bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical utility of Foundation One tissue molecular profiling in men with metastatic prostate cancer.
Authors: Zhu Jason , Tucker Matthew D , Healy Patrick , Humeniuk Michael Sandon , Jarvis Casey , George Daniel J. , Armstrong Andrew J.
Published: February 2018

318

Background: In the era of precision medicine, significant effort has been placed on identifying clinically actionable molecular targets to aid in the treatment of metastatic prostate cancer (mPC). Recent data supports homologous repair and mismatch repair deficiencies to guide the use of PARP inhibitors/platinum chemotherapy or pembrolizumab, respectively. We analyzed the clinical utility of Foundation One (FO) somatic genomic profiling in men with mPC. Methods: We performed a retrospective review of men with mPC in the Duke Cancer Center who received FO testing 01/2010 - 04/2017. We asked whether FO testing identified actionable genomic lesions that led to a change in clinical practice, and if men benefited from this novel genomic matched approach to treatment. Results: We identified 77 men with FO tests. Of these, 77% (59/77) had adequate tissue for FO testing. 76% had mCRPC, 42% had > 3 prior systemic therapies (enzalutamide 51%, docetaxel 39%, abiraterone 41%, sip-T 34%, radium-223 22%). The most common FO genomic alterations were: TP53 deletion/mutation (37%), TMPRSS2-ERG fusion (32%), and PTEN loss (31%). FO revealed 207 genomic alterations, classified into actionable (6), potentially actionable (44), non-actionable (126), and non-informative (31). Of the 6 patients with actionable mutations (BRCA2, ATM, PALB mutation/loss), 4 (67%) received matched olaparib therapy and 3 had PSA or prolonged radiographic stabilization, with durations of therapy of 3-19 months. Of 28 men with potentially actionable genomic findings, 3 (11%) received targeted therapies, including olaparib for a CDK12 mutation, and pembrolizumab for a PMS2 mutation and for a PD-L2 genomic gain. No responses to pembro were observed; the man with a CDK12 mutation responded to olaparib for 8 months. Overall, 42% (25/59) of evaluable men did not have a targetable mutation; 4/77 (5%) had clinical benefits from testing. Conclusions: A small but significant minority (~5%) of men with mPC appear to benefit from FO somatic tumor profiling, particularly those with homologous repair deficiencies. Larger prospective studies are needed with clinical outcomes in order to further understand the clinical utility of routine FO testing in this setting.
The role of reference pathology to assess MRI-TRUS fusion prostate biopsies in a tertiary referral center.
Authors: Kohl Tobias , von Brandenstein Melanie , Kuru Timur H. , Hansen Nienke , Persigehl Thorsten , Porres-Knoblauch Daniel , Pfister David , Hartmann Arndt , Heidenreich Axel
Published: February 2018

32

Background: Risk stratification for patients diagnosed with prostate cancer (PCa) through MR-TRUS fusion biopsy still relies on Gleason (GL) grading of the biopsy specimens. GL grading of the same sample can differ between pathologists. In our tertiary high-volume center GL grading of the biopsy specimens is crucial for further therapy planning. Methods: Reference pathology of 42 patients after transperineal MR-TURS fusion plus saturation biopsy was assessed by one specialized genitourinary pathologist. GL grading of the original pathology and the reference pathology for the saturation and targeted biopsy cores were compared. Risk groups for this study were set as GL 6 for low, GL 7a and GL 7b for intermediate and GL 8, GL 9 and GL 10 for high-risk. Results: In 42 patients 49 lesions were identified by mpMRI (PI-RADS 3-5) in which 150 biopsy cores were taken. In addition, 709 cores were taken as saturation biopsies. The highest GL grading per patient differed in 18 (43 %) of the cases. In 16 cases, there was a difference within the targeted biopsies but only in 8 cases there was a difference in the saturation biopsies. In 6 cases both saturation and fusion biopsies were different. Taking risk stratification into account there was a misclassification with low- and intermediate risk in 9 (21 %) cases, an intermediate- and high risk in 2 cases and a misclassification within the same risk group in 6 (14 %) cases. In 16 of the 18 differences there was an upgrading of the Gleason score by the reference pathologist whereas only in 2 cases there was a downgrading. Conclusions: The data shows that in times of mpMRIs and transperineal MRI-TRUS fusion biopsies it still is the GL score graded by the pathologist who accounts for many potential therapy plan mistakes. In this study 21 % of the patients were misclassified as GL 6 while reference pathology graded for GL 7a or GL 7b. The demonstrated data suggests that there should be a reference pathology at least for every GL 6 cancer and that the quality of GL grading should be monitored. Also this data again addresses the need for a better risk stratification irrespective of the GL score that can be done in a more objective way with less potential for misclassification.
Patterns of prostate cancer management across Canadian prostate cancer treatment specialists.
Authors: Shayegan Bobby , So Alan I. , Malone Shawn , Hotte Sebastien J. , Finelli Antonio , Canil Christina M. , Hew Huong , Park-Wyllie Laura , Chi Kim N. , Saad Fred
Published: February 2018

321

Background: The Canadian GU Research Consortium (GURC) was recently established to bring comprehensive prostate cancer centres together to collaborate on research, education, and adoption of best practices. As an initial step to inform the work of the GURC, an electronic questionnaire was designed to assess management of advanced prostate cancer care in Canada and better understand patterns of care. Methods: A 59-item online questionnaire was developed by a multidisciplinary scientific committee to measure physician practices, patterns of care, treatment sequencing, and management of mCRPC. After pre-testing, the online questionnaire was sent to 93 urologists, uro-oncologists, medical oncologists, radiation oncologists, and general practitioner oncologists who are actively involved in the treatment of prostate cancer. Results: A total of 49 (53%) respondents completed the questionnaire between April 17, 2017 to May 17, 2017. Although all respondents indicated a role in initiating life-prolonging oral therapy for mCRPC and monitoring treatment and side effects, chemotherapy initiation was mainly a medical oncologist role compared to other specialties (p < 0.05, chi-square). Symptom management such as palliative care and end-of-life care were provided mainly by radiation oncologists (100%) and medical oncologists (81%) compared to urologists (33%) and uro-oncologists (50%), p < 0.05, chi-square). Patient mix varied across the disciplines. Urologist practices were composed primarily of non-metastatic prostate cancer patients (73%), as were radiation oncologist practices (77%), while uro-oncologist practices included both non-metastatic (58%) and metastatic (40%) patients. Medical oncologists practices were mainly (91%) metastatic patients. Referral patterns also varied by discipline. Conclusions: In Canada, prostate cancer treatment involves multiple disciplines providing a range of care at different points across the treatment continuum. We plan to do further research to better understand variation in practice and improve multidisciplinary coordination for patients with advanced prostate cancer.
Impact of new agents (NAs) on survival of metastatic castration-resistant prostate cancer (mCRPC) patients (pts): A single-Institution retrospective analysis.
Authors: Caffo Orazio , Kinspergher Stefania , Maines Francesca , Macrini Sveva , Veccia Antonello
Published: February 2018

323

Background: Until few years ago, docetaxel (DOC) was the only agent able to significantly prolong overall survival (OS) of mCRPC pts: at the time of disease progression, other drugs without any survival benefit (mitoxantrone, vinorelbine, cyclophosphamide) or DOC re-challenge (DOC-re) in selected cases could be proposed. In the last years several NAs [abiraterone (AA), cabazitaxel (CAB), enzalutamide (ENZ), radium 223(RA223)] have been introduced in the clinical practice since they demonstrated an OS improvement. Moreover, a hypothetical cumulative OS advantage could derive from their sequential use. The present report is aimed to assess the impact on NAs on mCRPC pts’ OS in the daily clinical practice. Methods: We retrospectively evaluated all mCRPC pts treated in our Institution from 02/2002 to 06/2015 and recorded their medical history, anticancer treatments and survival outcomes. For the purpose of the present study, we consider pts who never received at least one NA (group A) and pts who received at least one NA (group B). To avoid selection bias due to a fast performance status worsening preventing further treatments, we consider only pts who received at least one agent after first line progression. For the OS analysis we considered the start of mCRPC first line. Results: We selected a consecutive series of 212 pts: 80 not treated (Group A) and 132 treated (Group B) with NAs. In the Group A 50 pts received first-line DOC followed by DOC-re only, while the remaining 30 pts received also agents different than DOC. In the group B 78, 35, and 19 pts received one, two, and three NAs, respectively. Group A pts were significantly younger and had higher baseline levels of PSA and lactate dehydrogenase (LDH). The OS was significantly longer in Group B than in Group A (36.0 vs 19.6 mos, p < 0.0001). The impact of NAs use on OS was confirmed at the multivariate analysis comprising the other factors which significantly affected OS (hemoglobin, LDH, alkaline phosphatase, pain, performance status, PSA). Conclusions: Although the limitation due to its retrospective nature, our analysis confirms that the introduction of NAs in the daily clinical practice led to an OS improvement.
Upfront docetaxel with androgen deprivation therapy in the elderly patient with metastatic hormone-naïve prostate cancer: Single institution experience.
Authors: Rayner Lindsay Jennifer Andrew , Challapalli Amarnath , Blackmore Eve , Rea Katherine , Wells Natasha , White Paul , Hilman Serena , Masson Susan , Huckett Rebecca , Garadi Krishna , Kirk Hannah , Kabala Julian , Oikonomopoulou Viktoria , Bahl Amit
Published: February 2018

328

Background: Following CHAARTED & STAMPEDE, upfront Docetaxel chemotherapy became standard of care for metastatic hormone-naïve prostate cancer (mHNPC). We sought to evaluate our experience in the elderly group of patients (>70 yrs) compared with the non-elderly cohort. Methods: A retrospective analysis was undertaken of 38 patients commenced on upfront docetaxel chemotherapy, from Jan 16 - Jan 17. Patients were stratified as low (LR) and high risk (HR), as per the LATITUDE study. Progression was defined as per PCWG-3 criteria. The progression free survival (PFS) was calculated as time from start of treatment to date of progression and analysed by Kaplan-Meier estimates and log-rank test. Rates of febrile neutropenia (FN) were also evaluated. Results: The median age was 69 (range: 53-80) yrs, with 50% (19/38) HR patients. The median PFS was 11.5m for progressors (P; 42%) and not reached for non-progressors (NP; 58%), (p<0.0001). Granulocyte colony stimulating factor (G-CSF) was used in 13/38 (34%) patients; these did not experience FN. The overall rate of FN was 20% where G-CSF was not used. Overall 31/38 (81.6%) completed 6 cycles of chemotherapy, with 26% requiring dose reductions (Table). Overall, of the 9/16 (56.3%) patients who progressed within 6m of completing docetaxel, 3 had Cabazitaxel as the next treatment (P: 2/3 (66.7%), median PFS 6.2m) and 6 had novel androgen receptor targeted therapy (P: 5/6 (83.3%), median PFS 3.3m). Conclusions: Upfront docetaxel is reasonably well tolerated in the elderly with comparable median PFS to younger patients. Use of GCSF significantly minimizes the risk of FN in this group and should be considered as standard of care. In patients who progress within 6m of completing docetaxel, we feel optimal sequencing to be Cabazitaxel followed by subsequent therapies.[Table: see text]
The survival outcome, prostate-specific antigen (PSA) response and risk of fatigue of enzalutamide as first- and later-line treatment options in patients with metastatic castration-resistant prostate cancer (mCRPC): The real-world experience.
Authors: Poon Darren M.C. , Wong Kenneth C.W. , Chan T.W. , Law Kitty , Chan Kuen , Lee Ka Chai , Lee Conrad , Ting Chan Fong ,   Hong Kong Society of Uro-Oncology
Published: February 2018

330

Background: The real-world data regarding the efficacy and toxicity, particularly fatigue, of Enzalutmide (Enza) as first and later line treatment options in mCRPC patients is currently lacking. We aimed to evaluate the survival outcome, PSA response and rate of fatigue of Enza in clinical practice outside trial setting. Methods: The clinical records of mCRPC patients treated with Enza from all 7 public oncology centers in Hong Kong between August 2015 and October 2017 were reviewed. The treatment efficacy and its determinants, and toxicities were determined. Results: A total of 117 mCRPC patients were treated with Enza, of whom 29.1%, 48.7%, 19.3% had Enza as their first (chemo-naïve), 2nd (post-docetaxel or abiraterone) and 3rd or above (had at least 2 of the prior followings: docetaxel, abiraterone, cabazitaxel or radium-223) line treatment options. Visceral metastases were present in 20.6/29.8/50% patients with 1st/ 2nd / 3rd or above line Enza. The median overall survival (OS) and progression-free survival (PFS) were not reached (1yr OS rate: 82%)/15.8/7.4 and 7.1/3.9/2.2 months for 1st/2nd/3rd or above lines Enza, respectively (p = 0.0002). PSA responses ( > 50% decline of PSA from baseline with Enza) were achieved in 73.5/35.1 (post-docetaxel: 53.8%/post-abiraterone: 29.5%)/19.2% patients with 1st/2nd/3rd or above lines Enza (p < 0.001). The presence of PSA response was associated with both favorable OS (HR 0.19; p < 0.0001) and PFS (HR 0.29; p < 0.001) in the multivariate analysis of whole cohort. Grade 1-2 and 3-4 fatigue was present in 44.1/59.6/57.7% and 5.9/7.0/19.2% patients with 1st/2nd/3rd or above line Enza, respectively (p = 0.023). The use of 3rd or above lines of Enza is significantly associated with grade 2 or above fatigue in multivariate analysis of whole cohort (HR = 8.05; p = 0.01). Conclusions: In real-world clinical setting, more frequent PSA response, longer OS and PFS was found in chemo-naïve patients with Enza. Patients with later lines of Enza had higher risk of fatigue.
Use of low-dose, weekly carboplatin in men with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: O'Leary-Kelly Meghan , Gao Dexiang , Weisdack Sarah , Lam Elaine Tat , Bernard Brandon David , Flaig Thomas W. , Kessler Elizabeth Riley
Published: February 2018

331

Background: Medical treatment options for advanced prostate cancer have evolved rapidly in recent years, with multiple new agents available. Our group had previously reported the use of weekly carboplatin for mCRPC in the pre-docetaxel era. The efficacy and toxicities of low-dose, weekly carboplatin were evaluated in a more contemporary patient cohort. Methods: We performed a retrospective review of patients with mCRPC treated with carboplatin from 2006-17 at a single health system. Carboplatin (AUC 2) was given weekly for 4 weeks of a 6-week cycle in combination with 1mg daily dexamethasone. Results: Sixty-four carboplatin-treated patients were identified, with a mean baseline prostate-specific antigen (PSA) of 568.55 ng/mL (range 0.02-4322). The median number of treatment cycles was 3 (range 1-10). The therapy was generally well tolerated and a dose-reduction was required for only 4 patients. Previous therapy included: docetaxel 95.3%, cabazitaxel 21.9%, abiraterone 53.1%, and enzalutamide 29.7%. A PSA decline of 30% occurred in 20 of 64 patients (31%). The response rate varied based on prior therapy. The most common adverse events were fatigue (80%), anemia (64%), and neuropathy (48%). There were 20 patients with Grade 3 adverse events. The most common was thrombocytopenia (n = 9), and 1 grade 4 thrombocytopenia. No other grade 4 toxicities were noted. Conclusions: New treatment options are needed for mCRPC after progression on currently approved agents. Platinum therapy may have increased activity in specific genomic subtypes of prostate cancer. These results compare favorably with the TROPC study of cabazitaxel (39% PSA response) in spite of the heavy pretreatment of our population. This retrospective report shows that carboplatin has activity and little toxicity in an unselected cohort of mCRPC.
Prediction of outcome in bone metastatic, castration-resistant prostate-cancer-patients under enzalutamide by combining biomarkers.
Authors: Schlack Katrin , Schrader Andres Jan , Krabbe Laura-Maria , Kannen Karoline , Semjonow Axel , Boegemann Martin
Published: February 2018

334

Background: Under early Enzalutamide (Enza) treatment of bone mCRPC (bmCRPC), prostate-specific antigen (PSA) might be misleading, since a PSA-flare may occur. Bouncing of alkaline phosphatase (APB) was shown as a promising surrogate for survival outcome. Low lactate dehydrogenase (LDH) usually predicts better outcome. The purpose of this study was to evaluate the prognostic ability of APB, LDH, PSA and information of the pooled markers after initiation of Enza. Methods: 89 bmCRPC-patients were analyzed. PSA, LDH and AP were monitored at 2, 4, 8, 12 and 20 weeks. APB was defined as an increase of AP after initiation of Enza with a subsequent, significant decline below baseline during the first 8 weeks of therapy. APB vs. no Bounce as well as LDH and PSA increase vs. decline were analyzed using Kaplan-Meier analyses (KMA) and uni- and multivariate (UV/MV) cox-regression models. Results: In KMA declining PSA and LDH as well as APB were associated with longer median PFS with 7 (95% confidence interval: 4.2-9.8) vs. 3 months (2.3-3.7) for PSA, 6 (4.1-8) vs. 2 (1.2-2.8) for LDH and 8 (0-16.3) vs. 3 (1.9-4.1) for APB. Analysis of OS showed similar results with 17 (11.7-22.3) vs. 12 months (7.0-17.1) for PSA, 17 (13.2-20.8) vs. 7 (5,8-8.2) for LDH and 19 (7.9-30.1) vs. 12 (7.7-16.3) for APB. In UV APB (Hazard Ratio (HR): 0.52 (0.3-1.0); p = 0.02), PSA-decline ≥50% (HR: 0.49 (0.3-0.7); p < 0.01) and LDH-normalization (LDHnorm) (HR: 0.39 (0.2-0.6); p < 0.01) were significantly associated with longer PFS. Considering OS LDHnorm was a significant prognosticator for longer survival (HR: 0.39 (0.2-0.6); p < 0.01). In MV only LDHnorm showed a trend towards better OS (HR: 0.49 (0.2.-1.1); p = 0.09). Combining those markers and separating a group with APB, LDHnorm and PSA-decline and a group with PSA-decline alone KMA showed better PFS (11 (0.2-21.8) vs. 4 (0-8.6)) and OS (20 (17.7-22.3) vs. 8 (0.3-15.7)) in favor of the group with 3 beneficial markers. In UV the presence of all 3 markers was significantly associated with longer PFS (HR: 0.23 (0.1-0.7); p < 0.01) and OS (HR: 0.26 (0.1-0.8); p = 0.02). Conclusions: APB and LDHnorm may add to identifying bmCRPC-patients with favorable prognosis during early Enza-therapy.
Relationship between neutrophil lymphocyte ratio (NLR) and MDSC concentration in localized and metastatic castration resistant prostate cancer (mCRPC) patients.
Authors: Basu Arnab , Kollengode Kanthi Athreya , Rafatnia Ali , Manoli Hugh , Danenberg Genevieve , Chakravartty Eesha , Epstein Alan L. , Pinski Jacek K.
Published: February 2018

338

Background: Human Myeloid Derived Suppressor Cells (MDSCs) have gained recognition as a significant population of cells that arise in cancer patients to mediate immune tolerance. MDSCs have been validated as a prognostic factor in several tumor types. The Neutrophil-Lymphocyte Ratio (NLR) is an easily obtained marker of inflammation that has also been validated as a prognostic marker in tumors including prostate cancer. We measured and compared MDSC concentrations and NLR in a cohort of patients with prostate cancer and also examined thier relationship with PSA Progression, a validated marker of overall survival. Methods: Blood was collected from patients with localized prostate cancer (n = 14) and mCRPC (n = 44) at 0 and 6 months. The percent CD33+ HLA-DRlow HIF1a+, CD33+ HLADRlow C/EBPb+, CD11b+ HLA-DRlow HIF1a+, and CD11b+ HLA-DRlow C/EBPb+cells as a fraction of PBMC were determined and reported. NLRs were obtained within 4 weeks of MDSC measurements. Patients were followed for a period of 2 years; PSA-Progression (PSA-P) was defined as a PSA doubling time of < 3 months in association with an increase of at least > 5ng/mL from PSA nadir Results: Higher Gleason scores were statistically associated with a NLR of greater than 2 (r = 0.07, p = 0.02, 95% CI [0.01-0.14]). Increasing MDSC% did not correlate with increasing Gleason scores (r = 0.13, p = 0.31) or predict PSA-P at 6 months (p = 0.16). MDSC% in patients with mCRPC (4.25%, 95% CI[3.34-5.17]) were significantly higher than localized prostate cancer (1.7%, 95% CI[1.02-2.37]) . There was a highly statistically significant relationship between the percentage of MDSC in PBMC with the neutrophil lymphocyte ratio (r = 0.68, p = 0.001, 95% CI [0.31-1.05]). Conclusions: MDSC concentrations in metastatic prostate cancer patients are significantly higher than those with localized disease and are associated with an increased neutrophil lymphocyte ratio. Although a trend was detected towards MDSC% predicting PSA-P, in this limited sample it was not statistically significant.
CYP11A1 inhibition as a therapeutic approach for the treatment of castration resistant prostate cancer.
Authors: Oksala Riikka , Karimaa Mari , Simola Outi , Ramela Meri , Riikonen Reetta , Vehmaan-Kreula Pirjo , Rummakko Petteri , Wohlfahrt Gerd , Kallio Pekka , Mustonen Mika VJ
Published: February 2018

340

Background: Castration-resistant prostate cancer (CRPC) is a major cause of cancer mortality worldwide. The mechanisms behind the development of resistance are complex and not fully understood; altered androgen synthesis, androgen receptor (AR) overexpression or gene amplification, and mutations have been indentified. However, tumor growth may still be responsive to therapies that can further suppress de novo intratumoral steroid synthesis upstream of CYP17A1. ODM-208 is an oral, non-steroidal and selective inhibitor of CYP11A1 enzyme that suppresses the synthesis of all steroid hormones and their precursors. Methods: The inhibition of CYP11A1 was measured in vitro by the formation of radiolabelled isocapronic acid in a human adrenal cortex cell line (H295R), and further analysing pregnenolone (Preg) and testosterone (T) formation by ELISA. The tumor growth inhibition of ODM-208 alone or in combination with prednisone (Pred) was studied in VCaP CRPC xenograft where also concentrations of main steroid hormones progesterone (P), corticosterone (CORT) and T in tumors and adrenals were analysed. In addition, plasma ACTH and LH levels were measured at the end of the xenograft study. In dogs an ACTH stimulation test was done. Toxicity studies were conducted in rats and dogs. Results: ODM-208 potently inhibits CYP11A1 and synthesis of Preg and T with nM concentrations in vitro. In the VCaP CRPC xenograft ODM-208 alone and in combination with Pred significantly inhibited tumor growth. Concentrations of T, P and CORT were significantly decreased in the adrenals, indicating strong CYP11A1 inhibition. Also, significantly decreased steroid levels in tumors was observedhe Pred combination increased plasma ACTH levels less than ODM-208 alone, whereas no difference was seen in the LH. In dogs ACTH-stimulated cortisol production was significantly inhibited after single oral dose of ODM-208. In toxicological studies ODM-208 showed expected reversible findings in target tissues, mainly related to the pharmacology. Conclusions: ODM-208 shows promising antitumor activity in preclinical CRPC models with favorable toxicological profile. Thus, ODM-208 might have potential for treating the patients with CRPC.
Treatments for metastatic hormone-sensitive prostate cancer: A systematic review.
Authors: Firwana Belal , Sonbol Mohamad Bassam , Mahmoud Fade A. , Arnaoutakis Konstantinos
Published: February 2018

346

Background: Over the past few years, the treatment of metastatic hormone sensitive prostate cancer (mHSPC) was revolutionized with the addition of docetaxel (DOC) or abiraterone (ABI) to the previous standard of care androgen deprivation treatment (ADT). Here, we sought to compare the effectiveness of docetaxel and abiraterone directly against ADT and indirectly to each other. Methods: We included randomized controlled trials (RCT) evaluating the efficacy of treatments in adults with newly diagnosed mHSPC. First-line treatments with DOC and ABI were considered. Efficacy outcome measures are overall survival (OS) and failure-free survival as (FFS) as defined by individual trial. If FFS was not reported, biochemical progression-free survival was considered FFS due to its specificity. The overall effect was pooled using the DerSimonian random effects model. Testing for subgroup difference was conducted using meta-regression method. Results: A total of five RCTs were included; three RCTs compared DOC+ADT versus ADT involving 2,992 participants, and two RCT compared ABI+ADT versus ADT involving 2,201 participants. The addition of DOC to ADT showed a significant improvement in OS compared to ADT monotherapy (HR 0.77, 95% CI 0.66 to 0.89) as well did the addition of ABI to ADT (HR 0.62, 95% CI 0.53 to 0.71). p-value for subgroup interaction was <0.05, suggesting a significant difference between pooled DOC and ABI effects, favoring the addition of ABI vs. DOC to ADT. Similar effects were found in significantly improving FFS when adding DOC (HR 0.64, 95% CI 0.58 to 0.70) or ABI (HR 0.30, 95% CI 0.27 to 0.34) to ADT compared to ADT monotherapy. p-value for interaction subgroup interaction was again significant <0.05 favoring the addition of ABI vs. DOC to ADT. Conclusions: The addition of either DOC or ABI to ADT showed significant improvement in OS and FFS when compared to ADT monotherapy in patients with mHSPC. Test for interaction suggests better outcome of ABI in comparison against DOC. Discussion with patients is encouraged to choose the appropriate treatment considering the adverse event profile for each. Further head-to-head comparison is needed to determine the effect.
The docetaxel-abiraterone acetate sequence compared to the abiraterone acetate-docetaxel sequence in metastatic castration-resistant prostate cancer patients with a response to previous castration superior to 12 months.
Authors: Desle Maxime , Derminne Alexandre , Lejeune Sarah , Seront Emmanuel
Published: February 2018

353

Background: With the approval of the multiple new life-prolonging treatments for men with metastatic castration-resistant prostate cancer (mCRPC), the optimal sequencing of chemotherapy and androgen-receptor (AR) targeting agents remains unclear. Although response duration to castration could influence decision choice for second hormonal therapies, we do not know whether chemotherapy efficacy could be similar to AR targeting agents such as abiraterone acetate (AA). Methods: A retrospective analysis of mCRPC patients treated at Jolimont Hospital is reported. Patients included were castration-resistant PC with a response to castration superior to 12 months. They were treated with sequential docetaxel and AA, in either order. The combined progression-free survival (combined PFS: PFS1 + PFS2) of AA followed by docetaxel is compared to the reverse sequence (docetaxel followed by AA). Baseline characteristics are reported prior to the start of the first agent in the sequence. Results: Forty-two patients who started treatment for mCRPC between January 2013 and February 2017 were identified: 22 were in the docetaxel-AA sequence (Group A) and 20 were in the AA-docetaxel sequence (Group B). The median duration of response to castration was 16 months in Group A and 18 months in Group B. Proportion of Gleason > 8 was higher in group A (60% vs 50%). Visceral or lymph node disease was more important in group A (35% vs 16%). Median pre-treatment PSA was similar in the two groups (27 and 30). In the group A, PFS1 was 9 months and PFS2 was 8 months, resulting in a combined PFS of 17 months (range 5 to 47months). In the group B, PFS1 was 8 months and PFS2 was 7 months, resulting in a combined PFS of 15 months (range 4 to 45 months). Conclusions: We do not observe differences in clinical outcomes based on alternative sequencing of AA and docetaxel in men with mCRPC with a previous response duration to castration longer than 12 months.
Abiraterone or docetaxel in men with metastatic castration-sensitive prostate cancer: A pooled analysis of castration resistance-free survival and toxicity.
Authors: Helou Joelle , Catton Charles N , Bauman Glenn , Fazelzad Rouhi , Raphael Jacques
Published: February 2018

354

Background: Recent meta-analyses suggested an improvement in overall survival (OS) with the addition of Abiraterone (A) vs Docetaxel (D) to androgen deprivation therapy (ADT) in the treatment of men with metastatic castration-sensitive prostate cancer. However, none have reported castration resistance-free survival (CFS) and toxicity data; two clinically relevant outcomes for physicians and patients. Methods: We conducted a systematic review and meta-analysis to assess CFS and toxicity of adding A or D to ADT in men with castration-sensitive prostate cancer. The electronic databases Ovid MEDLINE, Cochrane Central Register of Controlled Trials and EMBASE, were searched for randomized controlled trials. Pooled hazard ratios (HR) for CFS, and pooled risk ratios (RR) for grade 3 or higher toxicity were analyzed using the Mantel-Haenszel method and generic inverse variance. To account for between-studies heterogeneity, random-effect models were used to compute pooled estimates. Subgroup analyses compared patients on A and D in terms of CFS. Results: Five studies were included. The addition of A or D to ADT decreased the risk of development of castration-resistance by 53% (5 studies, 4,462 participants, HR = 0.47, 95% CI 0.33-0.67). In a subgroup analysis, the addition of A seemed to be better than D for the outcome CFS (5 studies, HR = 0.31, 95% CI 0.27-0.34 versus HR = 0.62, 95% CI 0.56-0.69, test for subgroup difference, p< 0.001). Different profiles of toxicity were seen with A and D. While A increased the risk of hypokalemia (3,107 participants, HR = 6.63, 95% CI 3.5-12.5) and cardiac toxicity (3,107 participants, HR = 2.4, 95% CI 1.7-3.3), D increased the risk of neutropenia (2,151 participants, HR = 13, 95% CI 8.9-18.8) and neuropathy (2,151 participants, HR = 2.25, 95% CI 1.18-4.3). Conclusions: The addition of A and D to ADT increases CFS in men with castration-sensitive prostate cancer, with a longer CFS noted for A compared to D. Considering CFS and OS, A may be preferred to D as initial therapy. Toxicity profiles differed between A and D. Quality of life and cost differences between A and D are other important factors and were not considered in this analysis.
Association of single nucleotide polymorphisms (SNPs) in CYP17A1 and SLCO2B1 genes and clinical outcome in metastatic castration-resistant prostate cancer patients treated with abiraterone acetate: results of the ABIGENE prospective study.
Authors: Borchiellini Delphine , Mahammedi Hakim , Viotti Julien , Gravis Gwenaelle , Roubaud Guilhem , Beuzeboc Philippe , Largillier Remy , Linassier Claude , Khalil Ahmed , Kaphan Regis , Joly Florence , Eymard Jean-Christophe , Falkowski Sabrina , Bompas Emmanuelle , Zanetta Sylvie , Schiappa Renaud , Maurin Maeva , Etienne-Grimaldi Marie-Christine , Milano Gerard A. , Ferrero Jean-Marc
Published: February 2018

358

Background: Abiraterone acetate (AA), a CYP17A1 inhibitor, has been approved in the treatment of metastatic castration-resistant prostate cancer (mCRPC). Germline polymorphisms in genes involved in androgen biosynthesis or transport may influence response and survival in this setting. Methods: ABIGENE is a multicentric prospective non-randomized pharmacogenetic study (NCT01858441). The primary objective was to investigate the association between 13 SNPs in genes related to AA pharmacology (CYP17A1, SLCO2B1 and SLCO2B3) and radiographic progression-free survival (rPFS), according to PCWG2 criteria, in pts with mCRPC treated with first-line AA + prednisone. The main secondary objectives were to evaluate the impact of these SNPs on radiographic and PSA response, overall survival (OS) and toxicity. SNPs were detected in blood samples before starting AA and analyzed by pyrosequencing or PCR-RFLP methods. Kaplan-Meyer’s curves with log-rank tests and cox regression models were used to identify relationships between SNPs and survival. Chi2 tests and student t-tests were used to identify association with response rate and toxicity. Results: 147 pts in 17 french centers were included between 2013 and 2017. Here are presented the results for the first 109 pts. The median follow-up was 28.7 months. Overall response rate (ORR) was 17%, and 74% pts had stable disease as the best response. Median rPFS was 10.9 months (95% CI 9.2-15.3). One SNP (rs10883782) in CYP17A1 was associated with rPFS on AA therapy (Table). Two other SNPs in CYP17A1 (rs4919683) and SLCO2B1 (rs1077858) were significantly associated with radiographic response. Data on PSA response, OS and toxicity will be presented at the meeting. Conclusions: This is the first prospective dedicated study to show an association between SNPs related to androgen metabolism and clinical outcome in mCRPC treated with AA. Clinical trial information: NCT01858441. [Table: see text]
Experience of a Brazilian oncological center using abiraterone acetate in metastatic castration-resistant prostate cancer patients.
Authors: Preto Daniel D`Almeida , Zucca Luis Eduardo , Carcano Flavio Mavignier , Zylberberg Ricardo , Neif Joao Antonio Junior , Fruet Filho Carlos Alberto
Published: February 2018

364

Background: Abiraterone acetate (AA), a selective inhibitor of androgen biosynthesis, improves overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients. In Brazil, despite this medication has been approved by health regulatory agency since 2013, due to the high cost, few public services release to their patients. It's interesting to note that this drug configures the eighth most judicial request medication in the country, as the way brazilian constitution ensures equal treatment for all patients. Methods: We performed a unicenter retrospective cohort study of 45 patients with mCRPC, receiving AA after chemotherapy with docetaxel, in the period from 2014 to 2016. The primary end point was OS. The secondary end points included the epidemiological profile, assessing the type of access to medication (judicial request, health insurance and patient's resource) and PSA response rate. Results: The median OS was 15 months. The mean duration use of AA was 10.87 months (± 6.8). Most patients (75.6%) have filed a lawsuit to get the medication and the average time between the request and the application of AA was bigger in this judicial request group (2.7 vs 1.4 months). Biochemical response was evidenced in 39% of patients. Conclusions: Our unicenter data on post-Docetaxel use of AA improved overall survival in a select group of mCRPC patients, and it is in line with the COU-AA-301 trial. Cost effectiveness evaluations combining with a patient`s protocol should be performed in order to incorporate this medication into the brazilian public health system. Characteristics of the patients. [Table: see text]
Survival after sipuleucel-T (SIP-T) and low-dose ipilimumab (IPI) in men with metastatic, progressive, castrate-resistant prostate cancer (M-CRPC).
Authors: Ku Justine , Wilenius Kirk , Larsen Claire , De Guzman Kyle , Yoshinaga Steven , Turner Jeffrey S. , Lam Richard Y. , Scholz Mark C.
Published: February 2018

368

Background: Phase III trials evaluating enzalutamide or abiraterone in MP-CRPC prior to docetaxel report a median survival of 35 months. SIP-T functions by stimulating cancer-specific dendritic cells and prolongs survival. IPI showed a borderline survival advantage in a large randomized trial. Thus, there may be potential synergy with SIP-T and IPI (SIPIPI) in combination. Methods: Between April 2013 and April 2014, 9 docetaxel-naive men with MP-CRPC were treated prospectively with SIP-T followed immediately by low-dose IPI 1 mg/kg given for a total of 1 to 3 doses every three weeks. As has been previously published (Immuno Targets and Therapy, March 2017), cancer-specific immunoglobulins (IGS) directed at PA2024 and PAP showed a statistically-significant increase after SIP-T and a further statistically-significant increase, above the level achieved with SIP-T, after IPI. Three patients died from progressive disease after 9, 18, and 20 months. This abstract updates the outcome and survival of the remaining 6 patients. Results: Adverse events from SIPIPI were negligible. For the 9 men, the median age, Gleason score, and number of previous hormonal interventions were 77 years, 8, and 3, respectively. Median baseline PSA and Gleason score were 1.7 and 8, respectively. Eight men had bone metastases and 1 had lymph node metastasis. For the 6 surviving men, median follow-up since SIPIPI is 50.5 months (40-53). Their median PSA as of September 2017 is 5.5 (range: 0.27–18.10). Further treatment since SIPIPI includes abiraterone (4) enzalutamide (5) radium-223 (3) docetaxel (2) cabazitaxel (1) carboplatin (1) pembrolizumab (2) and Olaparib (1). One patient continues with a stable PSA of 0.27 without any further treatment post SIPIPI except SBRT. Conclusions: In this small trial of SIPIPI performed in men with docetaxel-naive MP-CRPC, median survival has now surpassed 4 years and the 6 surviving men still maintain a relatively low median PSA of 5.5. One man continues in durable remission without any further therapy except SBRT administered immediately post IPI.
Impact of 2012 USPSTF prostate cancer screening recommendations on prostate cancer detection and presentation at Kaiser Permanente Northern California (KPNC).
Authors: Presti Joe , Horton Brandon , Alexeeff Stacey , Prausnitz Stephanie , Avins Andy
Published: February 2018

37

Background: In 2012, the USPSTF gave a “D” grade to PSA-based prostate cancer screening stating “the benefits of PSA-based screening for prostate cancer do not outweigh the harms”. The impact on prostate cancer screening, detection and presentation are unknown. Methods: A retrospective cohort design encompassing the years 2010 to 2015. In screen-eligible, KPNC members (African American men ages 45-69 and all other men ages 50-69), the annual rates of PSA testing, prostate biopsy and the grade and stage of all prostate cancers at presentation were compared between the pre-guideline period, 2010/2011; and the post-guideline period , 2014/2015. Results: The rate of screening declined substantially from the pre-guideline period to the post-guideline period, from a rate of 42.7% of eligible men screened per year during 2010/2011 to a rate of 32.5% of eligible men screened per year during 2014/2015; the relative rate and 95% confidence interval (CI) was 0.762 (0.759-0.765). Comparing the same time periods, the rates of prostate biopsy and overall prostate cancer detection declined even more sharply, with relative rates of 0.391 (95%CI 0.375-0.407) and 0.455 (95%CI 0.436-0.475) respectively. There was a modest increase in the rate of metastatic disease between these two time periods, with a relative rate of 1.29 (95%CI 1.11-1.48). Conclusions: Following the 2012 USPSTF statement, significant declines in PSA testing, prostate biopsy and overall cancer detection rates were seen along with a significant increase in the rate of patients presenting with metastatic disease. [Table: see text]
Retrospective analysis of fatigue in men with metastatic castration-resistant prostate cancer treated with enzalutamide.
Authors: Sridhar Srikala S. , Smith Alan D. , Fallah-Rad Nazanin , Hansen Aaron Richard
Published: February 2018

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Background: Enzalutamide (E) improves survival in men with metastatic castration-resistant prostate cancer (mCRPC). Fatigue (F) while taking E is poorly understood and may limit the use of this life-prolonging drug. Methods: All men treated with E for mCRPC at Princess Margaret Cancer Centre from August 2010 and July 2016 were included. Relevant factors collected, include age, ECOG, Charleston Comorbidity Index, disease characteristics, prior therapies, concomitant medications, and details regarding E treatment and response. Univariate (UVA) and multivariate (MVA) analysis were performed using logistic regression. Results: 415 men started E for mCRPC during this period. Median age at diagnosis was 66 years (range 42-94) and median time to castration-resistance (TTCR) was 113 days. Prior therapies included docetaxel (21%) and abiraterone (26%). Bone was the most common site of metastasis (76%) followed by lymph nodes (45%) and visceral (20%). Concurrent corticosteroid use was 18% and PSA response (≥50%) rate was 55%. Median duration on E was 224 days. F on E occurred in 178 patients (43%) and 56 (13%) men required a dose-reduction due to F. 26 men (6%) stopped E due to F (Table). Conclusions: F is an important and common side effect of E in men with mCRPC. Duration of exposure to androgen deprivation, markers of systemic inflammation (such as increased NLR and platelets) and advanced age appear to be associated with E-related F and difficulty administering drug. There was no association between corticosteroid use and E-related F and difficulty administering drug. [Table: see text]
68-Ga prostate-specific membrane antigen-PET as a diagnostic and clinical decision making tool in biochemical recurrences post-radical prostatectomy.
Authors: Tan Janice Ser Huey , Goh Charles Xian-Yang , Li Youquan , Tuan Jeffrey , Chua Eu Tiong , Tan Terence , Wang Michael L. , Lee Lui Shiong , Tay Kae Jack , Lam Winnie Wing Chuen , Chua Melvin
Published: February 2018

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Background: In patients with biochemical relapse (BCR) following radical prostatectomy (RadP), risk stratification by clinical indices alone is suboptimal for identifying subgroups likely to benefit from salvage radiotherapy (RT). It is also recommended that combination hormonal therapy (HT)-RT improves rates of salvage and survival, hence the need for a clinical tool to better stratify patients for RT and HT-RT; the latter approach for patients at risk of occult metastases. Herein, we investigated the role of 68Ga-Prostate-specific Membrane Antigen (PSMA)-PET in the detection of regional and distal recurrences, and for clinical decision making in a prospective cohort of patients with BCR post-RadP. Methods: 68Ga-PSMA-PET and CT were performed in a cohort of 50 RadP patients with BCR. Radiological interpretation was independently performed by two assessors, who were blinded to the patient identifiers. PSMA+ lesions were considered as true positives; negative-PSMA in the presence of continued PSA rise defined false negative. Impact on clinical decision making was reviewed by comparison of PSMA-PET and CT findings in the post-RadP PSA 0.5-2.0 ng/ml subgroup. Results: Overall detection rate for 68Ga-PSMA/PET was 74% (37 of 50) in our cohort with a median post-RadP PSA level of 2.19 (IQR = 0.45-4.26). Detection rates were significantly increased at a PSA cut-off > 1.0; 96% (25 of 26) at > 2.0 and 100% (5 of 5) at 1.0-2.0 compared to 67% (4 of 6) at 0.5-1.0, and 23% (3 of 13) at < 0.5 (P < 0.001). In 0.5-2.0 PSA subgroup, 3 regional nodes and 11 distal (6 nodes, 4 bones, 1 lung) lesions were detected. This altered treatment in 5 of the 11 (46%) cases; 3 N+ cases would have been recommended for HT-RT and pelvic nodal RT, while RT would be omitted in 2 patients due to low volume systemic disease. Conclusions: Our findings support the existing data for PSMA-PET as a sensitive diagnostic tool for clinical recurrences post-RadP. Additionally, the detection of small volume nodal and distal lesions at post-RadP PSA levels of < 2.0 ng/ml highlights the potential utility of PSMA-PET for selecting patients to treatment intensification with HT-RT or omission of RT in cases of distal relapse.
Predictors of improved biochemical progression free survival for salvage prostate bed radiotherapy after radical prostatectomy.
Authors: Wright Emma Grace , Challapalli Amarnath , White Paul , Persad Rajendra , Masson Susan , Kirk Hannah , Hilman Serena , Koupparis Anthony , Rowe Edward , Bahl Amit
Published: February 2018

38

Predictors of improved biochemical progression free survival for salvage prostate bed radiotherapy after radical prostatectomy Background: About a third of patients undergoing radical prostatectomy (RP) develop biochemical recurrence, the rate of which increases to ~50% in high risk patients, with adverse features such as positive margins & seminal vesicle invasion. Postop salvage radiotherapy (SRT) to the prostate bed improves biochemical progression free survival (bPFS). We sought to evaluate the benefit of SRT and predictors of bPFS. Methods: Patients who received SRT from Jan11 to Dec15 were retrospectively analysed. All patients had prostate bed radiotherapy (66Gy/33#/6.5wks). Hormone therapy (HT), when used was for a short duration of 3-6 months. PSA relapse after SRT was defined as serum PSA rising above the posttreatment nadir to a level of ≥0.2 ng/mL or by the initiation of HT after completion of SRT. The bPFS was calculated as the time from start of SRT till date of undetectable PSA, analysed by Kaplan-Meier estimates and log-rank test. Results: Overall, 111 patients were analysed. Median follow-up was 46 (range; 6-80) months. 46% (51/111) patients received HT. The median pre-SRT PSA was 0.4 ng/mL (range, 0.07 to 4.9). The bPFS rate was 60.4% overall, 65%for those with a pre-SRT PSA (ng/mL) level of ≤0.5 (n = 74), 53.6% for those with a PSA of > 0.5 to ≤1.5 (n = 28), 44.4% for those with a PSA of > 1.5 (n = 9); (p = 0.33). There was no significant difference in bPFS rates for pre-SRT PSA of ≤0.2 compared to PSA ≤0.5. Significantly improved bPFS rates were seen with an interval of > 6m from detectable PSA to start of SRT (69% vs. 46.5%: p = 0.026), and a trend towards better bPFS rates when the time interval was > 24m from RP to first detectable PSA (73% vs. 53%: p = 0.08). However, bPFS was similar in the proportion of patients (46%) who had HT compared to those (54%) who did not have HT. Conclusions: We have shown that there was no significant difference in bPFS rates between early (detectable PSA at 0.2) and deferred SRT and our data supports the practice of deferred SRT prior to PSA going above 0.5. Short course of HT was not shown to improve bPFS. The ongoing RADICALS and RAVE trials will further clarify these aspects.