bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunotherapy for biochemically recurrent prostate cancer.
Authors: Madan Ravi Amrit , Karzai Fatima , Bilusic Marijo , Strauss Julius , Slovin Susan F. , Harshman Lauren Christine , Theoret Marc Robert , Arlen Philip M. , Rauckhorst Myrna , Couvillon Anna , Hankin Amy , Williams Monique , Kantoff Philip W. , Dahut William L. , Schlom Jeffrey , Gulley James L.
Published: February 2018

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Background: Annually about 30-50,000 men are diagnosed with biochemically recurrent prostate cancer (BCRpc), defined by a rising PSA after radical prostatectomy (RP) or definitive radiation therapy (RT) with negative conventional imaging (CT and bone scan). Standard treatments include salvage therapies, androgen deprivation or surveillance. The role of immunotherapy in BCRpc is undefined. Methods: This study evaluates PROSTVAC, a pox-viral based therapeutic cancer vaccine targeting PSA, in BCRpc. Key eligibility criteria include PSA > 0.8 after RP or > 2.0 after RT with a maximum PSA of 30, PSA doubling time (DT): 5-15 months; testosterone > 100, negative CT and bone scan. Patients (pts) are randomized to vaccine for 6 months or 6 months surveillance followed by 6 months of vaccine. In a post hoc analysis delayed PSA declines were characterized as a confirmed PSA decline after an intra-study apex PSA (ISAP) defined by a peak PSA affirmed by a contiguous PSA within 10% (to exclude lab variations). 80 pts will be enrolled at NCI, Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center. Results: Of the 26 pts enrolled thus far, 22 have been followed for > 9 months after vaccine and are evaluable. On-study median values were age 66.8 years (54-78), PSA 2.67 ng/ml (0.83-28.5), PSA DT 7.5 months (5.1-14.9). 8 pts (38%) had delayed PSA declines after ISAP (-12% to -99%). Of 13 pts on surveillance for 6 months, only one pt had a similar decline lasting only 56 days. Conclusions: Preliminary data from this study suggests that PROSTVAC may be associated with delayed, but sustained PSA declines in BCRpc which are rarely seen in surveillance alone. Additional data will be acquired from this study, but this provides rationale to develop immunotherapy combinations in BCRpc. Clinical trial information: NCT02649439. [Table: see text]
Phase II trial of carfilzomib for metastatic castration-resistant prostate cancer (mCRPC) following androgen pathway inhibitors.
Authors: Naik Gurudatta , Bae Sejong , De Shazo Mollie R. , Dixon Pam , Merritt Lynn , Sartor A. Oliver , Schnell Frederick M. , Sonpavde Guru
Published: February 2018

224

Background: mCRPC is an incurable disease with suboptimal outcomes following prior therapy. Bortezomib, a proteasome inhibitor, has exhibited activity in a subset of patients. Carfilzomib is a second-generation selective and irreversible proteasome inhibitor and is approved for refractory myeloma. Methods: A non-randomized phase II trial (NCT02047253) was designed to evaluate carfilzomib for mCRPC following abiraterone acetate (AA) and/or enzalutamide (enza); prior docetaxel (D) was allowed. A 6-month progression-free survival (PFS) rate ≥30% defined by Prostate Cancer Working Group (PCWG) guidelines was considered important, while PFS < 10% was not. History and physical exam, and prostate specific antigen (PSA) was performed every 4 weeks. Circulating tumor cells (CTCs) were measured at baseline and 12 weeks later. Radiographic evaluation was performed every 12 weeks. Carfilzomib was administered on days 1,2,8,9,15,16 every 28 days. The starting dose was 20 mg/m2 during the first week followed by dose escalation to 56 mg/m2 if no serious toxicities occurred. Daily oral acyclovir was administered for herpes zoster prophylaxis. Therapy continue until PCWG or symptomatic progression or severe toxicities. Results: Twenty-eight patients were recruited and prior AA, enza or D had been received by 21 pts each and 20 pts received > 1 of these agents. The median age was 70 (range 55-88). One patient attained 6-month PFS; 2 other patients progressed at 6 months. Minor PSA declines and CTC declines were observed in 3 patients each, and one patient exhibited both PSA and CTC declines. The major toxicities of any grade were: anemia (n = 13, 46%), Fatigue (n = 7, 25%), and Constipation (n = 5, 18%), with anorexia, cough, fever, headache and thrombocytopenia in 4 patients each (14%). The major toxicities of grade ≥3 in > 1 patient were: anemia (n = 3, 11%) and hypertension (n = 2, 7%). Conclusions: Carfilzomib is not active as salvage therapy following AA and/or enza in unselected patients with mCRPC. Minor and transient activity may be present in a small subset of patients. Clinical trial information: NCT02047253.
Impact of statins on outcomes in patients (pts) with metastatic castration resistant prostate cancer (mCRPC): Post-hoc analysis of data from COU-AA-301 and COU-AA-302 trials.
Authors: de Velasco Guillermo , Lora David , Lorente David , Choueiri Toni K. , Sweeney Christopher , Castellano Daniel E.
Published: February 2018

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Background: Retrospective database studies have suggested that statins may have a positive impact on some mCRPC pts treated with prednisone (P)/abiraterone (AA) Methods: We conducted a post-hoc analysis of individual pt data of mCRPC pts treated with AA and/or P on randomized phase III clinical trials COU -AA-301 and COU-AA-302 to analyze the impact of statins on overall survival (OS). Statistical analyses were performed using the Kaplan Meier method and Cox regression adjusted for known prognostic factors. This study, was carried out under YODA Project #2016-1136 Results: 458 (41%) prechemotherapy pts and 348 (29%) postchemotherapy pts were statins users (Table). Improved OS was observed for mCPRC pts who were statins users in the postdocetaxel setting [HR: 0.82 (95% CI: 0.71 to 0.94); p = 0.006], and there was a trend towards a prolonged OS in the predocetaxel setting [HR: 0.89 (95% CI: 0.77 to 1.03); p = 0.13] adjusted by interventional treatment (AA and/or P). In the predocetaxel setting there were no significant differences in OS between the groups AA/P/non-statin users and placebo/P/statin users (p=0.3). In the multivariate analysis, patients randomized to AA/P who were statins users and presenting ECOG <2 had superior OS in the postdocetaxel setting. Similarly, age, ECOG and statin use were the strongest prognostic factors in the predocetaxel setting. Conclusions: In a post-hoc analysis of two prospective randomized clinical trials statin use was associated with superior OS in mCPRC pts treated with P or AA/P. Further studies are needed to confirm these results and guide use of statins as adjunct to P and A. [Table: see text]
Abiraterone acetate plus prednisone (AAP) in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC) and prior diethylstilbestrol (DES) therapy: Preliminary results.
Authors: Bastos Diogo Assed , Machado Marcos Tobias , Panhoca Renato , Pioner Giovani Thomaz , Werutsky Gustavo , Grings Mariana , Lopes Lizis , Gonzalez Francisco , Santos Telma Murias , Gidekel Rosemarie ,   On Behalf of the ABIRA DES Investigators
Published: February 2018

235

Background: AAP is approved for patients with chemotherapy-naïve mCRPC, but the population with previous use of DES was not studied before. DES is a commonly used hormone therapy for mCRPC in second and plus lines, especially in developing countries, due to lack of access to novel and efficacious therapies. The objective of this trial is to describe the efficacy and safety of AAP after DES treatment in patients who are chemotherapy-naïve, potentially affecting chemotherapy onset. This is the first and only prospective trial to show this data. Methods: This phase 2 multicenter, open-label single-arm study evaluated 46 patients receiving AA (1000 mg daily) + low-dose prednisone (P; 10 mg daily) and androgen deprivation therapy in patients with DES–refractory mCRPC enrolled from Oct 2014 to Oct 2015. The primary efficacy endpoint was time to prostate-specific antigen progression (PSAP) by Prostate Cancer Working Group (PCWG2) criteria. Secondary endpoints included PSA response (≥50% reduction), overall survival, and safety. Results: At baseline, median age was 69 years, median PSA was 40 ng/mL, there were no visceral metastases, 98% of patients had Eastern Cooperative Oncology Group Performance Status 0-1, and 44% had Gleason scores ≥7. Thirty two subjects (71.1%) had PSAP. PSA response was achieved by 47% of patients at week 12 and 56% at any time. Three patients remain on study drug and 4 are in follow-up. AA treatment continued until PSAP, clinical progression, consent withdrawal, or unacceptable toxicity. The median duration of study treatment was 8.6 months. The median time to PSAP was 7.4 months (95% CI = 5.6-9.4) and the median overall survival was 25.6 months (95% CI = 15.7-NE). Treatment-related adverse events included hypertension (19.6%), hyperglycemia (19.6%), fatigue (17.4%), and hypokalemia (4.5%); most grade 1-2. Conclusions: The present study confirmed that AAP provides PSA responses even in heavily treated patients, showing clinical benefit post-DES in chemotherapy-naive mCRPC patients. It also confirmed tolerability of AAP, with an easily manageable toxicity profile. Clinical trial information: NCT02217566.
Effects of a 6-month moderate-intensity exercise program on metabolic parameters and bone mineral density in men on androgen deprivation therapy for prostate cancer.
Authors: Alibhai Shabbir M.H. , Durbano Sara , O'Neill Meagan , Santa Mina Daniel , Ritvo Paul , Sabiston Catherine , Krahn Murray Dale , Tomlinson George A. , Matthew Andrew , Warde Padraig Richard , Timilshina Narhari , Segal Roanne , Culos-Reed S. Nicole
Published: February 2018

237

Background: Androgen deprivation therapy (ADT) is commonly used to treat prostate cancer (PC) but is associated with significant side effects including metabolic abnormalities and bone loss. Although multiple trials have demonstrated that exercise is associated with improvements in multiple side effects of ADT, its effects on metabolic and skeletal outcomes is unclear. We conducted a phase II randomized controlled trial (RCT) comparing three different exercise delivery models. The present analysis examined prespecified endpoints of change in metabolic parameters and bone mineral density. Methods: Men with stage TxNxMx PC starting or continuing ADT for at least 6 months were enrolled and randomized equally to personal training (n = 18), supervised group training (n = 14), or home-based training (n = 16). Participants in all intervention arms underwent moderate to vigorous physical activity with a target of 150 minutes per week for 6 months. Fasting blood work and dual x-ray absorptiometry (DXA) were done at baseline and 6 months (blood work) and 12 months (DXA). Paired t-tests and ANCOVA were used to analyze findings. Results: 48 participants (mean age 69.9 years) were enrolled. The primary analysis demonstrated no significant difference between arms on most quality of life and fitness outcomes so groups were combined for the present analysis. Exercise was not associated with statistically significant changes in hemoglobin, total cholesterol, low density lipoprotein, high density lipoprotein, triglycerides, or fasting blood glucose (p = 0.075 to 0.87). Similarly, exercise was not associated with changes in bone mineral density at lumbar spine, total hip, or femoral neck sites on DXA (p = 0.44 to 0.71). Mean weight change was +0.8 kg. There was no difference between exercise arms on any outcome. Conclusions: Although our study is limited by a small sample size, our results suggest that 6 months of moderate intensity exercise is not associated with improvements in either metabolic or skeletal outcomes in men on ADT. More intensive behavioural interventions and/or pharmacological interventions will be required to reverse the deleterious effects of ADT. Clinical trial information: NCT02046837.
Prevalence of overweight and prediabetes in men receiving systemic therapies for metastatic prostate cancer.
Authors: Finstad Warner , Galiauskas Raimundas , Cook James , Murphy Kate , O'Connor Derbrenn , O Sullivan Eoin , Markey Geraldine , Murphy Conleth G.
Published: February 2018

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Background: Patients with metastatic prostate cancer receive several therapies which may be associated with a tendency to overweight and impaired glucose tolerance. These include androgen deprivation therapy and long term steroid therapy. We set out to assess the prevalence of overweight and diabetes/prediabetes in a cohort of patients attending an oncology day ward for a variety of systemic therapies. Methods: We performed a retrospective review of the medical records of men attending an oncology day ward for prostate cancer treatment. As part of their usual care, these men had regular height and weight checks and also had periodic hemoglobin A1C (HbA1C) measurements performed. The prevalence of prediabetes and diabetes in this patient population was assessed from the HbA1C results using the American Diabetes Association 2016 definitions. Information on patient steroid use (and type), and treatment type were also recorded. Results: Among 34 men with metastatic prostate cancer, the mean age was 74 (range 57-88). Therapies received included androgen deprivation therapy in all cases, with chemotherapy or novel androgen receptor pathway inhibitors such as abiraterone and enzalutamide. Only 12% had a pre-existing diagnosis of diabetes mellitus (all type 2). The majority (79%) are overweight or obese. 59% have pre-diabetes as per the American Diabetes Association 2016 Guidelines, while a further 24% meet criteria for diabetes. Only 18% have HbA1c in the normal range. 56% are on continuous long term steroid therapy, usually as part of their prostate cancer therapy. A further 23% receive intermittent steroids. Only 21% had received no steroids in the 6 months prior to first HbA1C check. 18% had castrate-sensitive disease and 82% had castrate resistant disease. Even among patients with castrate sensitive disease, 2/3 had abnormal HbA1c values. Conclusions: Overweight and prediabetes are very prevalent in men receiving systemic therapies for metastatic prostate cancer. A large percentage of men are on long-term steroid therapy which may be contributing to their risk of these conditions. Intervention is required for this group of patients to reduce the impact of therapy on cardiovascular and overall health.
Real-world study of enzalutamide and abiraterone acetate (with prednisone) tolerability (REAAcT): Results.
Authors: Shore Neal D. , Saltzstein Daniel R. , Sieber Paul R. , Mehlhaff Bryan , Gervasi Lawrence , Phillips Jennifer , Wong Yu-Ning , Pei Huiling , McGowan Tracy
Published: February 2018

296

Background: Enzalutamide (E) and abiraterone acetate with prednisone (AAP) are approved for treatment (tx) of metastatic castration resistant prostate cancer (mCRPC). Concerns of differences in CNS manifestations and tolerability between E and AAP have been reported. REAAcT evaluated tolerability in patients (pts) newly starting E and AAP for mCRPC. Methods: This was a multicenter, Phase IV, non-randomized, prospective real-world study (NCT02663193). The tx (E or AAP) determined by the treating physician was prescribed per USPI. PROs (EORTC QLQ 30, FACIT-Fatigue, FACT-Cog) and tests of 4 cognitive domains (Cogstate) were assessed at baseline (BL) and after 2 months (M2) tx and analyzed for evaluable pts who completed BL and M2 assessments with no major protocol deviations. Descriptive statistics were provided. BL Cogstate scores were used to estimate the rate of cognitive impairment defined as ≥2SD from age-matched normative means of healthy males on ≥2 tests. Reliable change index (RCI) was calculated. Pts were noted to have clinically meaningful cognitive change with a performance decline of |RCI|≥2 on ≥2 tests. Results: Of 100 pts treated, 92 pts were evaluable (E = 46 and AAP = 46). Median age was 75 years. At BL, characteristics and median scores were similar between arms, with mild cognitive impairment in ~20% of pts. Drug discontinuations due to AEs were similar (1 vs. 2 pts), but more dose reductions due to AEs occurred on E vs. AAP (16% vs. 6%). Overall, more AEs were reported on E vs. AAP (52% vs. 36%), but Grade 3/4 AEs (4% E vs. 6% AAP) were similar. Unique neuropsychiatric AEs on E included amnesia, cognitive disorders, memory impairment, and confusional state; on AAP: cerebrovascular accident, presyncope, and spinal cord compression. Regarding fatigue, more AEs were noted on E than AAP (26% vs. 8%) and showed greater worsening in E than AAP (median change -4 vs. 0) by FACIT-Fatigue. This change within E group was statistically significant (mean, 95% CI -4 (-6.61, -1.39)). Four pts on E and 1 pt on AAP had clinically meaningful cognitive decline. Conclusions: While baseline values were similar between arms, after 2 months of tx, differences of fatigue and neurocognition were noted more often with E than AAP. Clinical trial information: NCT02663193.
Consensus statement on circulating biomarkers for advanced prostate cancer.
Authors: Sumanasuriya Semini , Omlin Aurelius Gabriel , Armstrong Andrew J. , Attard Gerhardt , Chi Kim N. , Bevan Charlotte L , Waugh David J. , Ijzerman Maarten J , De Laere Bram , Lolkema Martijn P. , Lorente David , Luo Jun , Mehra Niven , Olmos David , Scher Howard I. , Soule Howard R. , Stoecklein Nikolas H. , Terstappen Leon W M M , De Bono Johann S.
Published: February 2018

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Background: The need for validated circulating biomarkers is well recognised in advanced prostate cancer (PCa). Circulating biomarkers evaluating plasma cell-free nucleic acids and circulating tumour cells are being investigated for their clinical utility. There has been a lack of consensus with regards to analyses, reporting and clinical effectiveness of these biomarkers. A consensus meeting was held to address these issues. Methods: A multi-disciplinary panel comprising 18 international prostate cancer experts (including surgeons, medical and radiation oncologists) were consulted prior to the consensus meeting. Four key areas relating to the field of circulating biomarkers were deemed important for discussion: 1) The current utility of circulating biomarkers in 2017; 2) The clinical needs for circulating biomarkers in PCa; 3) The most pressing blood-based molecular assays required; and 4) The steps necessary for developing circulating biomarkers. Using a modified Delphi process, 50 consensus questions were pre-defined for the panel to answer by voting anonymously but publicly at the consensus meeting. Results: A consensus was declared (i.e. ≥ 75% of panellists who did not vote ‘unqualified’ or ‘abstain’ chose the same opinion) in 12/50 (24%) questions. A further 8/50 (16%) of replies were close to reaching consensus (≥ 60% of panellists choosing the same answer). The panel agreed that there is a very high and urgent unmet need for predictive biomarkers, with consensus that DNA repair biomarkers in particular are needed urgently. Metastatic PCa was identified as having the highest clinical need for development of biomarkers to measure response and as surrogate endpoints. Panellists unanimously voted that reproducibility validation studies are of paramount importance. The consensus panel also predicted that cfDNA will impact practice by 2020. Conclusions: This expert consensus identified the need for clinical trials of validated circulating biomarkers to develop predictive, response and surrogacy assays. These could have major clinical and healthcare economic implications, minimizing over-treatment and allowing the delivery of more precise patient care.
Real world patterns of treatment sequencing in Canada for metastatic castrate-resistant prostate cancer.
Authors: Hotte Sebastien J. , Finelli Antonio , Malone Shawn , Shayegan Bobby , So Alan I. , Canil Christina M. , Hew Huong , Park-Wyllie Laura , Saad Fred , Chi Kim N.
Published: February 2018

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Background: The Canadian GU Research Consortium (GURC) was recently established to bring advanced 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 how prostate cancer treatments are sequenced in a real-world setting. 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. Based on physician reports, the most frequently used treatment for first-line mCRPC was AR-targeted therapy (94%, n = 46 physicians) such as abiraterone acetate plus prednisone and enzalutamide. Among those 46 physicians, AR-targeted therapy was usually followed by docetaxel second-line therapy (57%, 31 physicians). The most common line 1 to line 3 treatment sequence for mCRPC was: AR-targeted therapy--Docetaxel--AR-targeted therapy (35%, 17 physicians), followed by AR-targeted therapy--Docetaxel--Radium 223 (14%, n = 7), Provincial differences were observed in the line 1 to line 3 treatment sequences, which aligned to variation in provincial policies for access to the treatments. In patients previously treated with docetaxel in the hormone sensitive setting, the most frequently used treatment for first-line mCRPC was AR-targeted therapy (76%, 37 physicians). Conclusions: AR targeted therapy followed by docetaxel is the predominant pattern of practice for management of mCRPC, with variability beyond these lines of therapy. Prospective ongoing work through the GURC in research, education and best practices will aim to understand these practice patterns.
Sequencing radium 223 (RA223) for metastatic castration-resistant prostate cancer (mCRPC) patients (pts) in the daily practice: Preliminary results from a retrospective study in Italian centers.
Authors: Caffo Orazio , Frantellizzi Viviana , Galli Luca , Monari Fabio , Facchini Gaetano , Baldari Sergio , Tucci Marcello , Alongi Filippo , Bortolus Roberto , Agostini Stefania , Biasco Elisa , Fanti Stefano , Rossetti Sabrina , Pignata Salvatore , Zichi Clizia , Salgarello Matteo , Borsatti Eugenio , Cortesi Enrico , Sbrana Andrea , De Vincentis Giuseppe
Published: February 2018

322

Background: The potential advantage of the sequential use of the active drugs (ADs) able to prolong overall survival (OS) in mCRPC (abiraterone, cabazitaxel, docetaxel, enzalutamide, RA223) could be limited by the development of common mechanisms of resistance. According to its unique targeted alpha-radiation mechanism of action, it could be postulated that RA223 does not induce and is not affected by cross-resistance with other agents and consequently its incorporation in therapeutic sequences may improve clinical outcomes. The present study is aimed to describe the clinical outcomes of pts who received RA223 and at least two other ADs for mCRPC. Methods: We collected data of pts who received sequentially 3 or more ADs of which one was RA223. For each pt we recorded the clinical outcome of all treatments received for mCRPC. We also compared the cumulative survival from the start of the first line to that of a contemporary series of 405 mCRPC pts without visceral mets sequentially treated with 3 or 4 ADs not comprising RA223. Results: A consecutive series of 119 mCRPC pts was collected: the median age was 72 yrs. Six pts received all 5 available ADs, 53 pts 4 ADs, and the remaining pts 3 ADs. Most of the pts received RA223 as the 3rd or 4th line of treatment (62 and 42, respectively), and the remaining were treated in less or more advanced lines (10 and 5 pts respectively). Overall the full 6-cycle treatment was completed in 61 pts (51.3%) and in 61.3% and 38.1% of pts when Ra223 was administered as 3rd and 4th treatment line respectively (p = 0.02). Partial response and stable disease as best objective response to RA223 was achieved in 11.3% and 24.5% of pts respectively, while a PSA reduction of ≥ 50% was observed in 7.2% of pts. Median OS from the start of the first line was 48 mos. In pts treated with 3 or 4 ADs that included Ra223, the median OS was significantly longer compared to that of pts whose treatment sequence did not include RA223 (48.4 vs 39.2 mos, p = 0.03). Conclusions: Despite the limitations of its retrospective nature, this preliminary data suggests that treatment sequencing of ADs that includes RA223 offers a survival advantage in mCRPC.
HSD3B1 genotype and abiraterone (Abi) metabolites in patients (pts) with prostate cancer (PCa).
Authors: Emamekhoo Hamid , Alyamani Mohammad , Park Sunho , Taylor Jennifer , Almassi Nima , Upadhyay Sunil , Tyler Allison Janine , Berk Mike , Hwang Tae Hyun , Grivas Petros , Rini Brian I. , Garcia Jorge A. , Auchus Richard J. , Sharifi Nima
Published: February 2018

325

Background: Abi, a potent inhibitor of 17α-hydroxylase/17,20-lyase (CYP17A1), is an oral treatment option for metastatic PCa in castration-resistant and -sensitive settings. Abi is converted to ∆4, 3-keto-abi (D4A) by 3β-hydroxysteroid dehydrogenase (3βHSD). D4A is further metabolized to multiple downstream steroidal metabolites including 3-keto-5α-Abi (5αA), which is an androgen receptor (AR) agonist and might affect response and/or resistance to Abi. The common HSD3B1(1245C) germline variant encodes for a 3βHSD missense that increases enzyme activity that allows tumors to utilize extragonadal androgens and is a predictive biomarker of resistance to ADT and sensitivity to CYP17A1 inhibition. However, the more active 3βHSD protein might increase 5αA synthesis, possibly limiting the clinical benefit of Abi. Methods: Blood was collected from CRPC pts on Abi and drug metabolites (MA) were extracted from serum, and analyzed by mass spectrometry. To correct for pharmacokinetics (PK) of time from last dose to blood draw in this cohort, data were normalized to the 8-hour time point of a separate PK study of Abi MAs and grouped by HSD3B1 genotype. HSD3B1 genotype was determined using germline DNA. Results: Abi MAs were evaluated in the sera of 30 CRPC pts on Abi. Abi, D4A, 5αA, were detectable in the sera of all pts. There were 8, 19, and 3 pts with homozygous wild-type, heterozygous, and homozygous variant HSD3B1 genotypes. HSD3B1 variant allele inheritance was associated with a statistically significant increase in 5αA concentrations, with highest concentration of 5αA MAs observed in homozygous variant HSD3B1 pts (Table). Conclusions: Germline HSD3B1 variant genotype is associated with higher 5αA metabolites with possible implications for AR stimulation and adverse clinical outcomes on Abi. [Table: see text]
Enzalutamide: Do treatment modifications allow drug continuation without losing disease control?
Authors: Massalha Emma Samah , Zvirinska Lenka
Published: February 2018

326

Background: Enzalutamide improves progression free and overall survival in men with metastatic prostate cancer (Beer T, et al. 2014; Cabot R, et al. 2012). Grade 3 adverse events occur in up to 48% (Beer T, et al. 2014; Cabot R, et al. 2012). and lead to treatment discontinuation in up to 8% (Beer T, et al. 2014; Cabot R, et al. 2012). The purpose of this retrospective analysis is to determine whether treatment modification (TM) with dose reduction (DR), treatment break (TB) or both, still allow control of prostate cancer in men who may have otherwise stopped treatment due to intolerable side effects. Methods: All patients in North Wales, UK, who commenced enzalutamide for metastatic prostate cancer in 2016 were eligible. Data was collected and recorded from electronic notes and prescriptions. Results: 66 men aged 61 to 92 (median 77) commenced treatment with enzalutamide in 2016. 17% performance status (PS) 0, 51% PS 2, 3% PS 3. Treatment has been discontinued in 80%. Adverse events (AEs) led to discontinuation in 25% cases including 2 deaths. The most common AE was fatigue in 37%. 11 patients (17%) had TM due to AEs. Mean treatment duration was 9.6 months (range 1 to 19.2 months), without TM 8.9 months, with TM, 12.8 months. Men with PS 2 were more likely to require TM or discontinuation (D) due to AEs (29% each) compared to PS 1 (24% TM, 21% D) or PS 0 (1% TM, 27% D). TBs lasted between 2 weeks and 7 months. PSA rose during that time but quality of life improved and PSA responded once treatment was recommenced. After a TB, enzalutamide was continued for 2 to 11 months (median 5.9 months). DR did not adversely affected PSA in 6 of 7 cases and improved quality of life in 2 cases. Patients continued enzalutamide 2-12 months (median 5.9 months) after dose reduction, including 4 still on treatment. Conclusions: This shows that both treatment breaks and dose reductions can improve quality of life whilst not adversely affecting outcome. However, the numbers are small and this needs to be confirmed in a prospective study. Those with lower PS are more likely to require modification.
Atezolizumab (atezo) vs. chemotherapy (chemo) in platinum-treated locally advanced or metastatic urothelial carcinoma (mUC): Immune biomarkers, tumor mutational burden (TMB), and clinical outcomes from the phase III IMvigor211 study.
Authors: Powles Thomas , Loriot Yohann , Ravaud Alain , Vogelzang Nicholas J. , Duran Ignacio , Retz Margitta , De Giorgi Ugo , Oudard Stephane , Bamias Aristotelis , Koeppen Hartmut , Leng Ning , Kadel Edward E. , Hegde Priti S. , Cui Na , Shen Xiaodong , Derleth Christina Louise , Green Marjorie C. , Banchereau Romain , Mariathasan Sanjeev , Van Der Heijden Michiel Simon
Published: February 2018

409

Background: IMvigor211 is a global study of atezo vs chemo in platinum-treated mUC. The study did not meet its primary endpoint of overall survival (OS) in programmed death-ligand 1 (PD-L1)–selected patients (pts),1 but exploratory analyses showed improved OS for atezo in the intent-to-treat (ITT) population. Here we compare clinical outcomes in ITT and prespecified PD-L1 subgroups with those in subgroups defined by immune transcriptional gene expression (tGE) signatures and TMB. Methods: Pts with ≤ 2 prior lines of therapy for mUC who progressed during or following platinum treatment were randomized 1:1 to atezo or chemo (vinflunine, paclitaxel or docetaxel, per physician). The primary endpoint was OS, hierarchically compared between treatment arms in PD-L1–selected and ITT pts. Planned exploratory biomarker analyses included tGE (RNA-seq) and TMB (FoundationOne). Results: The ITT population included 931 pts (atezo arm, 467; chemo arm, 464), and biomarker-evaluable subgroups were representative of the ITT population. PD-L1 expression positively correlated with tGE (R = 0.61) but not TMB (R = 0.13). OS and hazard ratios (HRs) are listed in the Table. Conclusions: In this randomized Phase III study, we show that high PD-L1 and high tGE are associated with improved outcomes with both chemo and atezo. In contrast, higher TMB predicted OS in favor of atezo; however, clinical benefit with atezo was also seen in the ITT population. Clinical trial information: NCT02302807. [Table: see text]
Erdafitinib (ERDA; JNJ-42756493), a pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRa): Phase 2 continuous versus intermittent dosing.
Authors: Loriot Yohann , Necchi Andrea , Park Se Hoon , García-Donas Jesús , Huddart Robert A , Burgess Earle Frederick , Fleming Mark T. , Rezazadeh Arash , Mellado Begona , Varlamov Sergei , Joshi Monika , Duran Ignacio , OHagan Anne , Avadhani Anjali Narayan , Zhong Bob , Stuyckens Kim , Dosne Anne-Gaëlle , Siefker-Radtke Arlene O. ,   On Behalf of the BLC2001 Study Group
Published: February 2018

411

Background: Although immune checkpoint inhibitors (ICI) have improved outcomes in some pts with platinum-resistant mUC, many pts (eg, pts with TCGA luminal 1 tumors, many of whom are FGFRa) may not benefit. ERDA, a pan-FGFR (1-4) inhibitor, demonstrated promising phase 1 activity: 11 partial responses among 24 FGFRa mUC pts. We report efficacy and safety of ERDA in the ongoing global open-label phase 2 study BLC2001 (NCT02365597). Methods: Pts had measurable mUC with specific FGFR2/ FGFR3 mutations or translocations per central lab Janssen assay, ECOG 0-2, and were chemorefractory (progressed during/following ≥ 1 line of prior systemic chemo or ≤ 12 mos of [neo]adjuvant chemo). Cisplatin-ineligible, chemo-naïve pts, and prior ICI treatment were allowed. Pts were randomized 1:1 to 28-d cycles of oral 6 mg/d continuous dosing (6 C) or 10 mg/d intermittent 7 d on/7 d off dosing (10 I) ERDA; the dose was further uptitrated if no significant treatment-related adverse events (TRAEs) were observed. The primary end point was ORR. Results: 78 pts received 6 C and 33 pts received 10 I (10 I cohort stopped early) ERDA. 31 pts in 6 C arm were further uptitrated. Across arms, 50% had ≥ 2 prior lines of therapy; 93% were chemorefractory. Confirmed ORRs (RECIST 1.1) were 35% and 24%, and disease control rates (CR+PR+SD) were 74% and 73% in the 6 C and 10 I arms, respectively. Adverse events (AEs) were manageable, and there were no treatment-related deaths (Table). Treatment is ongoing in 10 pts. Conclusions: ERDA (6 C or 10 I) has promising efficacy and tolerability in pts with FGFRa mUC. Based on these results and ERDA pharmacometric modeling, dosing was optimized at 8 mg/d (continuous), and this cohort is ongoing. Phase 3 study is planned. Clinical trial information: NCT02365597. [Table: see text]
Efficacy of programmed death 1 (PD-1) and programmed death 1 ligand (PD-L1) inhibitors in patients with FGFR mutations and gene fusions: Results from a data analysis of an ongoing phase 2 study of erdafitinib (JNJ-42756493) in patients (pts) with advanced urothelial cancer (UC).
Authors: Siefker-Radtke Arlene O. , Necchi Andrea , Rosenbaum Eli , Culine Stephane , Burgess Earle Frederick , O'Donnell Peter H. , Tagawa Scott T. , Zakharia Yousef , OHagan Anne , Avadhani Anjali Narayan , Zhong Bob , Santiago-Walker Ademi E. , Roccia Tito , Loriot Yohann
Published: February 2018

450

Background: FGFR3 mutations appear to be enriched in luminal 1 UC, which have low expression of markers associated with an immune response, including CD8-T-effector gene expression levels. Objective response rate (ORR) to PD-1 and PD-L1 inhibitors in luminal 1 tumors appear lower (10-19%) than in infiltrated luminal 2 and basal 3 tumors (ORR 31-34%). This suggests FGFR3 mutations occur within a group of tumors less likely to benefit from immune checkpoint inhibition (ICI). Here we describe outcomes of a subgroup of pts with FGFR2/3 mutations and gene fusions, previously treated with PD-1/PD-L1 inhibitors and included in an ongoing erdafitinib phase 2 study. Methods: Patients who had received prior immunotherapy for advanced UC were selected from those enrolled on BLC2001, an ongoing phase 2, open-label study of the pan-FGFR inhibitor erdafitinib in subjects with advanced UC with specific FGFR2/3 gene alterations (NCT02365597). We explored investigator-reported clinical outcomes including ORR and median time to progression (TTP) of pts treated with ICI preceding erdafitinib therapy. Results: 28/203 pts had previously received anti PD-1 or anti PD-L1 treatment. In this subgroup, the median age was 67.0 y; 82% were male, 79% had an ECOG score ≤1, 36% had liver metastases, and 93% had ≥2 prior lines of systemic therapy. The response rate to anti PD-1/PD-L1 agents was 3.6% (95% CI, 0.1%-18.3%) with one partial response. Median TTP was 3.4 mo (range 2-15 mo; 95% CI, 2.3-4.9). Conclusions: In this post-hoc analysis, FGFR mutations and gene fusions seem to select for a group of pts less likely to respond to immune checkpoint inhibition. Although caution is needed due to the retrospective nature of the data, the presence of these alterations may reflect an unmet need with currently approved agents. This finding highlights the need for FGFR alteration testing and an effective FGFR-targeted therapy. Clinical trial information: NCT02365597.
Phase Ib study of concurrent durvalumab and radiation therapy (DUART) followed by adjuvant durvalumab in patients with urothelial cancer of the bladder: BTCRC-GU15-023 study.
Authors: Joshi Monika , Tuanquin Leonard , Kaag Matthew , Zakharia Yousef , Liao Jason , Merrill Suzanne , Musapatika Dana , DeGraff David , Zheng Hong , Warrick Joshua , Holder Sheldon L. , Stein Mark , Drabick Joseph J.
Published: February 2018

455

Background: There is a significant variation in the treatment of locally advanced unresectable (T2-4 N0-2 M0) or cisplatin-ineligible (non-cis) bladder cancer (BC) patients (pts). The advent of immunotherapy (IO) in non-cis stage IV BC has been promising (response rate [RR] 23%; median survival 16 mo) but we are still in need of novel combinations for locally advanced unresectable BC. Durvalumab (Durva) is a human monoclonal antibody that inhibits the binding of PD-L1 to PD-1 on T-cell receptors. It has shown efficacy in platinum refractory BC with RR of 17%. Radiation (RT) is also effective in BC and can upregulate pro-inflammatory signals allowing for improved antitumor activity of IO. We report the safety data from phase Ib trial of combining RT with Durva (DurvaRT) in locally advanced BC. Methods: Treatment (Rx) naïve or post neoadjuvant chemotherapy pts with T3-4, N0-2, M0 who were either unresectable or unfit for surgery were treated with DurvaRT followed by Durva. Rx naïve locally advanced non-cis pts were also included in the study. DurvaRT: Durva 1500mg D1, D28 plus concurrent RT, 64.8Gy given in 36 fractions over 7weeks starting D1. These patients then started adjuvant Q4 weekly Durva after 4 weeks for 12 months. Primary end point for Ph Ib was safety of combining Durva with RT during 7-weeks period. Results: We enrolled 6 pts on phase Ib. 5/6 pts had completed the DurvaRT phase and none of them had any dose limiting toxicity. The table below summarizes the treatment related adverse events (TRAE). Post DurvaRT 3/4 pts have ongoing ORR; 1 pt. had progression; Rx response evaluation in 2 pts is ongoing. Clinical trial information: NCT02891161. Conclusions: DurvaRT was tolerable in pts with locally advanced unresectable BC, where there is a dearth for good Rx options. No grade 3 immune related AEs were observed during DurvaRT. Further investigation with DurvaRT is ongoing to evaluate the efficacy in this subset of pts (Clinical trial # NCT02891161).[Table: see text]
RUSSCO-RSP study of immunohistochemistry (IHC) diagnostic assays for PD-L1 expression in urothelial cancer (UC).
Authors: Tsimafeyeu Ilya , Zavalishina Larisa , Povilaitite Patrisia , Raskin Grigory , Andreeva Yulia , Petrov Alexey , Kharitonova Ekaterina , Pugach Inna , Rumyantsev Alexey , Frank Georgy , Tjulandin Sergei ,   RUSSCO-RSP study group
Published: February 2018

489

Background: This collaborative Russian Society of Clinical Oncology (RUSSCO) and Russian Society of Pathology (RSP) study assess the extent of concordance between three validated, commercially available PD-L1 IHC assays for UC patients. Methods: Tumors from 100 UC patients were stained with SP142 (Ventana), 22C3 (Dako) and SP263 (Ventana) clones as used in the clinical trials of second-line therapy of atezolizumab, pembrolizumab and durvalumab. Four trained pathologists independently evaluated the percentages of tumor (TC) and tumor infiltrating immune cells (IC) staining positive at any intensity. One test-specific cutoff rule for each assay in this analysis was pre-specified as: IC ≥5% for SP142, TC+IC ≥10% or TC ≥10% for 22C3, and TC ≥25% or IC ≥25% for SP263. Results: 300 IHC slides were scored. Patients were predominantly male (89%) with T1 (45%) and T2 (45%) stages, respectively. The percent of IC staining across 3 assays is shown to be higher than for TC staining (45% vs. 8% for SP142; 55% vs. 24% for 22C3; 72% vs. 27% for SP263). Pearson Correlation Coefficients for IC were: 0.5, 0.69 and 0.85 between SP142/22C3, SP263/22C3 and SP142/SP263, respectively. Pearson Correlation Coefficients for TC were: 0.93, 0.99 and 0.91 for the same pairs. Table indicates the agreement analysis using recommended individual cutoffs for each test. Conclusions: If a patient with UC is classified as negative by one of the three single tests using the corresponding recommended cutoff rule, the patient will be classified as negative by any other test with a high likelihood (91%-100%), and, therefore, repeated testing can be avoided.[Table: see text]
Fibroblast growth factor receptor 3 (FGFR3), peroxisome proliferator-activated receptor gamma (PPARg), and outcomes with nivolumab (nivo) in metastatic urothelial cancer (UC).
Authors: Galsky Matt D. , Saci Abdel , Szabo Peter , Wang Li , Zhu Jun , Azrilevich Alex , Fischer Bruce S. , Necchi Andrea , Siefker-Radtke Arlene O. , Sharma Padmanee
Published: February 2018

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Background: Prior studies have correlated FGFR3 mutations (mut) and increased PPARg expression with decreased T-cell infiltration raising the possibility that these might represent mediators of PD-1/PD-L1 blockade resistance in luminal UC and targets for combination strategies. The causality of these associations remains unclear and the clinical relevance in PD-1/PD-L1 blockade treated patients has been underexplored. Methods: Archival tumor specimens from patients enrolled on CheckMate 275, a phase 2 trial of nivo in patients with platinum-resistant metastatic UC, underwent whole exome sequencing (WES) and gene expression profiling (HTG EdgeSeq). CD8 expression was determined by immunohistochemistry. Results: WES and gene expression data was available for 139 and 217 patients, respectively; the baseline characteristics and outcomes of both cohorts were similar to the full CheckMate 275 cohort. FGFR3mut were detected in 15 patients (11%) and correlated with higher FGFR3 gene expression. Neither FGFR3mut nor FGFR gene expression correlated with CD8 expression (Pearson's r -0.13; p=0.16) or with response rate (RR), progression-free survival (PFS), or overall survival (OS); RR in FGFRmut vs. FGFRwt = 20% vs 20%. PPARg gene expression was inversely correlated with CD8 (Pearson’s r -0.44; P <0.001) and IFNg gene expression (Pearson’s r -0.52; P <0.001). Higher PPARg gene expression was associated with inferior outcomes (Table); RR in PPARg highest vs lowest tertile = 15% vs 24%. Conclusions: FGFR3 alterations (mut/increased expression) do not preclude response to nivo and were not associated with decreased CD8. Higher PPARg expression was associated with decreased CD8, lower RR to nivo, and significantly shorter PFS and OS. These data support exploring therapeutic modulation of PPARg or downstream mediators in an effort to overcome resistance to PD-1/PD-L1 blockade. Cox proportional hazards model. [Table: see text]
Results of phase I plus expansion cohorts of cabozantinib (Cabo) plus nivolumab (Nivo) and CaboNivo plus ipilimumab (Ipi) in patients (pts) with with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignancies.
Authors: Nadal Rosa Maria , Mortazavi Amir , Stein Mark , Pal Sumanta K. , Davarpanah Nicole N. , Parnes Howard L. , Ning Yang-Min , Cordes Lisa M. , Bagheri Mohammadhadi H. , Lindenberg Liza , Thompson Ryan , Steinberg Seth M. , Moore Tina , Lancaster Tiffany , Velez Milisyaris , Mena Esther , Costello Rene , Bottaro Donald , Dahut William L. , Apolo Andrea B.
Published: February 2018

515

Background: Tolerability and efficacy of CaboNivo and CaboNivoIpi were demonstrated in the initial phase I cohort, prompting longer follow-up and the addition of expansion cohorts to further evaluate both combinations Methods: Phase I cohort had 7 dose levels (DL). Recommended phase 2 doses for CaboNivo=Cabo 40mg/Nivo 3mg/kg (DL2) & CaboNivoIpi=Cabo 40mg/Nivo 3mg/kg/Ipi 1mg/kg (DL6) (Nadal ESMO 2017).In expansion cohorts, pts were treated: [1] DL8: Cabo 40mg/Nivo 1mg/kg/Ipi 3mg/kg; [2]DL2: mUC, metastatic renal cell carcinoma (mRCC), adenocarcinoma bladder (AcB): post-PD-1-PDL1 inhibitor mUC (p-mUC), and [3] DL6 mRCC. Objectives: safety, objective response rate (ORR), duration of response (DOR), progression-free survival (PFS) & overall survival (OS). Results: 75 pts enrolled. Median age 59 yo. 83% male, 17% female. 47 treated with CaboNivo (mUC n=24; AcB n= 9; germ cell tumor (GCT) n= 5; castrate-resistant prostate cancer (CRPC) n= 4; bladder squamous cell carcinoma (SCC) n= 2; penile n=1; mRCC n= 7). 28 treated with CaboNivoIpi: (mUC n=8; penile n=3; CRPC n=7; Sertoli n=1; mRCC n=6; bladder small cell carcinoma n=1; renal medullary carcinoma (RMC) n=2). Any grade (G) adverse events (AEs) (CaboNivo 96% & CaboNivoIpi 96%)/G3–4 AEs (CaboNivo 62% & CaboNivoIpi 71%). Most common any G, CaboNivo: fatigue 70%, diarrhea 60%, AST/ALT 60%, hypophosphatemia (hypoP) 45% & CaboNivoIpi: fatigue 71%, diarrhea 68%, hypoP 50%, AST/ALT 43%. Most common G3-4, CaboNivo: lipase 17%, hypoP 15%, fatigue 6% & CaboNivoIpi: hypoP 21%, AST/ALT 14%, lipase 14%. Selected irAs: colitis (2.6%), hepatitis (2.6%), pneumonitis (2.6%), aseptic meningitis (1.3%). ORR: 36%; 3CR (2mUC, 1SCC) & 20PR (5mUC, 2SCC, 7mRCC, 2Penile, 2AcB, 1CRPC, 1RMC). mDOR: 24.1 mo [95% CI: 14.7-NR], mPFS: 7.2 mo [95%CI: 5.1-18.4], mOS:18.8 mo [95%CI: 10.6-NR]. OS 6/12 mo: 83%/61%. Cohort of p-mUC pts(n=5):1PR/3SD/1PD Conclusions: Updated results from phase I and expanded cohorts confirm initial safety findings and promising antitumor activity for both combinations in mUC, mRCC, and rare GU malignancies Clinical trial information: NCT02496208.
Patient-reported anxiety with localized prostate cancer treated with stereotactic body radiation therapy (SBRT).
Authors: Aghdam Nima , Pepin Abigail , Johnson Colin , Danner Malika , Ayoob Marilyn , Yung Thomas M. , Lei Siyuan , Collins Brian Timothy , Dritschilo Anatoly , Suy Simeng , Lynch John , Collins Sean P.
Published: February 2018

52

Background: Anxiety is a common aliment among elderly men. It may be negatively impacted by the diagnosis of cancer. Effective cancer treatment may alleviate anxiety. The EORTC QLQ-ELD14 (ELD14) is a validated questionnaire, which evaluates patient reported anxiety. Using the ELD14 questionnaire, this study assesses the trends in prostate cancer patient’s anxiety before and after treatment with SBRT. Methods: All patients with localized prostate cancer who received SBRT at Georgetown University Hospital from 2007 to 2016 were eligible for inclusion in this cross-sectional cohort. The ELD14 questionnaire was used to assess quality of life before and following treatment. Initially, approximately 267 patients (median age of 70) responded to the ELD14 questionnaire. This study is focused on questions related to patient’s anxiety regarding their families, future, health and end of life. The responses to these questions were grouped into three clinically relevant categories (not at all, a little and quite a bit to very much). Results: Prior to treatment, 19% of patients felt quite a bit or very much worried about their families coping with their illness. This decreased to 9% at 24 months post-SBRT (p = 0.007). Initially, 27% of patients reported concerns for the future of their families, which subsequently decreased to 20% at 24 months (p = 0.15). At initial consult, 32% of patients reported being worried about their future health. This decreased to 13% at 24 months (p < 0.001). Twenty percent of patient reported concern about their future at initial consult; this declined to 11% at 24 months (p = 0.03). And finally, self reported anxiety about end of life was 18% at the initial consult and 12% at 24 months (p = 0.16). Conclusions: Self-reported anxiety surrounding family, health and future is prevalent amongst prostate cancer patients at initial evaluation. Significant reduction in anxiety is observed in our cohort post-SBRT. Further investigations in the causes of pre and post-treatment anxiety may offer valuable insight into preventable root causes and improvement in patient’s quality of life.