bluuebunny/crossref_metadata_2025 huggingface dataset:
The value of transperineal prostate apical zone biopsy in predicting urethral or apical margin status after radical prostatectomy in prostate cancer.
Authors: Dai Jindong , Shen Pengfei
Published: March 2019

127

Background: To investigate potential preoperative predictors of positive surgical margin (PSM) after radical prostatectomy, and how to reduce the possibility of urethral or apical PSM with positive biopsy cores in the apical zone of prostate (AZP). Methods: 531 patients who had radical prostatectomy during 2010-2017 in West China hospital was enrolled. The logistic regression was used to assess the preoperative factors associated with PSM. 399 patients with high/very high risk prostate cancer were recognized by National comprehensive cancer Network guidelines and 339 patients were reported positive biopsy cores in the AZP. Results: The overall PSM rate of all patients was about 30.1% (160/531) and 117 of them were reported urethral or apical PSM. The occurrence rate of urethral or apical PSM in patients with positive cores in AZP was obviously higher than that in total group (p = 0.022). We further found that the addition of positive AZP to a standard multivariable model could significantly increase the predictive value of urethral or apical PSM (p = 0.016) in different groups. The analysis also showed that neo-adjuvant hormone therapy was an independent protective factor for urethral or apical PSM in positive AZP patients, but not all patients. Conclusions: This is the first study to investigate the necessity of getting cores in the apical zone by transperineal prostate biopsy to predict the possibility of apical or urethral PSM. In clinical practice, neo-adjuvant hormone therapy should be given when patients with AZP(+) to reduce the presence of PSM, especially patients with high/very high risk prostate cancer.
Measurement science of the androgen receptor splice variant-7 protein in primary and castration-resistant prostate cancer tissue.
Authors: Sharp Adam , Coleman Ilsa , Welti Jon , Lambros Maryou B. , Yuan Wei , Nava Rodrigues Daniel , Sprenger Cynthia , Dolling David , Russo Joshua , Figueiredo Ines , Neeb Antje , Uo Takuma , Morrissey Colm , Carreira Suzanne , Nelson Peter S , Balk Steven P. , True Lawrence D. , Luo Jun , Plymate Stephen R , De Bono Johann S.
Published: March 2019

151

Background: Liquid biopsies demonstrate the constitutively active androgen receptor splice variant-7 (AR-V7) associates with reduced benefit from endocrine therapies in castration resistant prostate cancer (CRPC). These studies provide little information pertaining to AR-V7 expression in PC tissue. Methods: AR-V7 protein expression was determined for 358 primary PC samples and 293 metastatic CRPC biopsies by immunohistochemistry. Associations with disease progression, full length AR (AR-FL) expression, response to therapy, gene expression, and circulating tumor cell (CTC) AR-V7 status were investigated. Results: AR-V7 protein is rarely expressed ( < 1% of 358 cases) in primary PC but is frequently detected (75% of 40 cases) following primary androgen deprivation therapy (ADT) alone (H-score 40; interquartile range 1.25-92.5), with a further significant (p = 0.020) increase following abiraterone or enzalutamide therapy (90; 20-150). In CRPC, AR-V7 expression is mainly nuclear (94% of 144 cases), correlates with AR-FL expression (p = < 0.001), and is homogeneous within single metastases (p = 0.997) but heterogeneous in different metastases from the same patient (p < 0.001). In addition, AR-V7 expression correlates with a 59-gene signature, including HOXB13, a co-regulator of AR-V7 function. Moreover, AR-V7 negative disease associates with better PSA response (p = 0.03) and overall survival (p = 0.02) from endocrine therapies. Finally, CTC+/AR-V7+ blood samples had significantly (p = 0.004) higher AR-V7 protein expression (100; 62.5-147.5) in paired tissue biopsy compared to CTC+/AR-V7- blood samples (15; 0.0-112.5), and AR-V7 protein expression is frequently detected (63% of 16 samples) in tissue of patients with CTC- blood samples. Conclusions: AR-V7 protein is not expressed until castration resistance and occurs after primary ADT alone. Levels of AR-V7 protein vary between metastases, and although AR-V7 associates with response to endocrine therapies, this suggests multiple resistance mechanisms exist in the same patient. If developed, agents targeting AR-V7 may be best explored earlier in the course of disease and in combination with other therapies.
Outcome, costs and dollar value of docetaxel and abiraterone in prostate cancer.
Authors: Guirgis Helmy M.
Published: March 2019

155

Background: Questions have emerged on the role of diet, cost and value of Abiraterone (Abi) in prostate cancer. Abi improved the quality of life (QoL), in contrast to docetaxel (Doc) used > 6 cycles. We analyzed the data of 5 major clinical studies. Our objective was to weigh outcome, costs and dollar value of Abi and Doc in prostate cancer. Methods: Hazard ratios (HR) and company-posted prices were quoted. In hormone sensitive (HS), Doc costs x 6 cycles and Abi x 18-24 months were compared. Tests, follow-up and adverse events treatment costs (AEsTC) were computed separately. The probability of survival (PoS) was calculated as (1.0-HR) and dollar value as cost/PoS. Results: Doc costs x 6 cycles were $27,408 and AEsTC $1,450. In HS, at HR of 0.61 (Sweeney, 2015) and 0.73 (updated CHAARTED), Doc dollar value was $70,277 and $101,511 respectively. Abi costs x 2-years were $250,704, AEsTC $2,010, HR 0.73 (STAMPEDE) and value $928,533. In high risk HS (LATTITUDE), HR was 0.62 and value $659,747. At 18 months, Abi costs were $188,028. At an average HR of 0.73, value was $696,400. In comparison, in castrate-resistant (CR) chemo-naïve patients, Doc costs x 12 cycles were $54,816, AEsTC $4,840, HR 0.76 (Tannock, 2004) and value $228,400. Abi costs x one-year were $125,352 and AEsTC $1,050, HR 0.80 (COU-AA-302) and value $626,760. Conclusions: In HS, the results tend to suggest superior dollar value of Doc over Abi. In CR, the negative impact of Doc on QoL would undermine its dollar value.
Low incidence of microsurges with biodegradable polymer-delivered, subcutaneously-administered leuprolide acetate in prostate cancer patients.
Authors: Efstathiou Eleni , McLane John A. , Atkinson Stuart , Boldt-Houle Debbie , Sartor A. Oliver
Published: March 2019

158

Background: Androgen deprivation therapy is a foundational treatment of advanced prostate cancer (PCa) with the primary objective of suppressing circulating androgens.Consistent drug delivery with long-acting leuprolide acetate (LA) formulations is important in providing continuous testosterone (T) suppression throughout the course of treatment without T rising above castrate level (T breakthrough). To assess subcutaneously-administered LA (SC-LA) maintenance of T levels in PCa patients, the incidence of microsurges was evaluated in 4 pivotal trials. Methods: In 4 open-label, fixed-dose, pivotal trials, 424 eugonadal prostate cancer patients (age 40-86) who achieved medical castration (T<50 ng/dL) while on the first administration of SC-LA 7.5, 22.5, 30, or 45 mg, lasting 1, 3, 4, or 6 months, respectively, were evaluated for microsurges. A microsurge was defined as an absolute increase in T level of at least 25 ng/dL during the 4 week period after the second study dose was administered. T was measured 2-4 times on day 0 and once on days 1, 2, 3, 7, and every week until the next dose through the end of the studies. Results: Across the individual studies, 8 patients out of 424 (range 0.9-3.4% by dose, pooled 1.9%) experienced a microsurge during the acute period after the second SC-LA dose (Table). 6 of these 8 patients remained below castrate level at the peak of the surge. Conclusions: SC-LA demonstrated a very low incidence of T breakthroughs and microsurges in PCa patients and only 2 of 424 patients experienced a T microsurge above castrate levels. Limiting the occurrence of T levels above castrate levels may have clinical implications with respect to prolonged progression-free survival. [Table: see text]
Second cancer following radical prostate cancer treatment.
Authors: Aksnessaether Bjorg Y , Solberg Arne , Myklebust Tor Åge , Hoff Solveig Roth , Skovlund Eva , Klepp Olbjørn , Lund Jo-Åsmund
Published: March 2019

16

Background: We estimated second cancer (SC) risk following radical prostate cancer (PC) treatment and evaluated if the risk was influenced by treatment. Methods: We analyzed data from the Cancer Registry of Norway on all patients with PC (first cancer diagnosis) from 1997-2014. Standardized incidence ratios (SIRs) for SC were calculated. Subdistribution hazard ratios (SHRs) were estimated in treatment groups (prostatectomy (RP) reference). Results: Median follow-up in 24155 radically treated patients was 6 and 4 years in the external beam radiotherapy (EBRT) and RP-groups, respectively. SC-incidence was indifferent from that of the reference population in 24155 radically treated patients, higher following EBRT, SIR 1.06(1.01-1.12), and lower following RP, SIR 0.91(0.84-0.98). EBRT-patients had higher rectal and urinary bladder cancer incidences. Compared to RP, the EBRT-patients had a 38 % higher risk of any SC. Respective figures for rectal, urinary bladder and lung cancer: 72, 38, and 113%. Conclusions: EBRT-patients had a slightly higher SC-incidence than the general population. The rectal and urinary bladder cancer risk should be taken into account in follow-up after EBRT.[Table: see text]
A retrospective observational study assessing bone metastases (mets) detection and management of patients (pts) with castration-resistant prostate cancer (CRPC) in Canada.
Authors: Saad Fred , Kapoor Anil , Aprikian Armen G. , Casey Richard , Caveen Michele , Reiner Maureen , Gillesby Brad , Finelli Antonio
Published: March 2019

161

Background: Canadian Urological Association guidelines outline the scheduling of imaging modalities based on prostate-specific antigen doubling time (PSADT) to screen for mets in pts with nonmetastatic (M0) CRPC and to manage pts with metastatic (M1) CRPC. Data describing guideline adoption and real-world timing of bone scans and treatment patterns in Canadian CRPC pts are limited. Methods: A retrospective chart review conducted at 13 Canadian urology practices included pts with CRPC (PSA ≥2 ng/mL despite androgen deprivation therapy) sequentially identified in reverse chronological order starting July 30, 2015. Pts had no mets at CRPC diagnosis (index date). Data were abstracted from the index date to the chart review date. Coprimary objectives were to describe CRPC management in terms of timing of the 1st and repeat bone scans in M0 and treatment patterns when pts became metastatic. Secondary objectives described nonbone imaging. Results: 232 pts enrolled. Over the observation period 109 remained nonmetastatic (M0 cohort); 123 developed mets (M1 cohort). Median index PSADT was ~1.5x greater for the M0 cohort than the M1 cohort. 68 pts (71.6%) in M0 and 117 pts (95.1%) in M1 had ≥1 bone scan. Median (95% CI) months from CRPC diagnosis to 1st bone scan was 7.5 (5.6–9.6) for pts in M1 and 15.7 (10.0–23.0) for pts in M0. Median (95% CI) months from identification of mets to start of treatment for the M1 cohort was 3.2 (2.3–5.7). The most common therapies were abiraterone (55%) and enzalutamide (42%), with respective median (95% CI) durations of 12.7 (8.7–23.3) and 15.7 months (10.4–NE). 25% of pts received a bone-targeted agent. Conclusions: In CRPC, time to first bone scan was shorter for pts who subsequently developed mets or had rapid PSADT. Abiraterone and enzalutamide were the most common therapies in pts with mets. [Table: see text]
Prostate cancer cost-of-care and evaluation of traditional cost control measures.
Authors: Bansal Dhruv , Wong John
Published: March 2019

163

Background: In the current era of rapid advances in cancer care, economic burden of these treatments is becoming increasingly apparent. Measures taken by Centers for Medicare & Medicaid Services (CMS) such as closely monitoring length of inpatient stay might be inadequate in their goal to curtail costs. SEER analysis shows a 5-year overall survival for prostate cancer of 98.2 % and incidence of 179.1 in 2000 versus 97.8 in 2015 per 100,000, respectively. This encouraging result comes at the cost of increasing healthcare costs. Methods: We used National Inpatient Sample (NIS) database to extract data for patients hospitalized with primary diagnosis of prostate cancer using ICD-9 code 185. The 15-year time from 2000 till 2014 was analyzed. The metrics focused on were mean length of stay (LOS), mean cost of hospitalization and rate of discharges. Results: Discharge rate was 32.2 +/- 1.3 in 2000 versus 20.4 +/- 0.8 in 2014 per 100,000, respectively. Mean LOS declined from 3.7 +/- 0.115 days in 2000 to 2.2 +/- 0.044 days in 2014. During this same time period mean hospitalization charges increased from $14,680 +/- 466 to $49,464 +/- 1,019. The average annual inflation rate during this time period was 2.26%. After adjusting for inflation, the cost of stay in 2000 was $20,072 versus $49,464 in 2014. This effect is magnified when analyzing the cost per day of hospitalization. Cost per day in 2000 was $5,424 versus $22,483 in 2014. Conclusions: The increase in cost of inpatient stay is likely due to the advances in multi-modality treatment in prostate cancer. With the aging population and focus on cost conscious allocation of resources, this increase in costs will remain a challenge for hospital decision makers and insurance companies. We have to apply models such as the Markov model that are increasingly used to justify exorbitant prices of individual drugs. Also, given the complexity of health care costs, more variables should be included to rationalize health care spending. Cost metrics such as LOS are out dated given costs of treatments will continue to exceed costs such as nursing care and room and board costs. These complex analyses might be feasible with advances in deep learning which enable consideration of multiple variables in the decision-making process.
Keynote-365 cohort C: Pembrolizumab (pembro) plus enzalutamide (enza) in abiraterone (abi)-pretreated patients (pts) with metastatic castrate resistant prostate cancer (mCRPC).
Authors: Fong Peter C.C. , Retz Margitta , Drakaki Alexandra , Massard Christophe , Berry William R. , Romano Emanuela , De Bono Johann S. , Feyerabend Susan , Appleman Leonard Joseph , Conter Henry Jacob , Sridhar Srikala S. , Shore Neal D. , Linch Mark David , Joshua Anthony , Gurney Howard , Wu Haiyan , Schloss Charles , Poehlein Christian Heinrich , Yu Evan Y.
Published: March 2019

171

Background: Pembro has antitumor activity as monotherapy in pretreated advanced mCRPC (KEYNOTE-028; KEYNOTE-199). A study has suggested that pembro + enza after progression on enza may have clinical activity. KEYNOTE-365 (NCT02861573) is a phase 1b/2 umbrella study testing combinations in mCRPC; we report early results from cohort C combining pembro + enza in mCRPC. Methods: Patients who failed or became intolerant to ≥4 weeks of abi in the pre-chemotherapy mCRPC state were included. Pts also had to have progressed within 6 months prior to screening as determined by either PSA progression or radiologic progression in bone or soft tissue. Pts received pembro 200 mg intravenously Q3W with enza 160 mg per day orally, and response was evaluated by PSA levels Q3W and imaging Q9W for the first year and Q12W thereafter. Primary end points were safety and PSA response rate (confirmed PSA decline ≥50%). Key secondary end points were investigator-assessed ORR (RECIST v1.1), disease control rate (DCR: CR+PR+SD ≥6 mo), time to PSA progression, rPFS, and OS. Results: 69 pts initiated treatment (median age 69 years; PD-L1+ 30%; visceral disease 26%; measurable disease 36%). Median (95% CI) follow-up was 9 (7-13) mo. See efficacy outcomes in table. Treatment-related AEs occurred in 63 (91%) pts; most frequent (≥20%) were fatigue (30%), rash (23%), and nausea (22%). Grade 3-4 treatment-related AEs occurred in 28 (41%) pts; no deaths were due to treatment-related AEs. Conclusions: Early results from the pembro + enza combination show sustained activity in abi-pretreated frontline mCRPC. Observed safety profile for the combination treatment was consistent with the known safety profiles of pembro and enza. Clinical trial information: NCT02861573. [Table: see text]
Associations of cell cycle genetic variants with aggressive prostate cancer in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.
Authors: Huynh Melissa , Vyas Chirag , Penney Kathryn L. , Kibel Adam S.
Published: March 2019

175

Background: The need to differentiate patients at risk for developing aggressive prostate cancer (CaP) from those at risk for less aggressive disease has led to efforts to identify genetic markers to predict disease course and personalize treatment. A study with participants from Johns Hopkins Medical Institutions (JHMI) and Washington University (WU) found single nucleotide polymorphisms (SNPs) in cell cycle genes were associated with risk of aggressive CaP. We sought to replicate those results in the European-American population of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Methods: We focused on variants associated with aggressive CaP in the JHMI and WU cohorts, which included 13 SNPs in 12 genes ( CCNC, CCND3, CCNG1, CCNT2, CDK2, CDK6, MDM2, SKP2, TERF2, WEE1, YWHAB, YWHAH). Variants were genotyped using the Pyrosequencing assay. Patients were classified into high risk (Gleason≥8, pT3b, N+, M+), low risk (Gleason≤7, ≤pT3a, N0, M0) or non-cancer control groups based on clinicopathologic characteristics. Logistic regression analysis was used to compare genotype frequencies of each variant between groups using the dominant model. Results: There were 108 aggressive and 1080 non-aggressive CaP patients, and 1155 controls . CDK6 ( rs8) was associated with increased risk of any CaP (OR 1.2, 95% CI 1.02-1.42; p = 0.032) and high risk disease (OR 1.63, 95% CI 1.09-2.42; p = 0.017) vs. controls. In contrast, the JHMI and WU cohort found CDK6 variants to be protective against aggressive CaP. CCNG1 ( rs11541970) approached significance (p = 0.052) between high risk and control groups, and CCNC conferred a protective effect consistent with the prior study, but did not reach significance (p = 0.101). No associations with any cell cycle gene variants were detected when comparing high and low risk patients. Conclusions: Our study did not replicate the results from the JHMI and WU cohorts. CDK6 predicted an increased risk of developing any CaP and high risk CaP. However, directionality was opposite to the prior study, indicating that this variant is unlikely to be a true predictor of increased risk of or protection from aggressive CaP.
Determining androgen inactivation status in prostate cancer by [18F] DHT PET.
Authors: Zhu Ziqi , Chung Yoon-Mi , Sergeeva Olga , Kepe Vladimir , Berk Michael , Li Jianneng , Ko Hyun-Kyung , Li Zhenfei , Petro Marianne , DiFilippo Frank , Lee Zhenghong , Sharifi Nima
Published: March 2019

191

Background: Castration-resistant prostate cancer occurs in part due to increased tumor tissue testosterone (T) and dihydrotestosterone (DHT) that sustain tumor growth. T and DHT are converted to inactive T- and DHT-glucuronide (T/DHT-G) by uridine 5'-diphospho-glucuronosyltransferase family genes (UGT2B15 and UGT2B17) in glucuronidation-competent cells and excreted, but not in glucuronidation-deficient cells. Thus, low glucuronidation activity enables prostate tumors to preserve androgens, which increases hormone treatment resistance and may be detectable by functional imaging. Methods: We knocked out (KO) UGT2B15 and 17 in LNCaP cells and tested the DHT retention rate in the cell lines by pulse-chase using [3H]DHT as a probe. Free and DHT-G retention rates were separately determined after 5 to 60 min. To increase the signal difference between control and KO cells, we screened several ATP-binding cassette transporter inhibitors to block DHT-G excretion. We performed [18F]DHT PET/CT in castrated mice having a control and a KO xenograft on contralateral flanks ( n = 3). The ratio of the standard uptake value (SUV) in control to KO xenografts in each mouse was calculated. To increase the ratio between control and KO tumors, 50µg cyclosporin A (CSA) was injected 30 min before injecting [18F]DHT. Results: After 5 minutes of chase, control cells retained twice the DHT of KO cells. In control cells, 50%-70% DHT was glucuronidated. Almost no DHT-G was detected in KO cells, and free DHT was similar to control. Of the inhibitors, only CSA increased DHT-G (but not free DHT) in control cells, resulting in a 3-4-fold increase in overall signal. In vivo PET/CT showed control xenografts had higher peak SUV but also a higher elution rate. CSA increased the SUV ratio by 1.5-2. Conclusions: We developed a PET/CT modality to detect androgen inactivation in a prostate cancer xenograft model. Androgen-glucuronidation-proficient tumors give off a stronger signal that is increased by ATP transporter inhibition. Our method can provide a noninvasive means of determining androgen metabolism status and therefore could possibly predict effectiveness of potential therapies in a subgroup of tumors predisposed to androgen deprivation resistance.
Investigating a novel recombinant antibody to attenuate prostate cancer progression by targeting cell surface GRP78.
Authors: Al-Hashimi Ali , Won Kevin Doyoon , Pham Elizabeth , Mariano Natalie , Bailis Julie , Austin Richard , Shayegan Bobby
Published: March 2019

206

Background: Prostate cancer (PCa) is characterized by increased activation of the procoagulant protein, tissue factor (TF) that drive tumour progression. We now show that this process is modulated by GRP78 on the cell surface (cs). In PCa GRP78 is a endoplasmic reticulum-resident chaperone that localizes to the cell surface where it functions as a signaling molecule with antigenic properties. In response to csGRP78 presentation, PCa patients produce autoantibodies (AutoAbs) against the N-terminus of GRP78. AutoAbs:csGRP78 complex acts as a potent driver of tumor growth via upregulation of the unfolded protein response (UPR) and TF activity. We hypothesize that inhibiting the binding of anti-GRP78 AutoAbs to csGRP78 will supress UPR and TF activity. Here we describe a recombinant anti-GRP78 antibody (AEP8587) that competes with the binding of AutoAbs to csGRP78 and may act as a novel therapeutic antibody with antitumor activity. Methods: Changes in TF activity or UPR markers were evaluated in vitro in the PCa cell line DU145 following treatment with anti-GRP78 AutoAbs or co-treatment with either enoxaparin, a low molecular weight heparin (LMWH), or AEP8587. Protein expression of TF and UPR markers was determined using western blotting and qRT-PCR. TF activity was determined using a real-time continuous assay. AutoAbs were purified PCa patients (St. Joseph’s Healthcare Hamilton). Results: Pre-prostatectomy PCa patients display high levels of anti-GRP78 AutoAbs (~60µg/ml), compared to healthy controls (~5µg/ml). Here, we show that anti-GRP78 AutoAb increases TF activation in vitro and leads to increased tumor progression in a DU145 xenograft model. In contrast, we show a co-treatment of anti-GRP78 AutoAb with either enoxaparin or AEP8587 completely abolishes the AutoAb-mediated increase in TF activity in vitro. Enoxaparin or AEP8587 co-treatment reversed the AutoAb effect on increased UPR markers. Conclusions: We have identified anti-GRP78 AutoAb as a driver of PCa progression. Our results indicate that a recombinant antibody, AEP8587, can bind to csGRP78 and prevent the binding of anti-GRP78 AutoAbs. This represents a potential novel means to manage PCa progression.
ARV7 and ARFL mRNA in blood to predict androgen receptor inhibitors and docetaxel response in castration-resistant prostate cancer patients.
Authors: Marin Mercedes , Jiménez Natalia , Reig Òscar , Pereira Maria Verónica , Mila Maria , Benitez Daniel , Cabezón Raquel , González Azucena , Mengual Lourdes , Alcaraz Antonio , Ribal Maria Jose , García-Recio Susana , Juan Manel , Prat Aleix , Mellado Begona
Published: March 2019

207

Background: The constitutively active androgen receptor (AR) variant 7 ( ARV7) has been associated with AR inhibitors (ARI) resistance, while its role predicting taxanes response remains controversial. We investigated the association between ARV7 and AR full length ( ARFL) expression pre-docetaxel treatment and changes pre- post-treatment in blood with docetaxel activity in metastatic castration-resistant prostate cancer (mCRPC) patients. Methods: ARV7 and ARFL mRNAs were tested by quantitative reverse-transcription PCR in peripheral blood mononuclear cells (PBMC) from mCRPC patients. Measurements were performed before docetaxel treatment and in a subset of patients also post-treatment. A cohort of patients treated with ARI was also included as a control. Results: We included 105 patients: 50 with treated with docetaxel and 55 with ARI. In 28 patients ARV7 and ARFL were evaluated pre and post-docetaxel. High ARV7 correlated with longer PSA-PFS (HR 0.42; 95%CI 0.18-0.99; P= 0.049), radiologic (RX)-PFS (HR 0.32; 95%CI 0.14-0.72; P= 0.006), and overall survival (OS) (HR 0.41; 95%CI 0.18-0.91; P= 0.028) to docetaxel. When relativizing to ARFL we observed that high ARV7/ ARFL ratio also correlated with a better PSA-PFS (HR 0.38; 95%CI 0.17-0.85; P= 0.0179) and RX-PFS (HR 0.43; 95%CI 0.2-0.91; P= 0.0273) to docetaxel. High ARV7 and ARV7/ ARFL were correlated with lower prostatic-specific antigen (PSA) progression-free survival (PFS) to ARI therapy (HR 2.18; 95%CI 1.03-4.6; P= 0.043 and HR 3.84; 95%CI 1.54-9.4; P= 0.004, respectively). ARV7/ ARFL and treatment- ARV7/ARFL interaction were independently associated with better PSA-PFS to docetaxel treatment and lower PSA-PFS to ARI. The increase of ARV7 mRNA levels after docetaxel treatment was indicative of longer OS (HR 0.07; 95%CI 0.008-0.57; P= 0.013). Conclusions: High ARV7 expression and ARV7/ ARFL ratio evaluated in PBMC pre-docetaxel are associated with better clinical outcome in mCRPC patients and lower ARI benefit. The increase of ARV7 levels after docetaxel exposure was also indicative of better outcome.
Impact of prostate specific antigen doubling time on time to metastasis and overall survival in non-metastatic castration-resistant prostate cancer patients.
Authors: Freedland Stephen J. , Ramaswamy Krishnan , Lechpammer Stanislav , Mardekian Jack , Schultz Neil M. , Huang Ahong , Wang Li , Baser Onur , George Daniel J.
Published: March 2019

211

Background: Prostate-Specific Antigen Doubling Time (PSADT) can help predict prostate cancer (PC) patient outcomes, particularly in hormone sensitive disease. However, PSADT has not been well validated in non-metastatic castration-resistant (nmCR) PC patients. This study examined the prognostic impact of PSADT on time to metastasis (TTM) and overall survival (OS) among nmCRPC patients in the Veterans Health Administration (VHA) database. Methods: VHA patients in this retrospective study were males with PC who had medical or surgical castration between Jan 1, 2012 and Dec 31, 2016. Patients actively receiving luteinizing hormone-releasing hormone treatment with ≥2 PSA post-castration increases were identified. The 3rd PSA value ≥25% and 2 ng/ml > the 1st PSA value was the CRPC (index) date; patients had continuous VHA enrollment for ≥12-months pre- to post-index date. Patients were followed until the earliest of death or disenrollment. PSADT was calculated as the natural log of 2 divided (Ln2) by the log slope of PSA using all PSA values after CRPC until metastases, and patients were categorized into 2-month cohorts. A demographically and clinically adjusted Cox regression model explored associations between PSADT cohorts and TTM and OS. Results: We identified 3,579 patients from which 1,389 (38.8%) progressed to mCRPC while 2,190 (61.2%) remained nmCRPC. Overall, patients averaged 73 years of age. PSADT was calculable in 2,800 patients with an average PSA value of 25.49 ng/mL. After a median follow-up of 820 days, the median PSADT was 17 months. Compared with the PSADT > 12 months cohort, PSADT ≤2, > 2 to ≤4, > 4 to ≤6, > 6 to ≤8, and > 8 to ≤10 month cohorts were associated with higher risk of metastasis (hazard ratio [HR]: 33.77, CI: 25.93-43.96; HR: 14.32, CI: 11.83-17.32; HR: 6.58, CI: 5.42-7.98, HR: 4.14, CI: 3.27-5.25; HR: 3.14, CI: 2.45-4.03, respectively) and death (HR: 12.27, CI: 9.20-16.35; HR: 5.32, CI: 4.26-6.64; HR: 3.50, CI: 2.74-4.47, HR: 2.29, CI: 1.68-3.14; HR: 1.64, CI: 1.14-2.37, respectively). Conclusions: Short PSADT strongly associated with TTM and poor OS in nmCRPC patients. Newer nmCRPC treatments are advisable for high-risk patients.
Immunogenomic landscape of neuroendocrine small cell prostate cancer.
Authors: Nappi Lucia , Kesch Claudia , Vahid Sepideh , Fazli Ladan , Eigl Bernhard J. , Kollmannsberger Christian K. , Gleave Martin , Zoubeidi Amina , Wyatt Alexander William , Chi Kim N.
Published: March 2019

217

Background: Neuroendocrine small cell prostate cancer (NEPC) is a lethal variant of prostate cancer (PCa) unresponsive to hormone therapy and associated with poor prognosis. Cisplatin induces short-lived responses and therefore alternative novel therapeutic options are urgently needed. Methods: Prostate specimens from radical prostatectomy or transurethral resection (benign prostate specimens n = 4, primary untreated or neoadjuvant hormone-treated adenocarcinoma n = 30, castrate-resistant prostate cancer-CRPC n = 38 and NEPC n = 16) were evaluated for PD-L1 (SpringBio, M4420), AR, chromogranin A, synaptophysin, NSE and CD56 expression by immunohistochemistry (IHC). Archival tissue from liver, lymph nodes and prostate from 30 additional patients with de novo and treatment emergent NEPC were analyzed for PD-L1 expression by IHC. The intensity was assessed as percentage of positive cells / mm2 of tissue. Targeted and whole exome sequencing of the high-density tumor areas were performed and correlated to the PD-L1 status (PD-L1+ve: > 1% of positive cells). OS was calculated from the date of diagnosis of NEPC to death. We set out to define PD-L1 expression and immunogenomic characteristics of NEPC. Results: PD-L1 was expressed in 0%, 5%, 10% and 41% of benign, adenocarcinoma, CRPC and NEPC specimens, respectively. The PD-L1 expression intensity was significantly higher in patients with NEPC (mean: 40%, range: 5-100%) compared to benign, adenocarcinoma and CRPC samples (mean: 0%, 2% and 8%, respectively, P < 0.0001). There was a higher prevalence of biallelic DNA Repair Defects (DRD) in the PD-L1+ve vs PD-L1-ve patients (65% vs 0%, P = 0.005). The median OS of the NEPC patients was 8.5 months vs 10.5 months in PD-L1+ve vs PD-L1-ve tumors (HR 1.24, 95% CI: 0.59-2.75, p = 0.55). Conclusions: NEPC have greater PD-L1 expression than adenoCa and CRPC. Biallelic DRD was exclusively observed in PD-L1+ve patients. Since PD-L1 expression and DRD have been associated to response to PARP and PD1/PD-L1 inhibitors in prostate and other cancers, further studies evaluating the activity of those agents in NEPC patients are warranted.
Direct evidence of a clonal and tumor-directed T cell response to prostate cancer brachytherapy.
Authors: Williams Scott , Keam Simon , Halse Heloise , Mitchell Catherine , Caramia Franco , Byrne David , Haupt Sue , Ryland Georgina , Darcy Phil , Sandhu Shahneen Kaur , Blombery Piers , Haupt Ygal , Neeson Paul J
Published: March 2019

22

Background: We characterised the immune response in human prostate cancer (PC) to high dose rate brachytherapy (HDRBT) using serial pre- and post-HDRBT biopsies. Methods: Prostate biopsies and peripheral blood samples were obtained from 9 men with clinically localised PC at baseline and again 14 days following a 10 Gy fraction of HDRBT. Immune infiltrates were characterised using multiplex immunohistology (T cell and pan-immune panels) and targeted gene expression profiling (Nanostring pan-cancer immune panel). T cell repertoire was assessed using T cell receptor (TCR) Vbeta CDR3 deep sequencing. Results: HDRBT induced profound but heterogenous immune responses. At the extremes, one patient had an extensive tumor-infiltrating lymphocyte (TIL) response post-HDRBT, comprising T cells (CD4+ > CD8+ > Treg), B cells, and PDL1+ antigen presenting cells (macrophages and CD11c+ dendritic cells); another had a substantial baseline immune infiltrate eliminated by HDRBT. TIL-hi cases (either before or after HDRBT) had a conserved signature of T cell activation, differentiation, and trafficking, with upregulation of checkpoint molecules PD1, IDO1, BTLA, CTLA4, ICOS, B7-H3 and FoxP3. Those TIL-hi specifically in response to HDRBT also had down-regulation of genes regulating myeloid differentiation and granulocyte chemotaxis pre-HDBRT. Conversely, a monocyte-like myeloid-derived suppressor cell signature was seen in the TIL-lo responders. The median number of dominant clones ( > 1% prevalence) determined by TCR sequencing was 24.5 and 26.5 pre- and post-HDRBT respectively. Only 2 clones (in 1 patient) were present at both time points with the T cell repertoire otherwise being completely new following HDRBT. A subset of PC-associated T cell dominant clones was also present in the PB in all patients, suggesting HDRBT can induce systemic immunity. Conclusions: We have shown that treatment of localized prostate cancer with HDRBT induces a marked clonal TIL infiltrate dominated by T cells likely to be operating under the control of multiple checkpoints. These first-in-human data may be able to inform the rational selection of immunotherapy to combine with HDRBT.
Interpreting survival outcomes for African-American (AA) patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with sipuleucel-T (SIP-T) with number needed to treat to benefit (NNTB).
Authors: Moses Kelvin A. , Flanders Scott C. , Harmon Matthew , Chang Nancy N. , Rayford Walter , Quinn David I. , Sartor A. Oliver
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Background: AA men often present with more aggressive prostate cancer and are less likely to receive treatment, negatively affecting quality-of-life and overall survival (OS). Sipuleucel-T is an autologous cellular immunotherapy approved for asymptomatic or minimally symptomatic mCRPC. Data from the PROCEED registry showed that OS for AA pts treated with SIP-T was 9.3 mo longer than OS for Caucasian pts. In a prior subgroup analysis of Phase III data, AA pts realized a 30.7-mo difference in OS with SIP-T vs. placebo (PBO). We calculated the NNTB to further interpret the OS benefit in AA pts. Methods: Data were pooled from 3 Phase III mCRPC SIP-T trials (D9901, D9902A, and IMPACT). The absolute risk reduction (ARR) is calculated from Kaplan-Meier estimates at 12-, 24-, and 36-mo for all SIP-T subjects, and an AA cohort, receiving ≥1 infusion. NNTB, the inverse of the ARR, represents the number of pts needed to be treated with SIP-T to prevent 1 additional death compared to PBO. All NNTB values are rounded up. Results: Of the 737 pooled mCRPC pts enrolled, 488 men were randomized to SIP-T (n=33 AA), and 249 to PBO. Baseline clinical characteristics between the SIP-T and PBO groups were well balanced; however, compared to overall SIP-T and PBO, AA SIP-T pts were more likely to have received prior chemotherapy, lower hemoglobin, and better performance status. The NNTB at 12-mo was the same (13) for both the pooled SIP-T and AA treated cohort. At 24-mo, the NNTB values were 10 for pooled and 5 for AA. At 36-mo, an NNTB of 8 (pooled) and 3 (AA) SIP-T treatments prevented 1 additional death (Table). Conclusions: This NNTB analysis shows a favorable survival benefit for AA men treated with SIP-T and all treated SIP-T subjects. NNTB values declined over 3-years, suggesting durability of clinical benefit with SIP-T, and that it may address a known survival disparity in AA with prostate cancer. Studies with larger sample sizes may confirm if AA pts derive a greater OS benefit from SIP-T. Clinical trial information: NCT00065442. [Table: see text]
Radium 223 treatment in metastatic castrate-resistant prostate cancer: Impact of sequencing on survival—Real-world outcomes from a single United Kingdom center.
Authors: Jiang Xue Yan , Atkinson Sarah , Cuming Sam , Burns Alexander , Pearson Rachel Anne , Frew John A. , Azzabi Ashraf S. , McMenemin Rhona Margaret , Pedley Ian David
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Background: Radium 223 (Ra-223) is a FDA and EMA approved alpha particle radiopharmaceutical used to treat men with metastatic castrate resistant prostate cancer (mCRPC) with symptomatic bone metastasis. In view of emerging systemic options, new EMA 2018 licence indication is for 3rd line onwards. We aim to evaluate the impact of systemic therapy sequencing on survival outcomes from a heterogeneous cohort of 228 patients treated with Ra-223 in a single UK centre. Methods: We prospectively collected data from 228 men underwent Ra-223 therapy for mCRPC between April 2014 and August 2018. Survival outcomes in relation to sequence of systemic treatment used prior to Ra-223 were analysed. Results: Medium age = 72 (51-87) years. Most patients (n = 142, 69%) received at least one systemic agent prior to Ra-223: docetaxel and/or cabaxitaxel chemotherapy (n = 60, 29%), abiraterone (n = 62, 30.1%) and enzalutamide (n = 67, 32.5%) in various sequences. No patients received concurrent Ra-223 /systemic treatment other than LHRH analogue. Key findings are summarized in table below. Conclusions: Our data demonstrated better survival trend in patients who received Ra-223 early. Patients who received prior chemotherapy have worse survival compared with those who were chemo-naïve likely due to bone marrow depletion. Ra-223 should not be offered to patients who have already had both cabaxitaxel and docetaxel as their medium survival is too poor to justify a treatment which takes 6 months to complete.[Table: see text]
Immunogenomic landscape of neuroendocrine prostate cancer (NEPC).
Authors: Ferguson Alison , Bhinder Bhavneet , Conteduca Vincenza , Sigouros Michael , Sboner Andrea , Nanus David M. , Tagawa Scott T. , Rickman David , Elemento Olivier , Beltran Himisha
Published: March 2019

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Background: Prostate cancer (PCa) shows limited clinical benefit from current immunotherapy strategies. NEPC is a histologic subtype of advanced PCa that most often arises clonally from castrate resistant prostate adenocarcinoma (CRPC) as a mechanism of resistance, but shares pathologic, clinical, and molecular features with small cell lung carcinoma (SCLC). We investigated the immune landscape of NEPC in relation to other PCa subtypes and SCLC to identify potential immunological targets. Methods: We evaluated RNA-seq from 190 patients comprising benign prostate (n = 29; 25 PCa matched), localized PCa (n = 68), hormone-naïve metastatic prostate adenocarcinoma (mPCa; n = 11), CRPC (n = 54), NEPC (n = 25) with follow-up data, and SCLC (n = 28) (Rudin et al., Nat Gen 2012). Additionally, 290 patients had WES data available for tumor mutational burden (TMB). Unsupervised clustering of FPKMs was performed to identify an immune rich cluster of 232 genes, which was used to categorize immune status and prioritize validation of select targets by IHC. Results: Median TMB of NEPC was similar to CRPC (38.0 vs 37.0 p= 0.44) but significantly lower than SCLC (38.0 vs 142.5, p< 0.001). Unsupervised assessment of T-cell related gene expression identified a predominantly cold immune status across subtypes, with hot (n = 8) tumors associated with metastatic tumors of the LN and bone. Worse overall survival was seen with intermediate vs cold T-cell immune status (66.5 mo vs 101.5 mo; p < 0.001). Further analysis of NEPC showed lower expression of cytokines ( p< 0.01) and variation in checkpoint markers. Specifically, NEPC had significantly lower expression of PD1 in relation to CRPC ( p= 0.0001) and SCLC ( p = < 0.0001), higher PDL1 than CRPC ( p= 0.05) but comparable with SCLC ( p= 0.93) and lower PDL2 than PCa and SCLC ( p= 0.03; < 0.001, respectively). Conclusions: NEPC is characterized by a relatively ‘cold’ tumor immune microenvironment similar to other metastatic prostate cancer subtypes but higher PDL1 expression comparable to SCLC. The inverse correlation between survival outcome and immune infiltration, as well as the novel expression changes in cytokines and checkpoint markers support further investigation into the immune landscape and potential targets for NEPC.
Results of a 50 patient single-center phase II prospective trial of Lutetium-177 PSMA-617 theranostics in metastatic castrate-resistant prostate cancer.
Authors: Hofman Michael , Violet John A , Hicks Rodney J , Ferdinandus Justin , Thang Sue Ping , Iravani Amir , Kong Grace , Ravi Kumar Aravind , Akhurst Timothy J. , Mooi Jennifer , Guo Christina , Tran Ben , Jackson Price , Scalzo Mark , Eu Peter , Williams Scott , Sandhu Shahneen Kaur
Published: March 2019

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Background: Lutetium-177 (177Lu)-PSMA-617 (LuPSMA) is a radiolabelled small molecule that binds with high affinity to prostate specific membrane antigen (PSMA) enabling targeted delivery of beta-radiation. We have previously reported favourable activity with low toxicity in a 30 patient study in men with metastatic castrate-resistant prostate cancer (mCRPC) and now report updated results including a twenty patient extension cohort. Methods: In this phase II trial, 50 pts with PSMA-avid mCRPC who had progressed after standard therapies received up to 4 cycles of LuPSMA every 6 weeks. The primary endpoints were PSA response (PCWG2) and toxicity (CTCAE v4). Other endpoints included imaging response, PSA PFS and OS. Cut-off for analysis 5 Oct 2018. Results: 76 men were screened to identify 50 patients eligible for treatment. Median PSA doubling time was 2.6 months. The majority of patients had received prior docetaxel (84%), cabazitaxel (48%), and abiraterone and/or enzalutamide (90%). The mean administered radioactivity was 7.5 GBq/cycle. PSA decline ≥ 50% was achieved in 32 of 50 patients (64%, 95% CI 50-77%), including 22 patients (44%, 95% CI 30-59%) with a PSA decline ≥ 80%. 27 patients had measurable soft tissue at baseline and 56% of these patients had a partial or complete response by RECIST 1.1. The most common toxicities attributed to LuPSMA were transient G1-2 dry mouth in 68%, G1-2 nausea in 48%, and G1-2 fatigue in 36%. G3-4 toxicities attributed to LuPSMA were infrequent with thrombocytopenia in 10% and anaemia in 10%. Median PSA PFS was 6.9 months (95% CI 6.0-8.7) and median OS was 13.3 months (95% CI 10.5-18.0). Upon subsequent progression, further LuPSMA was administered to 14 patients (median 2 cycles commencing 359 days from enrolment); PSA ≥ 50% response occurred in 9 patients (64%). Conclusions: This expanded 50 patient cohort confirms high response rates and low toxicity with LuPSMA in men who had progressed after standard therapies. In patients who subsequently progressed and were administered further LuPSMA, high response rates were also observed. These results have provided the basis for randomised controlled trials currently underway. Clinical trial information: ACTRN12615000912583.
The influence of treatment sequence in the prognostic value of TMPRSS2-ERG as a biomarker of taxane resistance in castration-resistant prostate cancer.
Authors: Reig Òscar , Marin Mercedes , Mila Maria , Font Albert , Domenech Montserrat , Rodriguez Vida Alejo , Carles Joan , Suárez Cristina , Gonzalez del Alba Aranzazu , Jiménez Natalia , Victoria Iván , Sala Nuria , Ribal Maria Jose , López Sandra , Etxaniz Olatz , Maroto Pablo , Fernandez Pedro L. , Prat Aleix , Mellado Begona
Published: March 2019

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Background: TMPRSS2-ERG expression at peripheral blood has been correlated with lower docetaxel benefit. This multicenter study prospectively assessed the role of TMPRSS2-ERG mRNA as a taxane-resistance biomarker in blood and retrospectively in tumors, and explored the impact of prior abiraterone/enzalutamide (A/E) in castration-resistant prostate cancer (CRPC) patients and in vitro. Methods: TMPRSS2-ERG was tested by quantitative reverse-transcription PCR. We included 204 patients (137 blood and 124 tumor samples) treated with taxanes. TMPRSS2-ERG expression was correlated with PSA-progression-free survival (PFS), radiological-PFS (RX-PFS), and overall survival (OS). Independent association with survival was evaluated by multivariate Cox modeling. ERG knockdown, combinatorial and sequential experiments with enzalutamide and docetaxel were performed in VCaP cells. Results: In the multivariate analysis prior A/E (HR: 1.833; P = 0.005) and blood TMPRSS2-ERG (HR: 2, 95%CI; 1.1-3.67; P = 0.018) , were independently associated to lower PSA-PFS. In patients without prior A/E, both blood and tumor TMPRSS2-ERG independently predicted lower PSA-PFS (HR 2.92; P = 0.014 and HR 1.82; P = 0.045, respectively) to taxanes. This was not observed in patients with prior A/E. There was a significant interaction between blood TMPRSS2-ERG detection and prior A/E related to PSA-PFS (P = 0.032) and RX-PFS (P = 0.009). In vitro stable ERG inhibition did not sensitize VCaP cells to docetaxel. Concomitant enzalutamide and taxanes were synergistic, but prior enzalutamide reduced docetaxel cytotoxicity in VCaP cells. Enzalutamide induced neuroendocrine markers and reduced E-cadherin expression. Conclusions: Prior hormone-therapy may influence taxanes response and TMPRSS2-ERG prognostic value. Thus, multiple and sequential biomarkers are needed in CRPC follow-up evaluation.
Adverse events of special interest assessed by review of safety data in enzalutamide castration-resistant prostate cancer (CRPC) trials.
Authors: TOMBAL Bertrand F. , Armstrong Andrew J. , Barrus Jeffrey Kent , Beer Tomasz M. , Chowdhury Simon , Evans Christopher P. , Heidenreich Axel , Higano Celestia S. , Kamba Tomomi , Lin Ping , Nikolayeva Natalia , Sugg Jennifer , Steinberg Joyce Leta , Taplin Mary Ellen , Saad Fred
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Background: Androgen receptor inhibitor enzalutamide improves survival in patients with metastatic CRPC (mCRPC) and reduces risk of metastasis or death versus placebo in patients with non-metastatic CRPC (nmCRPC). This post hoc analysis evaluated the incidence of adverse events (AEs) of special interest reported with enzalutamide versus placebo in CRPC trials. Methods: Safety data from four Phase 3, placebo-controlled enzalutamide trials in men with CRPC (PROSPER, nmCRPC, NCT02003924; PREVAIL, mCRPC, NCT01212991; AFFIRM, mCRPC, NCT00974311; and 9785-CL-0232, mCRPC, NCT02294461) were assessed for AEs of special interest, including ischemic heart disease (IHD) [defined by narrow Standardised MedDRA Queries “Myocardial Infarction”/“Other Ischemic Heart Disease”], falls, and fractures. Data were reported as overall incidence and adjusted for treatment exposure (per 100 patient-years), and summarized as follows: patients receiving enzalutamide (n = 2799) and placebo (n = 1898) in all four Phase 3 trials. Results: Median treatment duration was 13.73 months with enzalutamide and 4.80 months with placebo in the combined Phase 3 trials. Overall incidence of IHD was higher with enzalutamide versus placebo in the combined Phase 3 trials (Table), remaining higher once adjusted for treatment exposure (2.5 with enzalutamide vs. 2.2 with placebo). Similarly, exposure-adjusted rate of falls and fractures were also higher with enzalutamide versus placebo (Table). Clinical trial information: NCT02003924 (PROSPER); NCT01212991 (PREVAIL); NCT00974311 (AFFIRM); NCT02294461 (9785-CL-0232). Conclusions: In this combined analysis of CRPC trials, incidences of IHD, falls, and fractures were higher with enzalutamide versus placebo in all patients. Efforts to identify patients at high risk for these AEs and reduce their risk, e.g. via exercise and cardiovascular risk reduction, are important in these patients, particularly in elderly men and those with cardiovascular comorbidities.[Table: see text]