Search

Therapeutic alternatives in advanced urothelial carcinoma are limited, especially in advanced lines, with only a few drugs having demonstrated relevant clinical benefit. This article discusses about a young patient with significant cardiovascular comorbidities, already treated with recommended first- and second-line drugs, and suffering from liver metastases. Despite the known poor prognosis of this disease and the few supporting data, given his peculiar clinical history, we opted to treat him with a third-line gemcitabine rechallenge with a notable response on his liver lesions. We present an intriguing case, both in terms of the therapeutic sequence and the disease course.

46 Background: Bone is frequently involved in metastatic hormone sensitive prostate cancer (mHSPC). Whole-body diffusion-weighted magnetic resonance imaging (WB-DW-MRI) is a promising imaging technique for the assessment of bone response in prostate cancer. It is not known whether the addition of antiresorptive agents can improve disease response in bone in mHSPC patients undergoing next generation hormonal agents. Methods: In this multicenter phase II study patients with de novo or relapsed mHSPC and bone metastases at bone scan were randomly allocated with a 1:1 ratio to receive either androgen deprivation therapy (ADT) plus Enzalutamide (E arm) or the same combination with the addition of Zoledronic Acid (EZ arm). The study was designed to observe a significant increase in bone response rate in the experimental arm after 12 months of treatment, as assessed through WB-DW-MRI. WB-DW-MRI was performed centrally at baseline and after 6 and 12 months and images were evaluated by the same radiologist. Results: From February 2018 to June 2021, 126 mHSPC patients were randomized, 64 in EZ arm and 62 in E arm. A total of 111 patients, 54 from E arm and 57 from EZ arm, were eligible for WB-DW-MRI assessment (15 patients were excluded because of the absence of bone target lesions at MRI or specific contraindications to MRI). Bone response at 6 months was observed in 41 patients (76%) in E arm and 41 patients (72%) in EZ arm; the corresponding bone response at 12 months were 44 (82%) and 44 (77%), respectively (OR 0.77; 95%IC 0.30-1.93; p = 0.6). Complete response was the best overall bone response after 12 months in 9 patients (17%) from E arm and in 11 patients (19%) from EZ arm. In the same period, treatment was interrupted due to disease progression in 7 (13%) and 7 (12%) patients in E and EZ arm, respectively. Conclusions: The addition of Zoledronic Acid to Enzalutamide and ADT did not improve bone disease response in patients with mHSPC. WB-DW-MRI was able to detect bone responses in a great proportion of patients. Clinical trial information: NCT03336983 .

705 Background: mRCC prognostic stratification is currently based on the IMDC score. However, some patients experience outcomes markedly different from those predicted by the median outcome of their risk class. Moreover, risk scores are prognostic, rather than predictive, and developing reproducible, affordable, biology-based predictive biomarkers to tailor treatment choices in individual pts remains an unmet clinical need. Methods: A retrospective cohort of 113 mRCC pts treated at the Verona University Hospital Trust between 2013 and 2021 was explored to identify additional clinical prognostic factors for OS to complement IMDC score. Outlier pts (i.e. individual pts whose clinical outcome differed significantly from the median of the IMDC group they belonged to) were further explored to find putative molecular signatures, using FISH and IHC assays. Results: At a median follow-up of 69 months (range 18-136m), novel variables impacting on OS in addition to IMDC risk group were identified: bone, central nervous system (CNS) and pancreatic mets and high neutrophil/lymphocyte ratio (N/L) with a cut-off of 3.2. We also analyzed outliers: 3 good-risk pts with lower than expected OS, 4 poor-risk pts with longer than expected OS, and two intermediate-risk pts with long treatment response. Two putative signatures were found predictive of disease behavior: a cold signature (9p loss, poor of TILs) and a hot signature (rich in CD56+, CD15+ and CD8+ infiltrating cells). The cold and hot signatures were found in good risk pts with bad OS and poor-risk pts good OS, respectively; both intermediate-risk pts had a hot signature, consistent with their disease course. Conclusions: Additional clinical and molecular factors have been identified to possibly improve IMDC prognostic performance; multivariable models including them along with standard IMDC are being developed. Molecular analysis suggests potential signatures to be applied in routine clinical practice, whose predictive performance could be validated in prospective multicentric trials. [Table: see text]

Background Thyroid hormone impairment, represented as an alteration in levels of thyroid hormones and a lower fT3/fT4 ratio, has been correlated with a worse prognosis for both cancer and non-cancer patients. The role of baseline thyroid function in patients with metastatic renal cell carcinoma (mRCC) however, has not been studied yet. Materials and Methods We recorded clinical data, baseline biochemical results, and oncological outcomes from 10 Oncology Units in Italy. We stratified patients into three groups according to the fT3/fT4 ratio value and subsequently analyzed differences in progression-free survival (PFS) and overall survival (OS) in the three groups. We also performed univariate and multivariate analyses to find prognostic factors for PFS and OS. Results We analyzed 134 patients treated with systemic treatment for mRCC. Median PFS in the low, intermediate, and high fT3/fT4 ratio group were 7.5, 12.1, and 21.7 months respectively (p

Radium 223 was introduced for metastatic castration-resistant prostate cancer based on the results of a randomized controlled trial showing risk reduction for death and skeletal events. Our aim was to evaluate the outcome of patients receiving radium 223 in a real-world setting.We conducted a multicenter retrospective analysis in the Triveneto region of Italy.One hundred fifty-eight patients received radium 223 in our region. After a median follow-up of 9.5 months, 75 patients died. The median overall survival (OS) was 14.2 months, and the median progression-free survival (PFS) was 6.2 months. Seventy-one (45%) patients achieved progression as best response. Thirty-seven (23%) patients stopped the treatment early because of progression. Eastern Cooperative Oncology Group performance status was prognostic for OS (18.4 vs. 12.3 vs. 7.5 months; 0 vs. 1, P = .0062; 0 vs. 2, P = .0002), whereas previous prostatectomy or docetaxel exposure were not. A neutrophil to lymphocytes ratio ≥ 3 significantly impacted OS (18.1 vs. 9.7 months; P .001) and slightly impacted PFS (6.6 vs. 5.6 months; P = .05). Patients with a baseline alkaline phosphatase (ALP) value ≥ 220 U/L had worse OS and PFS (24.1 vs. 10.5 months; 7.2 vs. 5.5 months; P .001). Patients with changes in ALP value achieved better OS (P = .029) and PFS (P = .002). There was no difference according to the line of therapy (0 vs. ≥ 1; P = .490). The main grade 3/4 toxicities were anemia, asthenia, and thrombocytopenia.This large real-world report confirms comparable OS and PFS data when compared with the pivotal study, as well as the predictive role of ALP and neutrophil to lymphocytes ratio. The definition of the optimal position of radium 223 in the treatment of metastatic castration-resistant prostate cancer has still to be defined.

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has overwhelmed the health systems worldwide. Data regarding the impact of COVID-19 on cancer patients (CPs) undergoing or candidate for immune checkpoint inhibitors (ICIs) are lacking. We depicted the practice and adaptations in the management of patients with solid tumors eligible or receiving ICIs during the COVID-19 pandemic, with a special focus on Campania region.MethodsThis survey (25 questions), promoted by the young section of SCITO (Società Campana di ImmunoTerapia Oncologica) Group, was circulated among Italian young oncologists practicing in regions variously affected by the pandemic: high (group 1), medium (group 2) and low (group 3) prevalence of SARS-CoV-2–positive patients. For Campania region, the physician responders were split into those working in cancer centers (CC), university hospitals (UH) and general hospitals (GH). Percentages of agreement, among High (H) versus Medium (M) and versus Low (L) group for Italy and among CC, UH and GH for Campania region, were compared by using Fisher’s exact tests for dichotomous answers and χ2 test for trends relative to the questions with 3 or more options.ResultsThis is the first Italian study to investigate the COVID-19 impact on cancer immunotherapy, unique in its type and very clear in the results. The COVID-19 pandemic seemed not to affect the standard practice in the prescription and delivery of ICIs in Italy. Telemedicine was widely used. There was high consensus to interrupt immunotherapy in SARS-CoV-2–positive patients and to adopt ICIs with longer schedule interval. The majority of the responders tended not to delay the start of ICIs; there were no changes in supportive treatments, but some of the physicians opted for delaying surgeries (if part of patients’ planned treatment approach). The results from responders in Campania did not differ significantly from the national ones.ConclusionOur study highlights the efforts of Italian oncologists to maintain high standards of care for CPs treated with ICIs, regardless the regional prevalence of COVID-19, suggesting the adoption of similar solutions. Research on patients treated with ICIs and experiencing COVID-19 will clarify the safety profile to continue the treatments, thus informing on the most appropriate clinical conducts.

Background: Declines in prostate-specific antigen (PSA) levels at 12 wk are used to evaluate treatment response in metastatic castration-resistant prostate cancer (mCRPC). PSA fall by ≥30% at 4 wk (PSA4w30) has been reported to be associated with better outcome in a single-centre cohort study. Objective: To evaluate clinical relevance of early PSA decline in mCRPC patients treated with next-generation hormonal treatments (NGHTs) such as abiraterone and enzalutamide. Design, setting, and participants: This was a retrospective multicentre analysis. Eligible patients received NGHT for mCRPC between 6 January 2006 and 31 December 2017 in 13 cancer centres worldwide, and had PSA levels assessed at baseline and at 4 and/or 12 wk after treatment. PSA response was defined as a ≥30% decline (progression as a ≥25% increase) from baseline. Outcome measurements and statistical analysis: Association with overall survival (OS) was analysed using landmark multivariable Cox regression adjusting for previous chemotherapy, including cancer centre as a shared frailty term. Results and limitations: We identified 1358 mCRPC patients treated with first-line NGHT (1133 had PSA available at 4 wk, and 948 at both 4 and 12 wk). Overall, 583 (52%) had a PSA4w30; it was associated with longer OS (median: 23; 95% confidence interval [CI]: 21–25) compared with no change (median: 17; 95% CI: 15–18) and progression (median: 13; 95% CI: 10–15). A PSA12w30 was associated with lower mortality (median OS 22 vs 14; hazard ratio = 0.57; 95% CI = 0.48–0.67; p < 0.001). PSA4w30 strongly correlated with PSA12w30 (ρ = 0.91; 95% CI = 0.90–0.92; p < 0.001). In total, 432/494 (87%) with a PSA4w30 achieved a PSA12w30. Overall, 11/152 (7%) patients progressing at 4 wk had a PSA12w30 (1% of the overall population). Conclusions: PSA changes in the first 4 wk of NGHT therapies are strongly associated with clinical outcome from mCRPC and can help guide early treatment switch decisions. Patient summary: Prostate-specific antigen changes at 4 wk after abiraterone/enzalutamide treatment are important to determine patients’ outcome and should be taken into consideration in clinical practice., SCOPUS: ar.j, info:eu-repo/semantics/published

290 Background: Second (2L) or third-line (3L) treatment options for mRCC have dramatically changed in the last years. The standard of care as per Italian Regulatory Agencies approvals is N or C. To date, there are no criteria for the choice between N and C, which both demonstrated OS gain in the pivotal trials. Methods: We planned a retrospective, real world analysis of the use of N and C as 2L and 3L treatment in 17 Oncology Units of Veneto Region. All consecutive patients (pts) with mRCC treated in advanced setting in 2017-2018 were included. Results: We identified 170 pts, 73% males, median age 68.4 years. All pts started a 2L treatment while only 59% received a 3L treatment. In our cohort, patients with NLR > 3 at treatment start had a shorter OS (43 vs 90 months (mos), p < 0.0001); IMDC classification maintained its prognostic role. In 2L, N was administrated in 108 pts (63%), C in 29 pts (17%); in 3L N was administrated in 42 pts (25%), C in 49 pts (29%). Reported oncologists’ reasons for 2L choice were: change of mechanism of action compared to first line (28%), response to previous TKI (21.2%), intolerance to TKI (17.6%), previous toxicity (12.9%), tumor burden (11.2%), age of the patient (4.1%). Median OS and PFS in 2L were 28.4 and 6.6 mos for N, 16.8 and 6.6 mos for 2L C. Median OS and PFS in 3L were 27 and 5.2 mos for N, 16.6 and 7.5 mos for C. 46 pts received the sequence of drugs N > C, 12 the opposite sequence C > N. Median OS for N > C vs C > N were 96.6 vs 36 mos (p > 0.0001); median PFS for both the sequences were similar at 5.7 mos (p = ns). The cost per patient of the sequence N > C is 51.606 € while for the sequence C > N is 31.480,00 €. Between the two sequences a cost effectiveness per month of survival analysis was performed: the cost per month of OS for the sequence N > C was 534,18 € while for the sequence C > N was 874,46 €, heavily higher. Conclusions: In our real-world setting cohort, most of the pts received N as 2L treatment and a minority received C. Outcome of single drug are superimposable to published literature. With the limits of the retrospective nature of the study, with a cost per month of OS lower a much longer OS, the sequence N > C appear to be a better treatment strategy.

Purpose To determine the correlation between the volume of bone metastasis as assessed with diffusion-weighted (DW) imaging and established prognostic factors in metastatic castration-resistant prostate cancer (mCRPC) and the association with overall survival (OS). Materials and Methods This retrospective study was approved by the institutional review board; informed consent was obtained from all patients. The authors analyzed whole-body DW images obtained between June 2010 and February 2013 in 53 patients with mCRPC at the time of starting a new line of anticancer therapy. Bone metastases were identified and delineated on whole-body DW images in 43 eligible patients. Total tumor diffusion volume (tDV) was correlated with the bone scan index (BSI) and other prognostic factors by using the Pearson correlation coefficient (r). Survival analysis was performed with Kaplan-Meier analysis and Cox regression. Results The median tDV was 503.1 mL (range, 5.6-2242 mL), and the median OS was 12.9 months (95% confidence interval [CI]: 8.7, 16.1 months). There was a significant correlation between tDV and established prognostic factors, including hemoglobin level (r = -0.521, P < .001), prostate-specific antigen level (r = 0.556, P < .001), lactate dehydrogenase level (r = 0.534, P < .001), alkaline phosphatase level (r = 0.572, P < .001), circulating tumor cell count (r = 0.613, P = .004), and BSI (r = 0.565, P = .001). A higher tDV also showed a significant association with poorer OS (hazard ratio, 1.74; 95% CI: 1.02, 2.96; P = .035). Conclusion Metastatic bone disease from mCRPC can be evaluated and quantified with whole-body DW imaging. Whole-body DW imaging-generated tDV showed correlation with established prognostic biomarkers and is associated with OS in mCRPC. (©) RSNA, 2016 Online supplemental material is available for this article.

Background: This study had two aims: (a) to test the hypothesis that advanced age is associated with lower levels of tolerability and clinical benefit to experimental Phase I trial agents; (b) to assess the validity of the Royal Marsden Hospital (RMH) prognostic score as a patient selection tool in older patients. Methods: Clinico-pathological characteristics and treatment outcomes of all patients treated consecutively from 2005 to 2009 in phase I trials at the RMH were recorded. All toxicity and clinical outcome data were compared between patients aged below and above 65 years of age. Results: One thousand and four patients were treated in 30 Phase I trials, with 315 (31%) patients aged 65 years and older. Grade 3–5 toxicities (22.8% vs 24.8% (P=0.52)), trial discontinuation (6% vs 4% P=0.33), and dose interruptions (8.0% vs 8.0% (P=0.96)) were observed at similar rates in patients below and above 65 years of age, respectively. The overall response rate 5.2% vs 4.1%, progression-free survival (PFS) 1.9 vs 3.5 months and clinical benefit rate (CBR) at 6 months 15.2% vs 14.3% were comparable in both groups. To avoid bias due to the potential therapeutic benefit of abiraterone, comparisons were repeated excluding prostate cancer patients with similar results (ORR 4.6% vs 4%, PFS 1.8 vs 3.0 months, CBR at 6 months 13.5% vs 9.5%). Multivariate analysis indicated that the previously identified RMH score (including albumin and lactate dehydrogenase levels) was an accurate predictor of outcome. Conclusions: Phase I clinical trials should be considered in patients with advanced cancers regardless of age, as older patients who enter these have similar safety and efficacy outcomes as their younger counterparts. The RMH prognostic score can assist in the selection of suitable older patients.

e17093 Background: Thyroid hormones metabolism can be altered in patients (pts) with chronic diseases and/or undergoing cancer treatments. The prognostic role of T3/T4 ratio has been investigated in metastatic colorectal cancer pts in whom a high T3/T4 ratio predicted longer survival. No data are available in mRCC. Methods: We retrospectively reviewed the clinical charts of pts with mRCC treated in first line for metastatic disease at 8 Italian Oncology Units before March 2017, having at least one response assessment and baseline complete thyroid panel data available. T3/T4 was calculated as the ratio of the two value of hormones and categorized in tertiles. Results: We identified 96 pts, median age 62 years (range 27-82), 72% males. Sunitinib wad administered in 56% of pts, pazopanib in 38%, nivolumab and ipilimumab in 6%. According to Heng Score, 33% of the pts were at favorable risk, 58% at intermediate risk, 9% at poor risk. With a median follow-up time of 42.8 months, median PFS was 24.8 months, estimated median OS was 71.6 months. Tertile distribution of patients was 36.4% in the high, 29.1% in the medium and 34.5% in the low subgroup. A baseline high tertile value (≥ 0.35) predicted longer PFS (39.4 vs 21.8 1vs 4.5 months, p = 0.01), while median OS has not been reached in the three tertiles, with survival at 24 months being 69.7%, 82.1% and 91.4%, respectively in the low, medium, high group (p = ns). The high T3/T4 ratio is also strongly associated with the chance to achieve a partial or complete response (42.8% vs 39.9% vs 21%, X squared test, p < 0.001). Heng prognostic model retained its prognostic role in this cohort (median OS was 77.1 vs 48.4 vs 22.3 months, p < 0.001, respectively for favorable, intermediate or poor risk group) and also predicted PFS (median PFS 38.2 vs 17.2 vs 8.4 months, p = 0.004). Baseline NLR ≥ 3 predicted shorter OS (46.5 vs 77.1 months, p = 0.02) in the whole group. Conclusions: In our retrospective multicenter experience, a high T3/T4 ratio was associated with longer PFS and a higher probability to respond to the treatment. Median OS had not been reached for all the subgroups, probably due to a favorable patients selection. A longer follow-up is needed to validate the prognostic value of T3/T4 ratio in this cohort.

Background The new generation anti-androgen enzalutamide and the potent CYP17 inhibitor abiraterone have both demonstrated survival benefits in patients with metastatic castration-resistant prostate cancer (CRPC) progressing after docetaxel. Preliminary data on the antitumour activity of abiraterone after enzalutamide have suggested limited activity. The antitumour activity and safety of enzalutamide after abiraterone in metastatic CRPC patients is still unknown. Patients and Methods We retrospectively identified patients treated with docetaxel and abiraterone prior to enzalutamide to investigate the activity and safety of enzalutamide in a more advanced setting. Prostate specific antigen (PSA), radiological and clinical assessments were analysed. Results 39 patients with metastatic CRPC were identified for this analysis (median age 70 years, range: 54–85 years). Overall 16 patients (41%) had a confirmed PSA decline of at least 30%. Confirmed PSA declines of ⩾50% and ⩾90% were achieved in 5/39 (12.8%) and 1/39 (2.5%) respectively. Of the 15 patients who responded to abiraterone, two (13.3%) also had a confirmed ⩾50% PSA decline on subsequent enzalutamide. Among the 22 abiraterone-refractory patients, two (9%) achieved a confirmed ⩾50% PSA decline on enzalutamide. Conclusion Our preliminary case series data suggest limited activity of enzalutamide in the post-docetaxel and post-abiraterone patient population.

Study Type – Therapy (individual cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Sorafenib is an oral receptor tyrosine kinase inhibitor that inhibits RAF serine/threonine kinases and receptor tyrosine kinases (vascular endothelial growth factor receptors 1, 2, 3 and platelet-derived growth factor-beta, Flt-3 and c-kit) that are implicated in tumourigenesis and tumour progression. Sorafenib is approved for the treatment of advanced renal cell cancer. B-RAF mutations (V600E and K601E) may be interesting negative predictive markers in metastatic kidney cancer patients treated with Sorafenib. Larger trials are needed to validate this hypothesis and should include B-RAF molecular analysis for better patient selection. OBJECTIVE • To assess both clinical and biological efficacy and toxicity of sorafenib in patients with metastatic renal cell carcinoma (mRCC) previously treated with an anti-angiogenic vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor. METHODS • Sorafenib is an orally active multikinase inhibitor approved for the treatment of mRCC. • Drug-focused translational research on tissues (i.e. B-RAF) and plasma (VEGFR-α, circulating endothelial cells, endothelial progenitor cells) was performed to define biological predictive and prognostic markers and their related kinetics. • Patients with mRCC pretreated with an anti-angiogenic treatment, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2 and adequate organ function were eligible. • Patients received sorafenib 400 mg twice a day continuously in 4-week cycles. Patients with no progressive disease at 12 weeks continued to receive sorafenib at the standard dose, whereas progressing patients received an increased dose (600 mg twice a day) with early disease restaging after 4 weeks. Patients who progressed at 600 mg twice a day went off study. Efficacy (overall tumour control) was assessed by Response Evaluation Criteria in Solid Tumors. RESULTS • In all, 19 patients were entered. The baseline characteristics were as follows: ECOG PS 0–1 94.8%; median (range) age 62 (41–81) years; nephrectomy 100%; surgery for metastatic disease 26.4%; clear cell 79.1%; papillary cell 15.7%; sarcomatoid/high grade 5.2%; two or more metastatic sites 84%. • Overall, 11 patients (58%) had disease control at 6 months without significant correlation between response to prior therapy and hypertension. Progression-free survival (PFS) of 8.3 months was observed. • Of six patients for whom the dose was escalated due to early progression, three benefitted with PFS of >3 months. Three (15.7%) of 19 patients had a V600E mutation and one had a K601E mutation; PFS appeared to be substantially shorter in these patients compared with 15 patients with wild-type B-RAF (2.5 vs 9.1 month, P < 0.05). • The most common toxicity (National Cancer Institute Common Toxicity Criteria, NCIC 3.0, all patients) was grade ≥1 diarrhoea and grade 2–3 hand–foot syndrome in 11 patients. Grade 3 mucositis was observed in one patient. CONCLUSIONS • Sorafenib at doses of 400–600 mg twice a day continuously results in acceptable and well tolerated salvage treatment after VEGFR tyrosine kinase inhibitor failure. • In progressive patients, treatment with a higher dose could be a valid option and B-RAF mutations may be an interesting predictive marker to be studied in a larger randomized trial.

IMPORTANCE OF THE FIELD Treatment options for patients with advanced prostate cancer (PCa) remain limited. Improved understanding of the underlying molecular drivers of prostate cancer pathogenesis, progression and resistance development has provided the fundamental basis for rational targeted drug design. AREAS COVERED IN THIS REVIEW This review will discuss the most recent developments in the field of prostate cancer therapies including key findings such as the identification of ETS gene rearrangements, the dissection of prostate cancer molecular heterogeneity and the discovery that castration-resistant prostate cancer (CRPC) remains androgen-driven despite the androgen-depleted milieu, thus making androgen receptor signaling a continued focus of molecularly targeted treatments. A multitude of new molecularly targeted agents are in clinical development and are highly likely to change the current treatment paradigm. WHAT THE READER WILL GAIN This review will outline the current clinical development of molecular targeted treatments in CRPC. TAKE HOME MESSAGE Unraveling the complex molecular biology that underpins this heterogeneous disease may pave the way to personalized therapy with a wide range of rationally targeted agents and combination treatments. In conclusion, we can predict that the rational clinical development of new targeted drugs will improve the outcome of men with prostate cancer in the years ahead.

5063Background: Declines in prostate specific antigen (PSA) levels at 12-weeks are currently used to evaluate treatments response in metastatic castration resistant prostate cancer (mCRPC). Early P...

e16558 Background: Prostate cancer (PCa) is the most commonly diagnosed cancer in men. Around 80% of PCas are diagnosed as early, localised stage yet a subset of these will metastasise and eventually prove fatal. Management decisions are based on risk stratification systems. However, these systems are not able to clearly distinguish indolent from aggressive PCa’s and as a result many patients with indolent cancers may be over treated. Circulating microRNAs (miRNA) may be an easily accessible, suitable biomarker to distinguish true indolent from clinically significant early PCas thus reducing overtreatments. Methods: Blood samples from 24 men with benign prostatic hypertrophy (BPH, n = 8), localised PCa (n = 8) or metastatic PCa (n = 8) were collected at time of diagnosis. All men had intact prostates and were naïve to any endocrine or other cancer therapy. A platform of circulating miRNAs were analysed in serum using Abcam FireflyTM technology. Data collected were independently verified using real-time qPCR (Exiqon TM ). The miRNAs identified as being significantly different between groups were then analysed in a published dataset. Results: Serum levels of seven of the miRs examined were significantly different in patients with prostate cancer compared to control across both platforms (miR-10b, miR-125b, miR-210, miR-21, miR-378a, miR-483 and miR93 all with P values < 0.005). A further four miRNAs could differentiate between the benign and metastatic cohorts (miR-126 P = 0.008, miR-150 P = 0.05, miR375 P = 0.007). Kaplein-Meier analysis further identified that the serum levels of four miRNAs showed significant association with survival rates (miR-21 P = 0.032, miR-126 P = 0.032, miR-150 P = 0.032, miR-93 P = 0.019). On examination in a cohort of 280 men from The Cancer Genome Atlas (TCGA), four miRs from the cohort had significantly different expression in patients who eventually relapsed (miR-21 P = 0.048, miR-375 P = 0.021, miR-210 P = 0.0003, miR-93 P = 0.008) Conclusions: Our circulating miRNA based signature could be used to stratify men at prostate cancer diagnosis and help identify those who are likely to harbour micro metastases and would benefit more from an early radical treatment. The data is being validated in larger cohorts.

108 Background: Prostate cancer (PCa) is the most commonly diagnosed cancer in men. Around 80% of PCas are diagnosed as early, localised stage yet a subset of these will metastasise and eventually prove fatal. Management decisions are based on risk stratification systems. However, these systems are not able to clearly distinguish indolent from aggressive PCa’s and as a result many patients with indolent cancers may be over treated. Circulating microRNAs (miRNA) may be an easily accessible, suitable biomarker to distinguish true indolent from clinically significant early prostate cancers (PCa) thus reducing overtreatments. Methods: Blood samples from 24 men with benign prostatic hypertrophy (BPH, n = 8), localised PCa (n = 8) or metastatic PCa (n = 8) were collected at time of diagnosis. All men had intact prostates and were naïve to any endocrine or other cancer therapy. A platform of circulating miRNAs were analysed in serum using Abcam Firefly technology. Data collected were independently verified using real-time qPCR (Exiqon). The miRNAs identified as being significantly different between groups were then analysed in a published dataset. Results: Serum levels of seven of the miRs examined were significantly different in patients with prostate cancer compared to control across both platforms (miR-10b, miR-125b, miR-210, miR-21, miR-378a, miR-483 and miR93 all with P values < 0.005). A further four miRNAs could differentiate between the benign and metastatic cohorts (miR-126 P = 0.008, miR-150 P = 0.05, miR375 P = 0.007). Kaplein-Meier analysis further identified that the serum levels of four miRNAs showed significant association with survival rates (miR-21 P = 0.032, miR-126 P = 0.032, miR-150 P = 0.032, miR-93 P = 0.019). On examination in a cohort of 280 men from The Cancer Genome Atlas (TCGA), four miRs from the cohort had significantly different expression in patients who eventually relapsed (miR-21 P = 0.048, miR-375 P = 0.021, miR-210 P = 0.0003, miR-93 P = 0.008) Conclusions: Our circulating miRNA based signature could be used to stratify men at prostate cancer diagnosis and help identify those who are likely to harbour micro metastases and would benefit more from an early radical treatment. The data is being validated in larger cohorts.

31/6_suppl/6>. [4] Scher HI, Fizazi K, Saad F, Taplin M-E, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367(13):1187–97. http:// dx.doi.org/10.1056/NEJMoa1207506. [5] Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008;26(7):1148–59. http://dx.doi.org/ 10.1200/JCO.2007.12.4487. [6] Schrader AJ, Boegemann M, Ohlmann C-H, Schnoeller TJ, Krabbe L-M, Hajili T, et al. Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abirater- one. Eur Urol 2013;65:30–6. http://dx.doi.org/10.1016/ j.eururo.2013.06.042. [7] Thomsen FB, Roder MA, Rathenborg P, Brasso K, Borre M, Iversen P. Enzalutamide treatment in patients with metastatic castration-resistant prostate cancer progressing after chemother- apy and abiraterone acetate. Scand J Urol 2013(October):1–8. http://dx.doi.org/10.3109/21681805.2013.860189. [8] Van Soest RJ, van Royen ME, de Morree ES, Moll JM, Teubel W, Wiemer EAC, et al. Cross-resistance between taxanes and new hormonal agents abiraterone and enzalutamide may affect drug sequence choices in metastatic castration-resistant prostate cancer. Eur J Cancer 2013:3821–30. http://dx.doi.org/10.1016/j.ejca.2013.

Abiraterone and docetaxel are both approved treatments for men with metastatic castration-resistant prostate cancer (mCRPC). Abiraterone pre-docetaxel is currently undergoing evaluation in a phase III study. In vitro studies indicate that taxanes may act by disrupting androgen receptor signalling. We hypothesised that prior abiraterone exposure would adversely impact docetaxel efficacy. We retrospectively evaluated activity of docetaxel in mCRPC patients previously treated with abiraterone, using Prostate Cancer Working Group and radiological criteria. Of the 54 patients treated with abiraterone, 35 subsequently received docetaxel. Docetaxel resulted in a prostate-specific antigen (PSA) decline of >= 50% in nine patients [26%, 95% confidence interval (CI) 13% to 43%], with a median time to PSA progression of 4.6 months (95% CI 4.2% to 5.9%). PSA declines >= 30% were achieved by 13 patients (37%, 95% CI 22% to 55%). The median overall survival was 12.5 months (95% CI 10.6-19.4). All patients who failed to achieve a PSA fall on abiraterone and were deemed abiraterone-refractory were also docetaxel-refractory (N = 8). In the 24 patients with radiologically evaluable disease, partial responses were reported in four patients (11%), none of whom were abiraterone-refractory. The activity of docetaxel post-abiraterone appears lower than anticipated and no responses to docetaxel were observed in abiraterone-refractory patients.

Castration-resistant prostate cancer (CRPC) has a poor prognosis and remains a significant therapeutic challenge. Before 2010, only docetaxel-based chemotherapy improved survival in patients with CRPC compared with mitoxantrone. Our improved understanding of the underlying biology of CRPC has heralded a new era in molecular anticancer drug development, with a myriad of novel anticancer drugs for CRPC entering the clinic. These include the novel taxane cabazitaxel, the vaccine sipuleucel-T, the CYP17 inhibitor abiraterone, the novel androgen-receptor antagonist MDV-3100 and the radioisotope alpharadin. With these developments, the management of patients with CRPC is changing. In this Review, we discuss these promising therapies along with other novel agents that are demonstrating early signs of activity in CRPC. We propose a treatment pathway for patients with CRPC and consider strategies to optimize the use of these agents, including the incorporation of predictive and intermediate end point biomarkers, such as circulating tumor cells.

Octreotide is a somatostatin analog, long-acting formulations of which have been used experimentally for the treatment of patients with invasive tumors and/or residual disease after conventional therapies. The objective of this retrospective study was to evaluate the efficacy of long-acting octreotide (Sandostatin LAR) for the treatment of thymic tumors, with a primary efficacy end point of progression-free survival.Between 1994 and 2010, 44 patients with thymic malignancies were evaluated. Twenty-seven patients underwent an OctreoScan, and 12 OctreoScan-positive patients were treated with long-acting octreotide at a dose of 20 mg, given as an intramuscular injection, every 2 weeks.Treatment with long-acting octreotide gave the following results: 3 cases of partial response (25%), 5 cases of stable disease (42%), and 4 cases of progressive disease (33%), with an average progression-free survival of 8 months (range, 3 to 21). Treatment compliance and tolerability were good for all evaluated patients.The results of this study confirm the somatostatin receptor as a valid target for the treatment of thymic malignancies. Overall, therapy with long-acting somatostatin analogs seems to be safe and effective.

Prostate cancer is the most common cancer, and the second leading cause of death from cancer, in males in most Western countries. Advanced prostate cancer is initially sensitive to androgen deprivation therapy, but usually progresses to the castration-resistant state. There is now incontrovertible evidence that castration-resistant prostate cancer (CRPC) remains hormone driven, with intratumoral steroid synthesis fueling tumor growth. Several novel agents targeted androgen receptor signaling are currently being evaluated including abiraterone and MDV3100. Recent results of the phase III trial of abiraterone acetate in post-docetaxel patients has shown an overall survival benefit in advanced CRPC. This new treatment is likely to become a new standard of care for patients with metastatic CRPC.

Background: The phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is frequently deregulated in cancer due to mutations in PIK3CA and AKT, hyperactivation of upstream receptor kinases, and loss of function of PTEN. DS-3078a is a dual inhibitor of mTOR complex 1 (TORC1) and 2 (TORC2) that modulate the PI3K/AKT/mTOR pathway. This first-in-human study was conducted to determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of DS-3078a. Methods: Dose escalation was performed using an accelerated titration method with single patient cohorts starting at 20 mg followed by a continuous reassessment method according to a Bayesian regression logistic model. DS-3078a was administered orally in a continuous once daily (QD) schedule in 28-day cycles. PK parameters including area under the curve (AUC) and maximum plasma concentration (Cmax) were assessed on cycle 1 days 1 and 8. PD analyses were performed on cycle 1 days 1 and 15 in platelet-rich plasma (PRP) for changes in phospho-AKT and, when available, in paired tumor biopsies for phospho-AKT and -S6. Results: Seventeen patients (pts) with a median age of 61 years (range 38-72 years) were evaluable for dose limiting toxicities (DLT) according to NCI-CTCAE v 4.0. Mesothelioma (n=4) and neuroendocrine carcinoma (n=3) were the most common tumor types. Other tumor types included adenoid cystic, renal, ovarian, cervical, peritoneal, colorectal, and lung carcinoma, and unknown primary. Pts were treated at seven different dose levels of DS-3078a (20, 40, 80, 160, 320, 450, and 640 mg). MTD had been exceeded at 640 mg with DLT of grade 3 vomiting and grade 2 refractory nausea resulting in two pts not being able to complete 75% of the cycle 1 dose. The lower dose of 450 mg QD was well tolerated by 6 pts and 4 additional pts will be treated at this dose level to confirm MTD. The most common non-DLT drug-related toxicities at any cycle included grade ≤2 nausea (61%), vomiting (56%), diarrhea (50%), fatigue (33%), anorexia (28%), mucositis (28%), and hyperglycemia (17%). The mean Cmax and AUC value on day 1 at 450 mg QD was 542 ng/ml and 1898 ng.h/ml, respectively. Preliminary PD data showed up to 89% inhibition of Akt phosphorylation in platelets and up to 60% inhibition retained at 24 hours post-dose at ≥320 mg QD in some pts. The best response according to RECIST v1.1 was stable disease ≥6 months in 3 pts (ovarian, renal, and peritoneal carcinoma) with minor tumor response observed in a pt with renal carcinoma. Conclusion: DS-3078a was well tolerated up to and pharmacodynamically active at 450 mg QD. A continuous twice daily dosing schedule has been opened to explore other schedules which may optimize the biological effects of DS-3078a. Clinical trial information NCT01588676. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C173. Citation Format: Marta Capelan, Prasana Kumar, Anthony W. Tolcher, Andrea Zivi, Madhuri Desai, Kyriakos P. Papadopoulos, Giorgio Senaldi, Amita Patnaik, Udai Banerji, Drew D. Rasco. A first-in-human Phase I study of DS-3078a, an oral TORC1/2 inhibitor, in patients with advanced solid tumors: Preliminary results. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C173.

Background: AZD5363 is an oral, potent, and selective inhibitor of AKT1, 2 and 3, with activity in a wide range of tumor cell lines and xenografts dependent upon PI3K/AKT signaling. Methods: Two phase I studies (NCT01226316 [West], NCT01353781 [Japan]) were initiated to define the toxicity, pharmacokinetic (PK), and pharmacodynamic (PD) profile of AZD5363. Two schedules, continuous bid dosing (7/7) and an intermittent schedule bid dosing 4 days on 3 days off (4/7), were investigated. PD biomarkers of AKT signaling were assessed (using pre- and on-treatment samples) in plasma (pPRAS40, pGSK3β, pAKT, glucose, insulin), plucked hair (pPRAS40) and tumor tissue (pPRAS40, pGSK3β, pAKT). Results: At data cut-off (January 2013), 92 patients had been treated in the dose-escalation phases of both studies. In the Western study, the maximum tolerated dose (MTD) for each schedule was 320 mg bid (7/7) and 480 mg bid intermittent dosing (4/7). In the Japanese study, 320 mg bid (7/7) was not tolerated; the MTD for intermittent dosing (4/7) was 480 mg bid. The most commonly reported adverse events, of note, were hyperglycemia, rash, and diarrhea. The PK profile suggests a dose proportional increase in Cmax and AUC. Exposures achieved at doses of 320 mg bid (7/7) and 480 mg bid (4/7) and above are consistent with activity seen in xenograft models. At the doses described, target engagement was seen as evidenced by PD changes in normal tissue (>50% reduction in pPRAS40 in 7/10 patients on AZD5363 480 mg bid (4/7) in plucked hair samples and 30-50% reduction in pPRAS40 and >30% reduction in pGSK3β in platelet rich plasma). Importantly, 7/9 paired biopsies showed an increase in pAKT consistent with the non allosteric inhibition of AKT. Investigation of another intermittent schedule of AZD5363 bid, 2 days on/5 days off treatment, is ongoing. Exploratory mutation analyses of plasma samples are ongoing. Two partial responses were observed, one endometrioid cancer of the ovary and one cervical cancer, in patients on AZD5363 at 480 mg bid (4/7) and 400 mg bid (7/7), respectively. Mutation of either AKT1 or PIK3CA was identified in tumor tissue from both patients. A further patient, with endometrioid cancer of ovary (PIK3CA mutation), had stable disease (SD) for 156 days. Conclusions: AZD5363 administered at 480 mg bid (4/7) was generally well tolerated and showed a PK and PD profile consistent with activity in preclinical models. Partial responses were noted in patients with mutations driving the PI3K pathway. Footnote: AZD5363 was discovered by AstraZeneca subsequent to collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Ltd). Citation Format: Udai Banerji, Malcolm Ranson, Jan HM Schellens, Taito Esaki, Emma Dean, Andrea Zivi, Ruud van der Noll, Paul K. Stockman, Marcelo Marotti, Michelle D. Garrett, Barry R. Davies, Paul Elvin, Andrew Hastie, Peter Lawrence, SY Amy Cheung, Christine Stephens, Kenji Tamura. Results of two phase I multicenter trials of AZD5363, an inhibitor of AKT1, 2 and 3: Biomarker and early clinical evaluation in Western and Japanese patients with advanced solid tumors . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-66. doi:10.1158/1538-7445.AM2013-LB-66

Background: AA, a potent oral irreversible inhibitor of CYP17A1, has been recently approved for patients with CRPC progressing after docetaxel. CTC count ≥ 5/7.5 ml correlates with worse survival in CRPC. In this analysis we evaluated PSA responses, radiological responses and CTC conversion rates in relation to patient outcome. Methods: 141 patients (ECOG Performance Status 0-2; Median Age: 69.7; 85 post-docetaxel, 56 pre-docetaxel) treated with AA at the Royal Marsden NHS Foundation Trusts between December 2005 and March 2011 were included in this retrospective analyses. CTCs were enumerated using CellSearch at screening, baseline, at multiple time points during the study and at treatment discontinuation. PSA and imaging (Computer Tomography and Bone Scans) were obtained at the same time points as CTC collection. The Kaplan-Meier method was utilized for these analyses. Results: Baseline CTCs of ≥ 5 cells/7.5 ml were detectable in 17/53 (32.1%) pre-docetaxel patients (3 inevaluable) and 58/77 (75.3%) post-docetaxel patients (8 inevaluable at baseline). CTC conversion (≥ 5 to < 5 cells/7.5 ml) was observed in 10/17 (58.8%) pre-docetaxel patients and in 12/52 (23.1%) (6 inevaluable) post-docetaxel patients. PSA responses by PCWG II were observed in 16/22 (72.7%) of patients who attained a CTC conversion. PSA responses were seen in 8/47 (17.0%) patients in the absence of a corresponding CTC conversion. The median duration of radiological SD was 12.13 months (n=55) and 5.4 months (n=75) in patients with a baseline CTCs count of ≤ 5 cells/7.5mls and ≥ 5 cells/7.5 mls respectively. Overall, radiological stable disease was observed for a median of 6 months (95% CI: 4.2, 8.4; range 0.3, 35.6) beyond PSA progression in the 105 patients who experienced PSA progression. Radiological and clinical disease stability during treatment of ≥ 1 year, ≥ 2 years and ≥ 3 years was observed in 43/141 (30.5%), 21/141 (14.9%) and 12/141 (8.5%) respectively. Conclusion: Radiological and clinical disease stabilization beyond PSA progression is seen in a significant proportion of patients treated with AA. CTCs conversion correlates with PSA response and radiological disease stability. Citation Format: Diletta Bianchini, Alison Reid, Gerhardt Attard, Johann De Bono, Shahneen Sandhu, Amy Cassidy Mulick, Deborah Mukherji, Carmel Pezaro, Andrea Zivi, Aurelius Omlin, Ajit Sarvadikar, Emilda Thompson. Treatment response to abiraterone acetate (AA) in patients with castration-resistant prostate cancer (CRPC) based on circulating tumor cells (CTCs), prostate-specific antigen (PSA), and imaging [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C9.

In their recently published article in Clinical Cancer Research , Lin and colleagues claim that the efficiency for capturing circulating tumor cells (CTC), using their filter-based microdevice, which they hold a patent on, is superior to the Food and Drug Administration (FDA)-cleared CellSearch

e13559 Background: Current development is focused on agents targeting the RAF-MEK-ERK and PI3K-AKT-mTOR pathways. Combinations of these agents may address causes of de novo resistance. Identifying patients (pts) most likely to benefit from these combinations is important. Methods: A panel of 20 cell lines (5 BRAFM, 5 KRASM, 5 PIK3CAM and 5 BRAF/PIK3CA/KRASWT) were exposed to MEK and/or AKT inhibitors and evaluated for inhibition of pathway signaling and cell growth. Inhibition of signaling output of the RAF-MEK-ERK (p-ERK) and PI3K-AKT-mTOR (p-S6) pathways was quantified by ELISA. Growth inhibition was determined using sulforhodamine B assay. Based on the results of preclinical experiments, at our center we prioritized enrolling pts with RAS mutant tumors (including ovarian cancer and non-small cell lung cancer [NSCLC]) into an ongoing phase 1b clinical trial (CMEK162X2109) evaluating the combination of MEK inhibitor binimetinib (MEK162) and the PI3K-α inhibitor BYL719 in pts with RAS and RAF mutant tumor...

2024 Background: Primary malignant brain tumours (PMBT) are a rare tumour group with a poor outcome and limited options at relapse. Despite recent incremental gains from multimodal therapy and an e...

5052 Background: EZN-4176 is a third generationLNA-ASO that binds the ligand binding domain of AR mRNA resulting in full length AR mRNA degradation and decreased AR protein expression. Methods: Patients (pts) (performance status ECOG≤1) with progressing CRPC were eligible; prior abiraterone and enzalutamide treatment were allowed. EZN-4176 was administered as a weekly (QW) one-hour intravenous infusion. The starting dose was 0.5 mg/Kg with a 4-week dose-limiting toxicity (DLT) period. After determination of the DLT and the maximum tolerated dose (MTD) for weekly administration, a fortnightly schedule (Q2W) was initiated; a 3+3 modified Fibonacci dose escalation design was pursued. PD studies evaluated AR expression in tissue utilizing antibodies to the amino and carboxy-termini of the AR. Results: 22 pts were enrolled (median age 70.6 years, range 59 – 84 years). One pt was treated with the Q2W schedule. Two DLTs (G3/G4 ALT/AST elevation) occurred at 10 mg/Kg, which was therefore identified as the MTD for the weekly schedule. Multiple pts treated at 6.5 and 10 mg/Kg (5/9 pts, 55%) developed ≥G2 ALT and/or AST elevation after the first cycle requiring dose reduction and treatment delay. The most frequent adverse events (AEs) all-grades were fatigue (21/22 pts, 95.4%), nausea (10/22 pts, 45.4%), constipation (8/22 pts, 36.3%), AST (8/22 pts, 36.3%) and ALT (10/22 pts, 45.4%) elevation. The most frequent G3/4 AEs were AST (4/22 pts, 18.1%) and ALT (5/22 pts, 22.7%) elevation. Maximum PSA and circulating tumor cells (CTCs) declines are summarized below. There were no objective soft tissue responses. PD studies did not document any knockdown of AR expression Conclusions: EZN-4176 has limited antitumour activity in CRPC at its MTD for weekly administration. Safety, PK, PD and efficacy data will be presented. Clinical trial information: NCT01337518. [Table: see text]

2608 Background: AR-12 (OSU-03012) is an oral celecoxib analogue lacking COX-2 inhibitory activity that inhibits pyruvate dehydrogenase kinase isoenzyme 1 (PDK-1), AKT and impacts the endoplastic reticulum stress pathway. Preclinical studies indicate antitumor activity of AR-12 in various models and enhanced activity in combination. We completed a first in human clinical trial to determine its safety and tolerability, maximum tolerated dose (MTD) and recommended phase II dose (RD). Secondary objectives included assessment of tumor response, pharmacokinetics (PK) and pharmacodynamics (PD) including food effect. Methods: Patients (pts) with advanced solid tumors, ECOG PS 0-1, and adequate organ function were recruited in a modified 3+3 dose-escalation study. Pts received a run-in dose of AR-12 to analyze PK-PD and food effect, followed by continuous daily (QD) dosing in 28-day cycles. A twice daily (BID) cohort was initiated based on safety data. PD analysis was performed in platelet-rich plasma (PRP) and paired tumor biopsies when feasible. Results: 35 pts received at least one dose of study drug; 30 were evaluable for dose limiting toxicities (DLT) at dose ranges 100-3200mg QD and 800-1600mg BID. No DLT were observed in the QD cohort; DLT in the BID cohort are listed in table 1. Drug-related events (NCI-CTCAE v3) included rash (G2-2pts; G3-1pt), fatigue (G2-2pts; G3-4pts), nausea (G2-7pts; G3-1pt) and bloating (G2-1pt). Cmax after single dose was dose-proportional but high PK variability was observed, likely due to inadequate disintegration and dissolution of the formulation in the stomach. At RD, partial GSK3ß inhibition in PRP after 4 hours suggests AKT-pathway modulation. Best response (RECIST v1.0) was stable disease >6 cycles for 2 pts. Conclusions: The RD based on safety data is 800mg BID. Signs of pathway modulation were observed in concordance with the expected mechanism of action but were short-lasting. Considering limited drug absorption and PK variability, a new formulation of the drug will be developed to overcome these limitations. Clinical trial information: NCT00978523. [Table: see text]

4511 Background: AZD3514 is a first in class, orally bio-available drug that inhibits androgen-dependent and –independent androgen receptor (AR) signaling through two distinct mechanisms; inhibition of ligand-driven nuclear AR translocation and down-regulation of AR levels. Methods: A rolling six design was employed initially using a once a day (QD) schedule (A). PK assessments led to a change to twice daily (BD) dosing (B) to increase exposure. PK profiles were studied over 96 hours after a single dose and over 24 hours at start of/following 21 days continuous dosing. PD analyses included PSA and CTC quantification. Results: 49 CRPC patients (pts) have been treated with escalating doses of AZD3514 (A 35 pts, B 14 pts). Starting doses were 100 mg (A) and 1000 mg (B). The AZD3514 formulation was switched from capsules to tablets at 1000mg (QD). 2000mg BD was considered non-tolerable due to multiple grade 2 toxicities (nausea [N], vomiting [V], fatigue). No adverse events (AEs) met the DLT definition. The most frequent drug-related AE’s were N; G1/2 36/49 (73%), G3 2/49 (4%) and V; G1/2 24/49 (49%) & G3 3/49 (6%). N/V were managed with oral anti-emetics. Dose proportional increases in plasma concentrations were observed following a single dose. Geometric mean (%CV) Cmax and AUC at MTD were 9,608 (38.5) ng/mL and 61,734 (40.6) ng.hr/mL, respectively. Compared with single dose continuous dosing led to a mean decrease of 26% in exposure. Maximum PSA and CTC declines are summarized below. Objective soft tissue responses per RECIST1.1 were observed in 2/26 (8%) pts. One pt with abiraterone resistant disease remained on study for 19 months. At 6 and 12 months 21 (43%) and 8 (16%) pts remained on study without evidence of bone or soft tissue progression, respectively. Conclusions: AZD3514 has antitumor activity in patients with advanced CRPC. Clinical trial information: NCT01162395. [Table: see text]

4553 Background: AA, a potent oral CYP17A1 inhibitor is approved for treatment of mCRPC with a survival advantage of 4.9 months. In clinical practice, response evaluation remains challenging for pts with mCRPC. CTC conversion from CTC ≥ 5 to CTC < 5 with treatment predicts for improved overall survival in mCRPC. We hypothesized that pts continue to have durable disease stability beyond PSA progression on AA. Methods: Prostate Specific Antigen (PSA) responses, radiological responses and CTC conversion rates were retrospectively analysed in pts treated on AA at our institution. CTCs, PSA and imaging were obtained at predefined time points during these studies. Radiological and PSA progression were defined by standard Prostate Cancer Working Group Criteria II. Clinical progression consisted of worsening disease related pain, skeletal events or declining performance status.Pearson’s chi-squared test and the Kaplan-Meier method were used for this analysis. Results: 141 patients [ECOG Performance Status 0-2; Median Age: 69.7 (range 44.7-87.1); 85 post-docetaxel, 56 pre-docetaxel] received AA. The median duration of clinical and radiological stable disease (SD) was 16.8 months (n=55) and 5.6 months (n=75) in patients with a baseline CTCs count of ≤ 5 cells/7.5mls and ≥ 5 cells/7.5 mls respectively. In the 105 patients with documented PSA progression on AA there was a median 5.7-month delay in detecting radiological and/or clinical progression (95% CI: 4.2, 8.4; range 0.3, 35.6 months). Radiological and clinical SD of ≥ 1 year, ≥ 2 years and ≥ 3 years on AA was observed in 43/141 (30.5%), 21/141 (14.9%) and 12/141 (8.5%) respectively. Conclusions: Radiological and clinical disease stabilization beyond PSA progression is maintained in a high proportion of mCRPC patients treated with AA. Future studies should evaluate whether continued AA treatment beyond PSA and radiological progression can impact outcome.

17 Background: Abiraterone acetate (AA) has recently been approved for men with metastatic castration-resistant prostate cancer (CRPC) following docetaxel chemotherapy. AA inhibits CYP17, reducing androgen production and thereby impacting androgen receptor (AR) signalling. Recent evidence suggests taxanes also impact AR signalling, raising concerns about potential cross-resistance. We have previously shown that docetaxel has no antitumor activity in AA refractory patients. We have now evaluated the antitumor activity of AA post-docetaxel to determine the activity of AA in docetaxel refractory patients. Methods: Forty four men with CRPC treated with docetaxel (75 mg/m2 every 21 days) followed by post-chemotherapy AA at the Royal Marsden Hospital were identified. Radiological response by RECIST, PSA response by PSAWG2 criteria and symptomatic benefit were evaluated. Results: An average of 9 cycles of docetaxel were given (range 3-17); 7 patients discontinued chemotherapy due to progression of disease and 10 for toxicity. Of 40 patients with PSA data available, 26 (65%) had a PSA decline of at least 50%. At commencement of AA, median age was 68 years. Bone, nodal and visceral metastases were present in 38 (86%), 23 (52%) and 6 (14%) of the cohort respectively. An average of 5 months of treatment were delivered and 23 patients continue on AA. Of the 44, 7 (16%) patients had a 50% or greater PSA decline on AA. None of the 7 patients who were docetaxel refractory had a subsequent PSA, radiological or clinical response to AA. Of the 6 patients who received less than 5 cycles of docetaxel due to toxicity, 2 had subsequent PSA response on AA. There was no relationship between length of time on LHRH agonist and PSA response to AA. Conclusions: Our data suggest that patients who are refractory to docetaxel do not respond to AA. Overall, in conjunction with our other evidence that in AA-refractory patients docetaxel has no antitumor activity, these data provide further evidence for cross-resistance between these two agents.

4577 Background: Prostate cancer (PCa) is the commonest male cancer in the Western world. Its biology and prognosis are heterogeneous and improved tools are needed to predict outcome more reliably....

e13534 Background: The potential advantage of combining satraplatin (S) a novel oral platinum with Gem is attractive. MTD and DLT of combination S and Gem in patients (pts) with advanced solid tumors was evaluated. Methods: Cohorts of 3–6 pts (modified Fibonacci) received escalating doses of i.v. Gem on days (d) 1, 8 and 15 Q 28 d followed by oral S on d 1–5. Seventeen pts with metastatic solid tumors were separated into 2 groups: A) Pts that had progressed following cytotoxic therapy and B) Pts who had received no prior chemotherapy. Starting dose was Gem 800 mg in both groups, S 40 mg and 60 mg for A and B respectively. Results: Group A. 6 previously treated pts with 1 or 2 regimens (3 prostate, 1 hepatocarcinoma, 1 bladder and 1 thymic ca) received 25 cycles, median 2 (2–12). 2 DLTs (G3 transaminases) were observed in 6 pts treated at level 1. Other G3 major toxicities were: thrombocytopenia (1 pt) and diarrhea (1 pt). 2 pts had PSA declines, with TTP of 630 days in 1 of them. Group B. 11 pts with no prior chemotherapy (4 hepatocarcinoma, 4 pancreas, 1 renal, 1 unknown origin and 1 gallbladder), received 38 cycles, median 2 (1–12). 1 DLT (G3 diarrhea) was observed in 8 pts treated at level 1 (2 not evaluable; received Gem d1 only), DLT (G3 thrombocytopenia) was observed in 3 pts treated at level 2 (Gem 1000, S 60). Other G3 toxicities were: thrombocytopenia (3 pts) and neutropenia (3 pts). 1 CR (pancreas) and 1 PR (gallbladder) were observed. Gem d8 or d15 was omitted in 11 of 17 pts during the 1st cycle. Conclusions: In this study the combination of S and Gem showed a clinically acceptable toxicity profile with promising antitumor activity. However, since in cycle 1, it was not possible to administer Gem on both d8 and d15 on 11 occasions, a 2nd study was initiated with S d1–3 and Gem d1 and 8 given on a Q 21 d schedule. Sponsored by GPC Biotech No significant financial relationships to disclose.

e16027 Background: Sorafenib is an orally active multikinase inhibitor (Raf kinase, VEGFR 1, 2, 3 and PDGFR inhibitor) for the treatment of advanced RCC. The purpose of this study was to assess the efficacy and toxicity of Sorafenib in mRCC patients (pts) previously treated with an anti-angiogenic VEGFR-TKI using escalating dose levels. Methods: Pts with mRCC, PS 0–2 and adequate organ function were eligible. Pts received Sorafenib 400 mg/BID/continuously in 4-wk cycles. Pts with no progressive disease (evaluated at 12 weeks) continued to receive Sorafenib at the standard dose, while progressive pts received an increasing dose (600 mg BID) with early disease restaging after 4 weeks. Pts who progressed at 600 mg BID were taken off study. Efficacy was assessed by RECIST criteria. Results: 18 pts were entered; baseline characteristics: PS 0–1: 94%; median age 62 years (41–82); nephrectomy: 100%; surgery for metastatic disease: 28%, clear-cell 78%, papillary-cell 16%, sarcomatoid 6%.≥ 2 metastatic sites: 84%. 10 pts were refractory to cytokine treatment and all progressed or experienced unacceptable toxicity after anti-angiogenic VEGFR-TKI treatment, Sunitinib (13 pts) or Pazopanib (5 pts). Median number of cycles was 7.5 (1–16). Overall, 72% of pts had disease control without significant correlations between response to prior therapy and hypertension. 14 pts had progression free survival (PFS) of 4.3 months (mos). 4 pts are still in treatment with a median PFS > 8 mos. Of 6 pts in which the dose was escalated, 3 benefitted with a PFS of > 3 mos. The most common toxicity (NCIC 3.0, all pts) was grade (g) ≥ 1 diarrhea in 10 pts, g2–3 hand-foot syndrome in 7 pts and g-3 mucositis in 1 pt. Other hematological and non-hematological toxicities were g1 with a frequency < 15%. Conclusions: Sorafenib at doses of 400–600 mg/BID/continuosly results in acceptable and well tolerated salvage treatment after VEGFR-TKI failure. In progressive patients, treatment with a higher dose could be a valid option. Final and mature data will be presented in combination with translational research evaluating biological characteristics on tissue and blood. No significant financial relationships to disclose.

Key Points Question Is there a role for platinum-based treatment in molecularly selected patients with advanced prostate cancer? Findings In a case series of 508 patients, platinum-based therapy was associated with antitumor activity, especially among patients with known DNA repair gene aberrations. In patients with DNA repair gene aberrations, nearly half had a decrease in prostate-specific antigen levels of at least 50% and experienced soft tissue responses. Meaning In patients with prostate cancer and DNA repair gene aberrations, platinum-based therapy may be considered a treatment option., This case series characterizes the antitumor activity of platinum-based therapies in men with castration-resistant prostate cancer with or without DNA repair gene alterations., Importance DNA repair gene aberrations occur in 20% to 30% of patients with castration-resistant prostate cancer (CRPC), and some of these aberrations have been associated with sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition platinum-based treatments. However, previous trials assessing platinum-based treatments in patients with CRPC have mostly included a biomarker-unselected population; therefore, efficacy in these patients is unknown. Objective To characterize the antitumor activity of platinum-based therapies in men with CRPC with or without DNA repair gene alterations. Design, Setting, and Participants In this case series, data from 508 patients with CRPC treated with platinum-based therapy were collected from 25 academic centers from 12 countries worldwide. Patients were grouped by status of DNA repair gene aberrations (ie, cohort 1, present; cohort 2, not detected; and cohort 3, not tested). Data were collected from January 1986 to December 2018. Data analysis was performed in 2019, with data closure in April 2019. Exposure Treatment with platinum-based compounds either as monotherapy or combination therapy. Main Outcomes and Measures The primary end points were as follows: (1) antitumor activity of platinum-based therapy, defined as a decrease in prostate-specific antigen (PSA) level of at least 50% and/or radiological soft tissue response in patients with measurable disease and (2) the association of response with the presence or absence of DNA repair gene aberrations. Results A total of 508 men with a median (range) age of 61 (27-88) years were included in this analysis. DNA repair gene aberrations were present in 80 patients (14.7%; cohort 1), absent in 98 (19.3%; cohort 2), and not tested in 330 (65.0%; cohort 3). Of 408 patients who received platinum-based combination therapy, 338 patients (82.8%) received docetaxel, paclitaxel, or etoposide, and 70 (17.2%) received platinum-based combination treatment with another partner. A PSA level decrease of at least 50% was seen in 33 patients (47.1%) in cohort 1 and 26 (36.1%) in cohort 2 (P = .20). In evaluable patients, soft tissue responses were documented in 28 of 58 patients (48.3%) in cohort 1 and 21 of 67 (31.3%) in cohort 2 (P = .07). In the subgroup of 44 patients with BRCA2 gene alterations, PSA level decreases of at least 50% were documented in 23 patients (63.9%) and soft tissue responses in 17 of 34 patients (50.0%) with evaluable disease. In cohort 3, PSA level decreases of at least 50% and soft tissue responses were documented in 81 of 284 patients (28.5%) and 38 of 185 patients (20.5%) with evaluable disease, respectively. Conclusions and Relevance In this study, platinum-based treatment was associated with relevant antitumor activity in a biomarker-positive population of patients with advanced prostate cancer with DNA repair gene aberrations. The findings of this study suggest that platinum-based treatment may be considered an option for these patients.