Neal D.
Published: February 2017

200

Background: Gonadotropin-releasing hormone (GnRH) antagonists achieve rapid decrease in testosterone (T) without transient T surge seen with GnRH agonists and thus may avoid clinical flare symptomatology. TAK-385 is an investigational, oral, non-peptide GnRH antagonist highly selective for the human GnRH receptor (IC50 0.12 nM). We report IA2 results from a phase 2, randomized, open label, parallel group study of TAK-385 in pts with advanced prostate cancer (NCT02083185). Methods: Pts aged ≥ 18 yrs with histologically confirmed prostate cancer, baseline T > 150 ng/dL and prostate-specific antigen (PSA) > 2 ng/mL, who were candidates for first-line androgen deprivation therapy, were randomized to receive oral TAK-385, 80 or 120 mg, once daily (QD) or leuprorelin (LEU) 22.5 mg subcutaneously every 12 wks, for 48 wks. The primary endpoint was effective castration rate of TAK-385 (T < 50 ng/dL) from wk 5–24. Secondary endpoints included: safety, pharmacokinetics (PK), and PSA. Results: At data cut-off, 75 pts had received TAK-385 (39 at 80 mg, 36 at 120 mg QD); 20 pts received LEU. Median age was 73 yrs with TAK-385 and 68.5 yrs with LEU; median treatment duration was 35.1 wks and 37.8 wks. After 3 days/4 wks/24 wks of treatment, median T was 36.9/10.6/8.9 ng/dL with TAK385 vs 648.1/13.0/11.5 ng/dL with LEU. T < 50 ng/dL was sustained over 5–24 wks in 92% vs 95% of pts (TAK-385 vs LEU). After 24 wks, PSA was reduced by 97.3% to a median of 0.1 ng/mL with TAK-385 vs 92.4% to 0.2 ng/mL with LEU. All-grade adverse events occurred in 91% vs 95% of pts (TAK-385 vs LEU); the most common were hot flush (59/60%), fatigue (21/15%), elevated alanine aminotransferase (9/10%), nasopharyngitis (8/5%), and elevated aspartate aminotransferase (5/10%). Initial analysis of pooled phase 1/2 data showed similar PK in the phase 2 pts and in previously studied healthy men, with dose-proportional plasma trough levels over > 6 mos. Conclusions: At IA2, the efficacy of TAK-385 was consistent with the GnRH antagonist mechanism of action and the safety profile was good. TAK-385 rapidly reduced T and sustained castration ( < 50 ng/dL) over 24 wks. Further investigation of TAK-385, as an option to injectable GnRH therapies, is warranted. Clinical trial information: NCT02083185.
Automated bone scan index as a quantitative imaging biomarker indicative of efficacy to enzalutamide in patients with metastatic castrate resistant prostate cancer (mCRPC).
Authors: Anand Aseem , Morris Michael J. , Larson Steven M. , Ohlsson Mattias , Joseffson Andreas , Helgstrand John Thomas , Edenbrandt Lars , Oturai Peter Sander , Roeder M. Andreas , Bjartell Anders
Published: February 2017

226

Background: The automated BSI (auto-BSI) is a computerized means of quantitatively expressing tumor burden in bone. Following the analytical validation of auto-BSI, we are now clinically qualifying the tool as a response biomarker in mCRPC. In the present study, we assess the association of auto-BSI and that of PSA with overall survival (OS) in mCRPC patients (pts) being treated with enzalutamide. Methods: All mCRPC pts who initiated enzalutamide treatment at Skåne Hospital, Sweden and at Rigshospitalet, Denmark, with a minimum of one year follow-up, were eligible for the study. Eligible mCRPC pts with baseline (BL) bone scan available before starting enzalutamide were enrolled in the study. PSA, hemoglobin (Hgb) and alkaline phosphatase (ALP) were obtained at BL. Treatment follow-up PSA and auto-BSI were obtained at week-12. auto-BSI was obtained using the analytically validated EXIN boneBSIversion 2.0. Cox regression and concordance index (c-index) were used to evaluate the association with OS. Results: 80 mCRPC pts with BL bone scans were enrolled in the study. Treatment follow-up bone scans were available from 62 pts. Univariate analysis demonstrated that auto-BSI, PSA, ALP and Hgb at BL were associated with OS (p < 0.0001). In the multivariate analysis, only auto-BSI and HgB were significantly associated with OS. The auto-BSI showed the highest c-index in prediction of OS (c-index 0.72, SE 0.03). Adding auto-BSI to the BL covariate model significantly improved the discrimination from c-index 0.67 to 0.72 (p < 0.05). At treatment follow-up, the univariate analysis of the change in auto-BSI and the percent change in PSA were strongly associated with OS with c-index 0.76 and 0.72 (SE 0.05), respectively. In bivariate analysis, the change in auto-BSI remained strongly associated with OS (p < 0.0001) whereas the percent change in PSA appeared to be less so (p = 0.07). Conclusions: Auto-BSI and its change demonstrated an independent and a strong association with OS in mCRPC pts being treated with enzalutamide. The study serve as a foundation for prospective validation of auto-BSI as an imaging biomarker indicative of efficacy to enzalutamide.
Evaluating abiraterone responses in African Americans with metastatic CRPC.
Authors: Stolten Michael D. , Ledet Elisa M. , Guccione Jeffrey R. , Feibus Allison H. , Lewis Brian E. , Silberstein Jonathan L. , Sartor A. Oliver
Published: February 2017

244

Background: A disparity between African American (AA) and other racial groups is documented in prostate cancer incidence and mortality. For metastatic CRPC, abiraterone (Abi) showed improvement in overall survival and gained FDA approval. However, Phase III trials enrolled mostly Caucasian (CA) patients. Documentation of Abi response rates in AA men is scant. Further characterization of Abi responses in AA men was the objective of this study. Methods: Age at diagnosis, prior enzalutamide (Enza) and/or docetaxel (Doc), and duration of Abi treatment were assessed. Baseline values at Abi initiation for alkaline phosphatase (ALP), hemoglobin (Hgb), and lactate dehydrogenase (LDH) were recorded. PSA values at baseline and throughout treatment were also logged. The velocity of PSA decline was determined by the PSA half-life (PSAHL) based on time to nadir. PCWG2 criteria were used to define PSA response and progression. Results: This was a single institution, retrospective cohort of 103 patients with mCRPC treated with Abi (n = 24 AA; n = 79 CA). Median age at diagnosis was 61.8 years and 62.4 years for AA and CA respectively. Prior Enza/Doc was 4.2%/33.3% for AA and 6.3%/29.1% for CA. Median duration of Abi therapy in AA was 207 days and 253 days for CA; neither median age or duration were statistically distinct. Median AA baseline ALP, Hgb, LDH, and PSA was 136 (range (r) = 59-653), 11.8 (r = 8.9-15.4), 256 (r = 157-401), and 59.9 (r = 4.8-1658) respectively. Median CA baseline ALP, Hgb, LDH, and PSA were 88 (r = 51-1600), 12.4 (r = 8.4-15.0), 204 (r = 100-528), and 40.6 (r = 2.5-2890) respectively. The difference in baseline lab values between AA and CA were insignificant. No statistical difference was seen in median PSAHL (AA = 55 days; CA = 64 days), or PSA decline of > 30% (AA = 50%; CA = 52%), > 50% (AA = 46%; CA = 39%), or > 90% (AA = 21%; CA = 14%). Finally, neither the median time to nadir (AA = 119 days; CA = 137 days) or progression (AA = 157 days; CA = 131 days) were significantly different. Conclusions: Comparison between AA men and CA men in mCRPC patients being treated with Abi showed no statistical difference in response rates, duration of response, or time to progression. Prospective, multi-institutional studies are needed to further assess these findings.
Docetaxel chemotherapy in metastatic castration-resistant prostate cancer (mCRPC): Cost of care for Medicare and commercially insured men.
Authors: Armstrong Andrew J. , Bui Cat N , Fitch Kate , Sawhney Tia , Brown Bruce , Flanders Scott C , Francis Peter St. John , Balk Mark A. , Deangelis Julie , Chambers James
Published: February 2017

262

Background: Docetaxel (DTX) is commonly used to treat metastatic prostate cancer, yet little data is available about the cost of a DTX chemotherapy episode of care (DEC) for treating mCRPC. This study analyzes DEC cost and health service utilization for men with mCRPC. Methods: We performed a claims-based analysis using Truven MarketScan and Medicare 5% sample data sets. Eligibility was required in all months of 2010 and ≥ 1 month of 2011, along with ≥ 1 2011 claim coded with prostate cancer and ≥ 1 DTX claim. Initial 2011 DECs required no DTX claim in the prior 12 months while subsequent DECs required a 60-day gap between DTX claims. DEC costs included all paid claims, except prescription drugs, from the 1st DTX claim to 30 days after the last DTX claim with early termination for death, insurance disenrollment or the end of a 24-month look-forward period. DTX drug costs were adjusted for 2011 generic DTX introduction while all other DEC costs were adjusted to 2015 using national average unit cost increase. Results: 155 commercially insured patients (COMM) and 281 Medicare patients (MDCR) were identified with 172 and 325 DECs, respectively. The average number of DTX cycles per DEC was 6.3 for COMM and 6.9 for MDCR, with 105 and 102 average days between the 1st and last infusion, respectively. The average DEC cost was $63,788 for COMM and $28,742 for MDCR with DTX drug costs contributing $13,169 (21%) and $2,588 (9%) per DEC, respectively. The average cost per DEC contributed by DTX-infusion days was $27,900 (44%) for COMM and $8,577 (30%) for MDCR. Non-DTX-infusion day costs per DEC included $10,838 (17%) for infused/injectable drugs for COMM and $7,074 (25%) for MDCR, along with $9,324 (15%) and $6,875 (24%) for inpatient admissions, respectively. 29% of COMM-DECs and 40% of MDCR-DECs had ≥ 1 inpatient admissions while 22% and 25% had ≥ 1 emergency room (ER) visit, respectively. 22% of COMM and 28% of MDCR inpatient costs and 15% of COMM and 33% of MDCR ER costs were chemotherapy related. Conclusions: Non-DTX drug costs including infusion day services, infused/injectable drugs administered on non-DTX days and inpatient admissions contributed the majority of DEC costs in COMM and MDCR mCRPC populations.
ARV-330: Androgen receptor PROTAC degrader for prostate cancer.
Authors: Neklesa Taavi K , Jin Meizhong , Crew Andrew P , Rossi AnnMarie K , Willard Ryan R , Dong Hanqing , Siu Kam , Wang Jing , Gordon Deborah A , Chen Xin , Ferraro Caterina , Crews Craig M , Coleman Kevin , Winkler James D.
Published: February 2017

267

Background: The transition from localized prostate cancer to metastatic disease often involves modulation of the Androgen Receptor (AR). During the disease progression, patients progressing on enzalutamide or abiraterone therapy exhibit amplified AR, increased intra-tumoral androgen production or AR mutations leading to promiscuity to other ligands. Therefore, AR is still the principal driver of the disease. Methods: A novel approach to block AR signaling is to specifically target AR for degradation. To this end, we have developed the PROteolysis TArgeting Chimera (PROTAC) technology that employs hetero-bifunctional small molecules that simultaneously bind VHL E3 ubiquitin ligase and a target of interest (e.g. AR). Due to induced proximity between VHL and AR, an AR PROTAC leads to ubiquitination and subsequent degradation of AR. Results: Our lead AR PROTAC, ARV-330, degrades 92-98% of total AR in all cell lines tested, with 50% degradation concentrations (DC50) < 1nM. AR degradation suppresses the AR-target gene PSA expression, inhibits proliferation, and induces potent apoptosis in VCaP cells with maximal apoptosis observed at 20 nM. While enzalutamide loses its activity in the presence of > 0.5 nM R1881, ARV-330 maintains its activity. In cells containing the ARF876L mutation, enzalutamide is an agonist; however, ARV-330 remains effective. In fact, ARV-330 is able to degrade all clinically relevant AR mutations. ARV-330 exhibits good pharmacokinetic properties, with t1/2 values of several hours and bioavailability of > 80% after sc injection. Treatment of mice with ARV-330, at doses ranging from 0.3 to 10 mg/kg, results in reduction of AR protein levels. The in vitro potency translates into in vivo efficacy, as ARV-330 demonstrates prostate involution in intact mice. In castrated mice implanted with VCaP tumors, ARV-330 shows robust reduction of plasma PSA and blockade of tumor growth. Conclusions: In summary, the AR PROTAC ARV-330 removes AR from prostate cancer cells in a potent manner and produces therapeutic effects as a result. This cellular efficacy has translated into biomarker activity and efficacy in animal models, and ARV-330 is now in preclinical development.
Taxane sensitivity markers in prostate cancer.
Authors: Feldman Rebecca , Castro Michael , Reddy Sandeep K. , Myers Charles E.
Published: February 2017

285

Background: The results from the CHAARTED and STAMPEDE trials that docetaxel plus androgen-deprivation therapy (ADT) significantly improves survival over ADT alone among men with metastatic, hormone-sensitive and hormone-naïve prostate cancers, represents a potential practice-changing movement. Clinical data exist to support the role of various predictive markers for taxane response, including low or negative class III beta tubulin (TUBB3), positive transducin-like enhancer of split 3 (TLE3) and low or negative p-glycoprotein (PGP/ABCB1). We examined a database of molecularly-profiled prostate cancer patients for taxane sensitivity markers for insight into the mechanism behind the clinical effect of docetaxel. Methods: 348 patients with prostate cancer were included in the study and tested centrally at a CLIA laboratory (Caris Life Sciences, Phoenix, AZ). Tests included one or more of the following: gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (C/FISH). Results: In all prostate cases tested, protein levels for taxane markers are: TLE3+ 58.6% (174/297), TUBB3 - 76.8% (228/297) and PGP – 89.9% (267/297). Combined rate of expression (TLE3+/TUBB3-/PGP-) is 41% (121/297), representing a subgroup of patients that may have best responses to taxane therapy. Taxane sensitivity markers by stage and AR status are shown in the table below. Conclusions: Taxane sensitivity markers are observed at a statistically significant higher frequency in AR-positive prostate cancer patients, providing a potential molecular hypothesis for the increased effectiveness of chemo-hormonal therapy observed in hormone-sensitive prostate cancers. A substantial number of both AR positive and negative patients have sub-optimal biomarker profile for taxane responsiveness highlighting an unmet need for on-going drug development in this disease. [Table: see text]
Somatic mutation detection from liquid biopsy-derived cellular aggregates formed by magnetic 3D bioprinting.
Authors: Tseng Hubert , Ionescu-Zanetti Cristian , Jensen Jeff , Gage Jacob A , Haisler William L , Desai Pujan K , Liao Angela , Brobey Reynolds , Dehghani Mehdi , Souza Glauco R , Amato Robert J.
Published: February 2017

291

Background: A challenge in the analysis of circulating tumor cells (CTC) is their scarcity, and the inability to expand them for further analysis. To overcome this obstacle, we used magnetic 3D bioprinting to form CTC spheroids that could grow. The principle of magnetic 3D bioprinting is the magnetization of cells with nanoparticles and their subsequent printing into spheroids. For this project, CTCs can be aggregated into close contact to interact and grow in culture. In this study, we demonstrated the ability to aggregate CTCs and perform next generation sequencing (NGS) to detect somatic mutations from renal and prostate cancers. Methods: Blood samples from prostate and kidney cancer patients were enriched for CTCs (Isoflux, Fluxion), from a starting blood volume of 7.5-14 mL. CTCs were isolated immunomagnetically for EpCAM+ EGFR+ cells, then enumerated for CK+ CD45-. The cells were then removed of microbeads, then magnetized by incubation with NanoShuttle (NS, Nano3D), a magnetic nanoparticle assembly, and printed into spheroids in 384-well plates. After 4 d of growth, the cells were lysed and DNA was amplified by whole genome amplificaiton (WGA) with the NGS kit (Fluxion) and quantified via qPCR. Targeted libraries were sequenced using the PGM (ThermoFisher) sequencing instrument; data was analyzed using a customized variant calling/filtering pipeline based on standard Ion Reporter alignment tools and VarSeq for variant filtering and functional interpretation. Results: CTCs were successfully aggregated using magnetic 3D bioprinting, and grew over 4 d. We then demonstrated the detection of somatic variants within a majority of the samples, for both prostate and renal cancers. Using the commercial Oncomine, we found a median of 5 COSMIC variants (32 total) per sample using cell cultures. Conclusions: We successfully developed methods to aggregate CTCs with magnetic 3D bioprinting, expanded them, and then detected somatic mutations using NGS.
Effect of androgen signaling in stromal cells on growth of prostate cancer.
Authors: Liao Chun-Peng , Chen Leng-Ying , Luethy Andrea , Kim Youngsoo , MacLeod A. Robert , Gross Mitchell E.
Published: February 2017

297

Background: Interactions between epithelial and stroma cells are important in the development of prostate cancer (PCa). Cancer-associated fibroblasts (CAFs) have been to support tumor progression, metastasis, and differentiation. Androgen receptor (AR) and related pathways are known to support the growth and survival of prostate epithelial cancer cells, the roles of AR-dependent processes in cancerous stroma are less clear. We sought to investigate if AR-dependent pathways present in CAF cells influence the growth and tumorogencity of epithelial cancer cells in relation to androgen-deprivation therapy in prostate cancer. Methods: Murine CAFs were isolated from a well-described PTEN-dependent cancer mouse model (Liao, et al Cancer Res, 2010. 70(18):7294). A co-culture system was developed based on multiple lines of murine CAFs grown along with human prostate cancer epithelial cells, and a murine-specific anti-sense oligonucleotide (ASO) against murine AR was used to specifically suppress AR expression in murine CAFs in this system. RT-PCR was used to investigate changes in gene expression. Results: Using this co-culture system, we found that murine CAFs promoted cell proliferation and colony formation in several human prostate cancer cell lines. Further, these processes were decreased by suppression of AR-expression in CAFs. Expression of genes related to tumorigenicity in epithelial cells were investigated. Markers associated with epithelial-mesenchymal transition (EMT, N-Cad) and “stemness” (OCT4, Sox2, Nanog) were increased in human prostate cancer cells grown with low-AR CAFs. Conclusions: Our data indicates that suppression of AR in CAFs results in down-regulation in the growth and tumorigenicity of prostate cancer cells through pathways related to EMT and “cell reprograming”. As such, development of therapies which inhibit the tumor-promoting pathways present in stromal cells may be one approach to improve the treatment of prostate cancer.
Study of PSMA-targeted 18F-DCFPyL PET/CT in the evaluation of men with an elevated PSA following radical prostatectomy.
Authors: Gorin Michael A. , Rowe Steven P. , Mana-ay Margarita , Szabo Zsolt , Schaeffer Edward M. , Tran Phuoc T. , Allaf Mohamad E. , Deville Curtiland , Cho Steve Y. , Pienta Kenneth J. , Pomper Martin G. , Ross Ashley
Published: February 2017

299

Background: Positron emission tomography/x−ray computed tomography (PET/CT) utilizing radiotracers targeting prostate membrane specific antigen (PSMA) offer the promise of improved sensitivity for visualizing low volume sites of prostate cancer. In this study we evaluated the sensitivity of PET/CT using 18F-DCFPyL, a novel small molecule ligand of PSMA, for imaging sites of disease in men with an elevated PSA following radical prostatectomy. Methods: Patients with an elevated PSA following radical prostatectomy (defined as ≥ 0.2 ng/mL) were imaged with CT or magnetic resonance imaging (MRI) of the abdomen and pelvis, 99mTc-methylene diphosphonate bone scan and 18F-DCFPyL PET/CT. Conventional imaging studies (CT, MRI and boen scan) were clinically reviewed by readers blinded to the PET/CT scan results. Similarly, PET/CT scans were blindly reviewed and then the sensitivity of this novel imaging test was compared to that of conventional imaging. Results: In total, 12 men with a median PSA of 0.34 ng/mL (range 0.2 to 11) were imaged as part of this study. 2 (16.7%) patients had persistently elevated PSA values after surgery and 10 (83.3%) had values which were initially undetectable but then rose to ≥ 0.2 ng/mL. On conventional imaging, only 4 (25.0%) patients had at least 1 detectable site of disease. This included 1 patient with a local recurrence detected on MRI and 3 patients with bony lesions detected on bone scan. In contrast, 9 (75.0%) patients had areas of detectable disease on PET/CT. This included 3 (25.0%) patients with a local recurrence, 3 (25.0%) with lymph node metastases, 2 (16.7%) with bony lesions and 1 (8.3%) with both lymph node and bone findings. All lesions detected on conventional imaging had corresponding areas of radiotracer uptake on PET/CT. Conclusions: 18F-DCFPyL PET/CT appears to be more sensitive for detecting areas of prostate cancer recurrence in patients with an elevated PSA following radical prostatectomy. Future work aims to more precisely define the sensitivity of this imaging test in a larger patient cohort. Clinical trial information: NCT02523924.
NRG Oncology/RTOG 9601, a phase III trial in prostate cancer patients: Anti-androgen therapy (AAT) with bicalutamide during and after salvage radiation therapy (RT) following radical prostatectomy (RP) and an elevated PSA.
Authors: Shipley William U. , Pugh Stephanie L. , Lukka Himu R. , Major Pierre , Heney Niall M. , Grignon David A. , Sartor Oliver , Patel Malti , Bahary Jean-Paul , Zietman Anthony L. , Pisansky Thomas Michael , Zeitzer Kenneth Lee , Lawton Colleen Anne , Feng Felix Yi-Chung , Lovett Richard Dana , Balogh Alexander G. , Souhami Luis , Rosenthal Seth A. , Kerlin Kevin , Sandler Howard M.
Published: February 2017

3

Background: Previous reports suggested that AAT when combined with salvage RT following RP in patients may improve prostate cancer control outcomes. Methods: Post-RP patients with pT3pN0 or with pT2pN0 and positive margins who had or developed elevated PSA levels from 0.2 to 4.0 ng/ml were randomized on a phase III, double-blind, trial of RT + placebo (64.8 Gy in 36 fractions of 1.8 Gy) vs. RT + AAT (24 months bicalutamide, 150 mg daily) during and after RT. The primary end-point was overall survival. Trial design required 725 patients and provided 80% power to detect a reduction in death rate by at least 28.5% and a 1-sided significance level of 0.046. Results: From 3/98 to 3/03, 761 eligible patients (median age 65) were randomized to RT + AAT (384) or RT + placebo (377). 248 patients (33%) were pT2pN0 and 513 (67%) were pT3pN0. 671 (88%) had a PSA nadir after RP of < 0.5 ng/ml. 649 (85%) had an entry PSA value of <1.6, 112 patients (15%) had an entry PSA of 1.6-4. Median follow up was 12.6 years. Actuarial overall survival at 10 years was 82% for RT plus AAT and 78% for RT + placebo and a hazard ratio of 0.75 (95% CI: 0.58-0.98) with a 1-sided p value of 0.018 (2-sided p = 0.036). The 12-year incidence of PC central-reviewed deaths were 2.3% for RT + AAT and 7.5% for RT + placebo ( p< 0.001).The cumulative incidence of metastatic PC at 12 years was less in the RT + AAT arm, 14% (51 patients), vs. 23% (83 patients) in the RT + placebo arm (p < 0.001). Subgroup analyses of the relative benefits of the addition of AAT to RT are planned and will be presented. Late grade III and IV toxicity were similar in the AAT and placebo arms. The combined grade III and IV toxicities for RT + AAT and RT + placebo were: bladder 7.0% vs. 6.7%, bowel 2.7% vs. 1.6%. Gynecomastia differed significantly by treatment arm, 70% vs. 11%. Conclusions: 24 months of AAT using 150mg bicalutamide daily during and after salvage RT significantly improved long term overall survival and reduced the incidence of metastatic PC and PC death. Support: NCI grants U10CA21661, U10CA180868, U10CA180822, and U10CA37422 and AstraZeneca. Clinical trial information: NCT00002874.
A randomized controlled trial to determine the effect of triptorelin on reduction of prostate volume preradiotherapy compared with standard therapy (goserelin).
Authors: Bahl Amit , Challapalli Amarnath , Masson Susan , Hilman Serena , Hurley Katrina , Persad Rajendra
Published: February 2017

30

Background: Hormone therapy in combination with radiotherapy is a curative treatment option for prostate cancer (CaP). Neoadjuvant goserelin is known to reduce prostate gland volume by about 26%, such that radiotherapy treatment volumes are smaller, reducing the risk of damage to bladder and rectum. Triptorelin is 100 times more potent than native LHRH and has a longer half life than both native LHRH and goserelin. This study evaluated the equivalence of cytoreductive efficacy of neoadjuvant triptorelin and goserelin. Methods: Seventy-onepatients with localized CaP who have chosen radical radiotherapy had been randomized by stratified block design, toreceive either triptorelin (n=37) or goserelin (n=34) with bicalutamide cover. Prostate volume was measured at baseline and 14 weeks after start of therapy on transrectal ultrasound (TRUS). PSA, testosterone levels, and EQ5D, QLQ-PR25, QLQ-C30 questionnaires were completed at baseline, 6, 10, and 14 weeks after start of therapy. All the patients had subsequent radical radiotherapy and followed up as per departmental protocol. Changes in TRUS volume and time to castrate levels of testosterone were evaluated. Results: The mean (±S.D) baseline prostate volume in the goserelin and triptorelin groups was 38.1(±12.8) cc and 39.4(±17.5) cc, respectively. The mean (±S.D) reduction in the prostate volume after 14 weeks of goserelin and triptorelin was 36.8(±18.4)% and 32.5(±20.9)%, respectively (p=0.36: Analysis of Covariance). Twenty-nine out of 34 in the goserelin group and 33 out of 37 patients in the triptorelin group achieved castrate levels of testosterone (£0.5nmol/L). The median time to castration was 6.1 (95% CI: 5.8-6.5) and 6.4 (95% CI: 5.9-10.0) weeks for goserelin and triptorelin, respectively (p=0.72: log rank). Conclusions: Goserelin and triptorelin both caused a reduction inprostate volume and achieved castrate levels of testosterone. The cytoreductive efficacy of neoadjuvant triptorelin was equivalent (non-inferior) to that of goserelin. To our knowledge, this is the first reported prospective randomized data demonstrating the equivalence of goserelin and triptorelin in the neoadjuvant setting. Clinical trial information: 2008-007028-25.
The use of whole genome copy number variation (CNV) to measure genomic instability in mCRPC CTCs.
Authors: Wang Yipeng , Greene Stephanie , Rodriguez Angel , Lee Jerry , Landers Mark , Dittamore Ryan Vance , Marrinucci Dena C.
Published: February 2017

307

Background: AR targeted therapies in combination with PARP inhibitors have recently shown efficacy in mCRPC patients with specific DNA repair gene mutations in metastatic tissue biopsies. Homologous recombination DNA repair deficiencies (HRD), associated with response to PARP inhibitors, can also be assessed by genomic instability/scarring. Accurate genomic scarring measurement in tumors can be confounded by intra-tumor heterogeneity and/or non-tumor genome contamination. To better identify PARPi sensitivity in mCRPC patients, we developed a genomic instability and scarring assay starting from single CTCs. Methods: VCaP, LnCaP or PC3 cell lines were spiked into healthy donor blood. Individual spiked cells were identified and recovered for genomic analysis using the standard Epic CTC assay. Post recovery, cells were lysed, whole genome amplified, constructed into shotgun libraries and sequenced to ~2M 2x150bp PE reads. Following alignment, whole genome copy number and instability analysis was performed to identify large scale transitions (LST, n of chromosomal breaks between adjacent regions of at least 10 Mb), % of genome altered (percentage of 1Mbp bins with copy number alterations), as well as specific tumor suppressor/oncogene copy number alterations. The association of PTEN loss with increases in genomic instability and scaring was performed. Results: Loss of PTEN function was previously shown to be associated with genomic instability. Our assessment of PTEN deletion was confirmed in PC3, while at least one genomic copy was observed in LnCaP and VCaP. The number of LSTs and % of genome altered was higher in PC3 (n = 19 +/- 3; 9.3% +/- 2.6%) than both VCaP and LnCap (n = 8 +/- 2; 6.1% +/- 0.4%). Conclusions: The association of higher genomic instability in a PTEN null cell line (PC3) vs. those with either heterozygous (LnCaP) or wild type (VCaP) PTEN status, matches published reports associating PTEN loss with increased genomic instability. Although, PC3 only demonstrates mild PARPi sensitivity in vitro, the detection of increased genomic scarring vs. cells with at least 1 functional PTEN allele confirms the assays ability to quantify genome instability at the single cell level from CTCs in a liquid biopsy.
68Ga-DOTA-Bombesin (68Ga-RM2 or 68Ga-Bombesin) PET versus 68Ga-PSMA PET: A pilot prospective evaluation in patients with biochemical recurrence of prostate cancer.
Authors: Iagaru Andrei , Minamimoto Ryogo , Hancock Steven Lee , Mittra Erik , Loening Andreas , Vasanawala Shreyas
Published: February 2017

331

Background: Detection of prostate cancer (PC) after biochemical recurrence (BCR) remains a great challenge. RM2 is a synthetic bombesin receptor antagonist, which targets gastrin-releasing peptide receptors (GRPr). PSMA is a membrane antigen expressed on prostate cancer cells. Here we present a comparison of 2 novel PET tracers, 68Ga-RM2 and 68Ga-PSMA, in patients with BCR with prior non-contributory conventional imaging. Methods: Ten men (67-83 year-old; mean ± SD: 74.3 ± 5.9) with BCR PC were imaged with 68Ga-RM2 and 7 of them also had 68Ga-PSMA PET. The SUVmax and SUVmean measurements were recorded in normal tissues and areas of uptake outside the expected physiologic biodistribution. Results: All 7 patients who had both scans had rising PSA (range: 3.5-36.5 ng/mL; mean±SD: 13.5 ± 11.5) and non-contributory conventional imaging (CT, MRI, 18F FDG PET/CT, 18F NaF PET/CT, 99mTc MDP bone scan). 68Ga-PSMA had the highest physiologic uptake in the salivary glands and small bowel, with hepatobiliary and renal clearance noted, while 68Ga-RM2 had the highest physiologic uptake in the pancreas, with renal clearance noted. Uptake values uptake outside the expected physiologic biodistribution were not statistically different between 68Ga-PSMA and 68Ga-RM2. 68Ga-PSMA localized in a lymph node and seminal vesicle in one patient with no abnormal 68Ga-RM2 uptake. In 2 patients abdominal peri-aortic lymph nodes were more easily visualized by 68Ga-RM2 due to lack of interference by radioactivity accumulation in the small intestine. Conclusions: 68Ga-PSMA and 68Ga-RM2 have distinct biodistribution in this small cohort of patients with BCR PC. High uptake in multiple areas outside the expected physiologic biodistribution suggests that both 68Ga-PSMA and 68Ga-RM2 are promising PET radiopharmaceuticals for localization of disease in patients with BCR PC and non-contributory conventional imaging. The differences in target density, biodistribution and clearance pathways may result in the superiority of one of the two tracers in different patients. 68Ga-RM2 shows similar sensitivity to 68Ga-PSMA and has the potential for being FDA-approved in the future. Clinical trial information: NCT02440308.
Correlation of galeterone-induced degradation of the androgen receptor with inhibition of a deubiquitinating enzyme.
Authors: Dransfield Daniel T. , Namdev Nivedita , Jacoby Douglas B , Ferrante Karen
Published: February 2017

345

Background: Galeterone is a highly selective oral small molecule drug candidate that disrupts androgen receptor (AR) signaling. It degrades the AR (IC50 ~1µM), is a potent CYP17 lyase inhibitor ( < 50nM), and possesses AR antagonist activity (~600nM). Galeterone-induced AR degradation was observed in models having either full-length AR or known constitutively active truncated forms of the AR receptor that lack the ligand binding domain (LBD), AR-V7 and AR567es. The LBD of the AR is not required for galeterone-dependent AR degradation. Galeterone-induced degradation activity is blocked by co-administration of the proteasome inhibitor MG132. Furthermore, galeterone-induced degradation of AR can be blocked by selective knock-down of the E3 ligases, Mdm2 and CHIP. Methods: We utilized a series of biochemical and cell-based in vitro studies to further elucidate and characterize additional signaling molecules in the proteasomal dependent mechanism of galeterone-induced AR degradation. Results: We screened a panel of 22 deubiquitinating enzymes (DUBs) in vitro and demonstrated that galeterone inhibited enzymatic activity of the DUB, USP12 with IC50 in the single digit micromolar range. In addition, we used surface plasmon resonance to demonstrate that dose-dependent inhibition of USP12 activity involves direct binding of galeterone to USP12 and USP12/UAF1 complexes with a KD of ≤ 10µM. Conclusions: Interestingly, USP12 is a co-activator of AR and selective knock-down of this DUB has been shown to increase AR degradation. USP12 has been linked to regulation of the phosphatases PHLPPs through ubiquitination. PHLPPs dephosphorylate AKT, providing an important regulatory mechanism for controlling the PI3K/AKT pathway. Since it is known that galeterone induces an increase in pAKT and pMdm2, the latter being a substrate of activated AKT, this suggests that inhibition of USP12 regulates pAKT levels through enhanced degradation of PHLPPs via increased ubiquitination. These data suggest that a differentiating mechanism of galeterone from other AR targeting agents is through inhibition of USP12, leading to enhanced AR degradation.