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Aim: We aimed to evaluate the role of Positron Emission Tomography (PET) targeting the Prostate-Specific Membrane Antigen (PSMA) for response assessment in metastatic prostate cancer (mPCa) patients treated with taxane-based chemotherapy (docetaxel or cabazitaxel) and its predictive value on patient outcome. Methods: We retrospectively evaluated 37 patients with metastatic hormone-sensitive or castration-resistant prostate cancer (mHSPC or mCRPC) who underwent 68Ga-PSMA-11 PET/CT at baseline and after the last cycle of taxane-based chemotherapy (docetaxel or cabazitaxel) without treatment modification between scans. Biochemical response (BR) was defined as an undetectable or decreased prostate-specific antigen (PSA) by ≥50% compared to baseline. Association between BR and different PET parameters were tested. A cut-off of ≥30% change in PSMA total tumor volume (PSMA-TV) was used to define PSMA responders (PSMA-R) vs PSMA non-responders (PSMA-NR). Correlation between PSMA-PET/CT response and BR was evaluated using the Phi coefficient. Association between PET-response and overall survival (OS) was performed using Cox regression and Kaplan-Meier method. Results: Our cohort was composed of 8 (22%) mHSPC and 29 (78%) mCRPC patients. Twenty-one patients received docetaxel, and 16 received cabazitaxel treatment (median: 6 cycles, interquartile (IQR):5-8). BR was found in 18/37 patients. Using PSMA-TV, PSMA-PET/CT response was concordant with BR in 35/37 patients (Phi=0.89, p

To investigate the association between Prostate-Specific Membrane Antigen (PSMA) expression changes on positron emission tomography–computed tomography (PET/CT) and the response to treatment following the start of enzalutamide or abiraterone in metastatic castration-resistant prostate cancer (mCRPC) patients. All consecutive 68Ga-PSMA-11 PET/CT scans routinely performed at our institution during more than 4 years were retrospectively screened for inclusion. We included mCRPC patients with a baseline PSMA PET/CT performed less than 2 months before the start of either enzalutamide or abiraterone, and a follow-up PSMA PET/CT performed no more than a year after, while still under those novel antiandrogen drugs (NAD). The associated clinical records were reviewed. Patients were considered treatment responders if they presented decreasing PSA levels > 50% or a radiological response based on RECIST 1.1 criteria. PSMA expression changes on the follow-up PET/CT were assessed using per-patient dominant response criteria to classify patients as PSMA-responders (complete disappearance of pathologic PSMA uptake, or a decreased uptake of the majority of lesions) or PSMA-non-responders (new PSMA-expressing lesions, increased uptake of the majority of lesions, or stable PSMA expression of the disease). Descriptive statistics and measures of associations (two-sided Fisher’s exact test and Phi coefficient) were calculated. A total of 11 and 15 patients were included in the enzalutamide and abiraterone groups. Median follow-up was 110 (IQR 76–124) and 87 (IQR 71–242) days, respectively. All treatment responders (3 enzalutamide and 4 abiraterone) were considered PSMA-responders, and all treatment non-responders (8 enzalutamide, 11 abiraterone) were considered PSMA-non-responders. PSMA PET response was thus perfectly associated with conventional response criteria (p = 0.006, Phi = 1 for enzalutamide; p = 0.001, Phi = 1 for abiraterone). In our cohort, no PSMA expression flare phenomenon was detected on follow-up PET/CT scans at a median follow-up of 3 months. However, an early and short-lived flare cannot be excluded. This retrospective study suggests that, after a median follow-up of 3 months under enzalutamide or abiraterone, PSMA expression changes on PET/CT are strongly associated with response to treatment. Prospective studies are needed to better understand PSMA expression dynamics following the start of enzalutamide and abiraterone, along with the role of PSMA PET/CT in response assessment.

The appropriate management of localized or metastatic hormone-sensitive prostate cancer (HSPC) patients harboring tumor BRCA mutations (tBRCAm) is not well-characterized. We sought to evaluate the prevalence and clinical outcomes of patients with tBRCAm and localized or de novo metastatic HSPC. We performed a multicenter, international, retrospective cohort study of localized (cohort 1) and de novo metastatic (cohort 2) HSPC patients who underwent tumor BRCA1 and BRCA2 sequencing from 2013 to 2019. Primary endpoints included event-free survival (EFS) and metastases-free survival (MFS) for cohort 1, and time to castration-resistant prostate cancer (TTCRPC) and overall survival (OS) for cohort 2. Kaplan–Meier method and Cox regression models estimated the association of endpoints with tBRCA status. Of 399 identified patients with localized and de novo metastatic HSPC who underwent tumor BRCA1 and BRCA2 sequencing, 3.1% (8/258) patients of cohort 1 and 10.6% (15/141) patients of cohort 2 harbored tBRCAm. The median follow-up was 33 and 36 months, respectively. In cohort 1, median EFS was 18.1 vs. 57 months (p = 0.28) and MFS was 37 vs. 153.4 months (p = 0.08) for patients with tBRCAm compared to patients with no tBRCAm. In cohort 2, the TTCRPC was 24 vs. 19 months (p = 0.65) and OS was 64 vs. 60 months (p = 0.95) in patients with and without tBRCAm, respectively. While tBRCAm seems to be associated with greater relapse risk in localized disease, tBRCAm did not influence the clinical outcomes of patients presenting with de novo metastatic HSPC treated with conventional therapies. tBRCAm may exert different prognostic effects across the clinical spectrum of prostate cancer.

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

Background: There is limited experience regarding the safety and efficacy of checkpoint inhibitors (CPI) in patients with autoimmune disorders (AD) and advanced urological cancers as they are generally excluded from clinical trials due to risk of exacerbations. Methods: This multicenter retrospective cohort analysis of patients with advanced renal cell cancer (RCC) and urothelial cancer (UC) with pre-existing AD treated with CPI catalogued the incidence of AD exacerbations, new immune-related adverse events (irAEs) and clinical outcomes. Competing risk models estimated cumulative incidences of exacerbations and new irAEs at 3 and 6 months. Results: Of 106 patients with AD (58 RCC, 48 UC) from 10 centers, 35 (33%) had grade 1/2 clinically active AD of whom 10 (9%) required corticosteroids or immunomodulators at baseline. Exacerbations of pre-existing AD occurred in 38 (36%) patients with 17 (45%) requiring corticosteroids and 6 (16%) discontinuing CPI. New onset irAEs occurred in 40 (38%) patients with 22 (55%) requiring corticosteroids and 8 (20%) discontinuing CPI. Grade 3/4 events occurred in 6 (16%) of exacerbations and 13 (33%) of new irAEs. No treatment-related deaths occurred. Median follow-up was 15 months. For RCC, objective response rate (ORR) was 31% (95% CI 20% to 45%), median time to treatment failure (TTF) was 7 months (95% CI 4 to 10) and 12-month overall survival (OS) was 78% (95% CI 63% to 87%). For UC, ORR was 40% (95% CI 26% to 55%), median TTF was 5.0 months (95% CI 2.3 to 9.0) and 12-month OS was 63% (95% CI 47% to 76%). Conclusions: Patients with RCC and UC with well-controlled AD can benefit from CPI with manageable toxicities that are consistent with what is expected of a non-AD population. Prospective study is warranted to comprehensively evaluate the benefits and safety of CPI in patients with AD., SCOPUS: ar.j, info:eu-repo/semantics/published

The development of new immune treatment in oncology and particularly for lung cancer may induce new complications, particularly activation or reactivation of auto-immune diseases. In this context, a systematic review on the auto-immune paraneoplastic syndromes that can complicate lung cancer appears useful. This article is the last of a series of five and deals mainly with onconeural antibodies involved in neurological paraneoplastic syndromes and provides the final discussion.

The development of new immune treatment in oncology and particularly for lung cancer may induce new complications, particularly activation or reactivation of auto-immune diseases. In this context, a systematic review on the auto-immune paraneoplastic syndromes associated with lung cancer appears useful. This article is the second of a series of five and deals with hematologic, cutaneous and vascular syndromes.

Objective To assess the impact of a novel molecular imaging technique, 68Ga-(HBED-CC)-prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT), in the clinical management of patients with prostate cancer with rising prostate-specific antigen (PSA) after treatment with curative intent. Patients and Methods In all, 131 consecutive patients were referred to our centre for a 68Ga-PSMA PET/CT in the setting of recurring prostate cancer. Of these patients, 11/131(8%) presented with persistent PSA after radical prostatectomy, while 120/131 (92%) were referred for biochemical recurrence after surgery, radiotherapy or both. The images where taken 1 h after injection of 2 MBq/kg of the 68Ga-(HBED-CC)-PSMA ligand. All examinations were interpreted by two experienced nuclear medicine specialists. Using the results of the examination, a multidisciplinary oncology committee (MOC) reported on the treatment strategy. A positive impact on clinical management was considered if the examination determined a modification in the treatment strategy compared to the MOC decision before PSMA imaging. Results All patients completed the examination with no adverse reactions. The median (interquartile range) PSA level at the time of the examination was 2.2 (0.72–6.7) ng/mL. Overall, 68Ga-PSMA PET/CT detected at least one lesion suspicious for prostate cancer in 98/131 (75%) patients. There was an impact on subsequent management in 99/131 patients (76%). The main modifications included continuing surveillance (withholding hormonal therapy), hormonal manipulations, stereotaxic radiotherapy, salvage radiotherapy, salvage node dissection or salvage local treatment (prostatectomy, high-intensity focussed ultrasound). Conclusion Our preliminary experience suggests that performing 68Ga-PSMA PET/CT in patients with prostate cancer with rising PSA after treatment with curative intent can be clinically useful as it changes the treatment strategy in a significant proportion of patients. However, larger prospective trials are needed to validate our present findings.

Prostate cancer (PCa) treatment monitoring usually relies on prostate-specific antigen to detect disease progression or relapse. PET/CT with prostate-specific membrane antigen (PSMA) ligands has shown high accuracy in detecting metastatic PCa lesions and could help assess response to therapy. We describe herein the early relapse detection of a hormone-sensitive metastatic upfront PCa treated with docetaxel on Ga-PSMA-11 PET/CT before biochemical progression. PSMA PET/CT should be considered to monitor PCa response to chemotherapy to detect early relapse, regardless of prostate-specific antigen levels, increasing the chances of finding low-volume oligoprogressive disease.

The aim of the present study was to investigate the efficacy of paclitaxel following a first-line cisplatin regimen in patients with metastatic bladder cancer. The present study retrospectively evaluated the clinical effects and toxicities of second-line paclitaxel regimens following first-line cisplatin treatment in metastatic bladder cancer. A total of 42 patients with progressing metastatic urothelial bladder cancer following cisplatin-based chemotherapy were enrolled. The patients received weekly treatment with paclitaxel (80 mg/m2) with a median duration of 3 months. The overall response rate, disease control rate and median progression free survival were 9.5, 45.2 and 6.4 months, respectively. Weekly paclitaxel was well-tolerated with rare grade III or IV toxicities. Second-line weekly paclitaxel treatment following first-line cisplatin-based chemotherapy is an effective and well-tolerated regimen in urothelial metastatic bladder cancer.

Corticosteroid agents (CA) are widely used in the treatment of metastatic castration-resistant prostate cancer (mCRPC) either as concomitant treatment with active agents such as docetaxel, cabazitaxel and abiraterone or in a palliative setting, predominantly due to their anti-inflammatory activity. However, the chronic use of CA has numerous side effects, especially in case of steroid-induced adrenal insufficiency. Furthermore, the latest clinical and preclinical data demonstrate that CA themselves are likely to promote tumour progression in certain populations of patients with mCRPC. Therefore, the role of CA in advanced disease should be carefully weighed for each patient and their withdrawal should be considered in some patients. This is necessary, especially in clinical trials that need good performance status patients to evaluate the activity and the safety of emerging drugs in mCRPC that do not require the concurrent use of CA. In oncology, there is no consensus on an algorithm of gradual steroid tapering and frequently the approach to this procedure is empirical. An algorithm is presented in this article based on clinical observations. Prospective studies are necessary to evaluate the efficacy and safety of the above-proposed algorithm in metastatic castration-resistant prostate cancer.

44 Background: Somatic BRCA gene mutations ( sBRCAm) have been identified in a significant proportion of patients (pts) with castration resistant PC (CRPC), with mixed data regarding effect on CRPC therapies. However, the prevalence and clinical significance in mHSPC are not well characterized. Methods: Sequencing of primary tumor for sBRCA1/2 was performed in unselected pts with de novo mHSPC. We assessed the association of sBRCAm on time to CRPC (TTCRPC) and overall survival (OS) from diagnosis using Kaplan-Meier method, as well as PSA response (50% fall from baseline). Associations were evaluated using a Cox regression model with multivariable analyses adjusting for docetaxel use. Results: We identified 69 pts with de novo mHSPC, of whom 7 (10%) harbored a pathogenic sBRCA2m. Median age at diagnosis was 66 years. The majority were classified as high volume disease (n=54; 84%) with Gleason 9-10 grade (n=40; 61%). Therapies in the HSPC setting included ADT alone (n=29, 42%), ADT + Docetaxel (n=35, 51%), and ADT + Docetaxel + Abiraterone (n=5, 7%). Only 1 s BRCA2m case compared to 39 wild-type pts were treated with docetaxel. PSA response was achieved in 65 (96%) and PSA £ 0.2 ng/ml at 7 mos in 20 (31%) pts, without significant association with BRCA status ( p=0.13 and p=0.66, respectively). At a median FU of 29 mos, CRPC occurred in 44 (64%) pts with a median TTCRPC of 24 mos. TTCRP was numerically shorter for non-mutated pts compared to sBRCAm (22 vs. 40 mos, HR 0.5, p=0.23); there was no significant association with docetaxel use. In multivariate analyses, there was no significant association between sBRCAm and TTCRPC (HR 0.43, p=0.175). Median OS was 74 mos without any difference according to BRCA status ( p=0.30) nor docetaxel use ( p=0.14). Conclusions: In this real-world study of routine s BRCA1/2 assessment, we found a 10% prevalence in de novo mHSPC. Time to CRPC trended longer in the sBRCAm population despite less use of docetaxel, indicating that pts with sBRCAm appear to have at least similar outcomes with standard mHSPC therapies. Larger datasets correlating genomics with outcomes in this subset of pts are warranted.

547 Background: Cisplatin-based NAC followed by surgery is the gold standard treatment of non-metastatic MIBC. However, predictive biomarkers have not been established yet. Here, we addressed the relevance of TILs for NAC response and prognosis in MIBC patients (pts). Methods: We conducted a single center, retrospective cohort analysis of consecutive MIBC pts treated with cisplatin-based NAC followed by surgery. Pts with pathological complete response (pCR; ypT0/isN0) were grouped as responders, pts with pathological residual disease as non responders. TIL stromal count were assessed pre- and post-NAC. Next Generation Sequencing of selected genes was performed on pre-NAC samples. We catalogued the 3-years(y) relapse free rate and 3-y overall survival rate (OS, Kaplan Meier) for the overall cohort and by subgroups. Results: Of the 25 pts who received cisplatin-gemcitabine NAC, a total of 14 (56%) pts achieved a pCR and 11 (44%) had residual disease. NAC was discontinued in 17 (65%) after completing treatment; and in 8 (32%) pts after 2 cycles due to toxicity. Median follow-up was 54.2 months(mos). At baseline, median TIL count was 60% in the overall cohort. Numerically higher TIL count was observed among responders (80%) compared to non-responders (50%) ( p=0.22). Median TIL count post-NAC in residual samples was 40%, not significantly different to matched pre-NAC samples ( p=0.93). Overall, 3-y relapse free rate was 74.7% (95%CI 51.7-87.9); 3-y OS rate was 79.6% (95%CI 57.6-91) with 6 deaths of which 4 were related to metastatic disease. Table reports subset analyses. Most frequently altered genes were PIK3CA and TP53 in the overall cohort (each 20%) and in the responders subgroup (each 29%). Conclusions: In our study, pts who achieved pCR had numerically greater TIL infiltrate in baseline samples and pCR was associated with reduced risk of recurrence. TILs did not increase in residual tumors after NAC. The independent predictive value of TILs warrants assessment in large cohorts.[Table: see text]

Background Loss of PTEN is a common genomic aberration in castration-resistant prostate cancer (CRPC) and is frequently concurrent with ERG rearrangements, causing resistance to next-generation hormonal treatment (NGHT) including abiraterone. The relationship between PTEN loss and docetaxel sensitivity remains uncertain. Objective To study the antitumor activity of docetaxel in metastatic CRPC in relation to PTEN and ERG aberrations. Design, setting, and participants Single-centre, retrospective analysis of PTEN loss and ERG expression using a previously described immunohistochemistry (IHC) binary classification system. Patients received docetaxel between January 1, 2006 and July 31, 2016. Outcome measurements and statistical analysis Response correlations were analyzed using Pearson's χ2 tests and independent-sample t tests. Overall (OS) and progression-free survival (PFS) were analyzed using univariate and multivariate (MVA) Cox regression and Kaplan-Meier methods. Results and limitations Overall, 215 patients were eligible. Established metastatic CRPC prognostic factors were well balanced between PTEN loss (39%) and normal patients (61%). PTEN loss was associated with shorter median OS (25.4 vs 34.7 mo; hazard ratio [HR] 1.66, 95% confidence interval [CI] 1.18–2.13; p = 0.001). There were no differences in median PFS (8.0 vs 9.1 mo; univariate HR 1.20, 95% CI 0.86–1.68; p = 0.28) and PSA response (53.4% vs 50.6%; p = 0.74). PTEN loss was an independent prognostics factor in MVA. ERG status was available for 100 patients. ERG positivity was not associated with OS or PFS. Limitations include the retrospective nature and the single-centre analysis. Conclusions Our findings suggest that metastatic CRPC with PTEN loss might benefit more from docetaxel than from NGHT. Patient summary In this study we found that metastatic prostate cancer with loss of the PTEN switch may benefit more from docetaxel than from abiraterone., Take Home Message PTEN loss in advanced prostate cancer may benefit more from taxanes than from abiraterone.

Soft tissue sarcomas (STSs) are rare, aggressive and heterogeneous malignancies with poor outcomes. They include more than 50 different histologic subtypes with variable molecular and cytogenetic profiles responsible for the heterogeneity of these tumors. Radical surgery, chemotherapy and radiation therapy are still the mainstay of treatment with limited therapeutic options in case of metastatic and locally advanced unresectable disease. The current available cytotoxic and targeted therapies are only offering short living disease control. In the era of immunotherapy, STSs were affected by this ‘tsunami’ with very promising results, but larger randomized trials are still needed to prove their benefit in terms of survival and efficacy. They are not included yet in the standard of care. In this review of the literature, we are developing the active immunotherapeutic strategies (vaccines), as well as the passive strategies (adoptive cell therapy) and the checkpoint inhibitors emphasizing on the most recent results and on the limitation of the immunotherapy in this heterogenic media.

Background: Abiraterone and enzalutamide are novel endocrine treatments that abrogate androgen receptor (AR) signalling in castration-resistant prostate cancer (CRPC). Here, we developed a circulating tumour cells (CTCs)-based assay to evaluate AR expression in real-time in CRPC and investigated nuclear AR expression in CTCs in patients treated with enzalutamide and abiraterone. Methods: CTCs were captured and characterised using the CellSearch system. An automated algorithm to identify CTCs and quantify AR expression was employed. The primary aim was to evaluate the association between CTC AR expression and prior treatment with abiraterone or enzalutamide. Results: AR expression in CTCs was evaluated in 94 samples from 48 metastatic CRPC patients. We observed large intra-patient heterogeneity of AR expression in CTCs. Prior exposure to abiraterone or enzalutamide was not associated with a change in CTCs AR expression (median intensity and distribution of AR-positive classes). In support of this, we also confirmed maintained nuclear AR expression in tissue samples collected after progression on abiraterone. AR staining also identified additional AR-positive CD45-negative circulating cells that were CK-negative/weak and therefore missed using standard protocols. The number of these events correlated with traditional CTCs and was associated with worse outcome on univariate analysis. Conclusions: We developed a non-invasive method to monitor AR nuclear expression in CTCs. Our studies confirm nuclear AR expression in CRPC patients progressing on novel endocrine treatments. Owing to the significant heterogeneity of AR expression in CTCs, studies in larger cohorts of patients are required to identify associations with outcome

The development of new immune treatment in oncology and particularly for lung cancer may induce new complications, particularly activation or reactivation of auto-immune diseases. In this context, a systematic review on the auto-immune paraneoplastic syndromes that can complicate lung cancer appears useful. This article is the fourth of a series of five and deals mainly with neurological paraneoplastic syndromes involving the peripheral nervous system and the neuromuscular junction and muscles.

The development of new immune treatment in oncology and particularly for lung cancer may induce new complications, particularly activation or reactivation of auto-immune diseases. In this context, a systematic review on the auto-immune paraneoplastic syndromes associated with lung cancer appears useful. This article is the second of a series of five and deals with hematologic, cutaneous and vascular syndromes.

Germ cell tumors primarily affect adolescents and young adult men. They occur much less commonly in older patients. The definition of elder age in this kind of tumors, as the detailed clinical and treatment characteristics in this age group are lacking. According to the literature, germ cell tumors are infrequent in men aged more than 50 years old, and there is a predominance of seminomatous histologic subtype. Here we report the case of a 56 years old male patient who was initially diagnosed with pure testicular seminoma at the age of 55. He underwent a right orchiectomy and didn’t receive an adjuvant treatment for a pure seminomatous germ cell tumor, staged pT1 with rete testis invasion. Unfortunately, he suffered from a retroperitoneal relapse of his disease 9 months after the surgery. He received a first line chemotherapy consisting of 4 cycles of Etoposide and Cisplatin. He tolerated very well the treatment with an excellent response and without developing any related toxicity. He is currently in complete remission on regular follow up. This case report and review of the literature are to emphasize on germ cell tumors diagnosed after the age of 50 years old. This category of patients should be treated with full curative surgical and cytotoxic treatments, as it is done in the younger population, in order to achieve a good overall response rate. However, they require careful observation and increased supportive care for better treatment tolerability and thus better outcome., info:eu-repo/semantics/published

To assess the impact of a novel molecular imaging technique,In all, 131 consecutive patients were referred to our centre for aAll patients completed the examination with no adverse reactions. The median (interquartile range) PSA level at the time of the examination was 2.2 (0.72-6.7) ng/mL. Overall,Our preliminary experience suggests that performing

To use a non-biased assay for circulating tumour cells (CTCs) in patients with prostate cancer (PCa) in order to identify non-traditional CTC phenotypes potentially excluded by conventional detection methods that are reliant on antigen- and/or size-based enrichment.A total of 41 patients with metastatic castration-resistant PCa (mCRPC) and 20 healthy volunteers were analysed on the Epic CTC platform, via high-throughput imaging of DAPI expression and CD45/cytokeratin (CK) immunofluorescence (IF) on all circulating nucleated cells plated on glass slides. To confirm the PCa origin of CTCs, IF was used for androgen receptor (AR) expression and fluorescence in situ hybridization was used for PTEN and ERG assessment.Traditional CTCs (CD45Heterogeneous non-traditional CTC populations are frequent in mCRPC and may provide additional prognostic or predictive information.

The availability of multiple new treatments for metastatic castration-resistant prostate cancer (mCRPC) mandates earlier treatment switches in the absence of a response. A decline in prostate-specific antigen (PSA) is widely used to monitor treatment response, but is not validated as an intermediate endpoint for overall survival (OS).To evaluate the association between early PSA decline and OS following abiraterone acetate (AA) treatment.We identified mCRPC patients treated with AA before or after docetaxel at the Royal Marsden NHS Foundation Trust between 2006 and 2014. Early PSA decline was defined as a 30% decrease in PSA at 4 wk relative to baseline, and early PSA rise as a 25% increase.Association with OS was analyzed using multivariate Cox regression and log-rank analyses. Spearman's rho correlation coefficient (r) was calculated to evaluate the association between PSA changes at 4 wk and 12 wk.There were 274 patients eligible for this analysis. A 30% PSA decline at 4 wk was associated with longer OS (25.8 vs 15.1 mo; hazard ratio [HR] 0.47, p0.001), and a 25% PSA rise at 4 wk with shorter OS (15.1 vs 23.8 mo; HR 1.7, p=0.001) in both univariate and multivariable models. The percentage PSA decline at 4 wk was significantly correlated with the percentage PSA change at 12 wk (r=0.82; p0.001). Patients achieving a 30% PSA decline at 4 wk were 11.7 times more likely to achieve a 50% PSA decrease at 12 wk (sensitivity 90.9%, specificity 79.4%). Limitations include the retrospective design of this analysis.Patients not achieving 30% PSA decline after 4 wk of AA have a lower likelihood of achieving PSA response at 12 wk and significantly inferior OS. Prospective multicentre validation studies are needed to confirm these findings.Prostate-specific antigen (PSA) is commonly used to evaluate response to treatment in metastatic castration-resistant prostate cancer. Expert recommendations discourage reliance on PSA changes earlier than 12 wk after treatment initiation. Our data suggest that early PSA changes are associated with survival in patients receiving abiraterone acetate.

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...

TPS535 Background: Avelumab, a fully human anti-PD-L1 IgG1 monoclonal antibody, is approved in monotherapy for the advanced disease. For patients with non metastatic muscle-invasive bladder cancer (MIBC) the preferred treatment nowadays consists of a multimodal approach comprising neoadjuvant cisplatin-based chemotherapy followed by surgery. However, the benefit of the neoadjuvant chemotherapy (NAC) is modest and an important proportion of patients do not benefit providing unnecessary toxicity. In addition, forty per cent of this population is ineligible for platinum-based therapies and currently no medical alternative option exist. This trial will attempt to answer several open questions: what is the role of the immunotherapy in the neoadjuvant setting? Is efficacy of immunotherapy influenced by the association with cytotoxic agents? Which agents (anthracyclins, platin or taxanes)? Do cisplatin-ineligible patients benefit from this approach? Is there any predictive biomarker for chemotherapy and/or immunotherapy? Methods: This is a randomized phase 2 study in subject candidates for a NAC followed by surgery (EudraCT Number: 2017-002758-35). The study will recruit cisplatin eligible and ineligible patients. For the group of cisplatin-eligible, chemotherapy with high dose of Metotrexate-Vinblastin-Adriamycin-Cisplatin or Cisplatin-Gemcitabine will be associated with Avelumab. For the group of cisplatin-ineligible, Avelumab as monotherapy or associated with Paclitaxel-Gemcitabine will be used. Four cycles of treatment are provided. A radiological evaluation will be performed after 2 cycles and if evidence of progressive disease exists the neoadjuvant treatment will be stopped and the surgery will be performed (Table 1 represents the study design). The primary objective is to determine the pathologic complete response as well as to assess the toxicity profile. Blood, urine and stool samples will be collected at different points to perform translational researches. Clinical trial information: 2017-002758-35.

The field of immunotherapy in urinary malignancy is expanding in several directions and checkpoint inhibitors are leading the way. The aim of this report is to highlight the efficacy and safety profile of the two classes of molecules, anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed death receptor-1/programmed death ligand type 1, that are under investigation and represent potential candidates to be used in the near future for the management of bladder and renal cell cancer. The preliminary results as well as the future perspectives of this novel immunotherapy are analyzed. Novel immune checkpoint targets are reviewed as well.

Long-term prognosis of germ cell tumor (GCT) types is excellent, however, treatment is associated with non-negligible complication rates and a negative impact on quality of life. The present study described treatment results in terms of survival, both short and long-term toxicity, and paternity rates in a cohort of patients treated at Jules Bordet Institute, University ULB of Brussels (Brussels, Belgium). The present study analyzed the data of a cohort of patients with GCT types. Pre-operative patient and tumor characteristics were described. Performance status, pulmonary function tests and renal clearance prior to chemotherapy were noted. Chemotherapeutic regimens and their associated toxicities were analyzed. The duration to event-free, cancer-specific and overall survivals were estimated using Kaplan-Meier curves. A total of 115 patients (median age, 31-years-old) were treated for a GCT at Jules Bordet Institute. At a median follow-up of 6-years, 11 (10%) patients had relapsed and 2 (2%) developed a second malignant neoplasm. At the final follow-up, 97 (89%) and 6 (5.5%) patients exhibited complete and partial remission, respectively. A total of 6% of patients exhibited a progressive disease. In terms of short-term toxicity, 11% of patients presented with febrile neutropenia. The 10-year overall survival rate and relapse-free survival rate were 93.4 and 89.8%, respectively. The paternity rate post-treatment was 27%. Testicular GCT survivors suffered from short- and long-term treatment-associated side effects on both a physical and psychological level. A long-term close follow-up is necessary in order to assist the patient with these treatment-induced complications.

A prognostic model was derived from the population of the COU-AA-301 phase 3 trial for metastatic castrate-resistant prostate cancer patients treated with abiraterone after docetaxel, and it stratifies patients into three risk groups based on clinical parameters. We validated this model in an independent cohort of patients treated with abiraterone after docetaxel outside a clinical trial (group A; n=94) and explored its utility in patients treated with abiraterone in the prechemotherapy setting (group B; n=64). For group A, median overall survival (mOS) was significantly different across the three prognostic groups (good: n=39, mOS: 21.8 mo; intermediate: n=44, mOS: 10.6 mo; poor: n=7, mOS: 6.8 mo; p

5043Background: The diagnosis (Dx) of LM in PCa pts carries a poor prognosis and its incidence is increasing. We conducted a retrospective analysis to identify clinical and radiological factors ass...

Aim: Standard CT and bone scans provide inadequate assessment of the extent of bone disease in mCRPC. WBDWI is a magnetic resonance technique with high sensitivity and specificity for detecting bone metastases, allowing quantification of disease volume and assessment of tumor cellularity by assessing apparent diffusion coefficients (ADC). We hypothesized that volume of bony disease, quantified by DWI assessment, is a prognostic biomarker of overall survival in mCRPC. Methods: mCRPC patients with bone metastases and WBDWI performed on a 1.5-T Siemens scanner between Jun-2010 and Jan-2013, prior to starting a new anticancer therapy, were selected. WBDWI and ADC maps were used to delineate volume of bone metastases (VBM) and represent ADC values on histograms. Clinical data were collected and correlated with VBM and ADC histogram variables. Survival (OS) analysis was performed with Kaplan-Meier analysis and Cox regression (SPSS). Correlations were calculated with Spearman ?s rho coefficient (r). Results: 43 patients were included in the study. Median OS was 12.9 months (m) (95%CI 8.7 – 16.1m). Median VBM was 503.1 mL (range: 5.6 to 2242 mL). Baseline CTC counts and bone scan index (BSI) were available for 21 (65.6%), and 32 (74.4%) patients respectively. VBM as a continuous variable was inversely associated with OS (p = 0.032). VBM with ADC > 775 µm2/s showed a significant inverse correlation with OS (p = 0.037), whereas VBM with ADC Conclusions: Volume of bone metastases estimated by WBDWI associates with OS in mCRPC. Studies of ADC value distribution provide valuable functional information on mCRPC. Disclosure: All authors have declared no conflicts of interest.

Aim: D and AA are approved as front-line treatments for mCRPC. Their optimal sequencing is as yet undefined. We retrospectively evaluated whether sequencing of AA and D has an effect on survival in mCRPC. Methods: We retrospectively identified mCRPC patients (pts) who received both D and AA at the Royal Marsden Hospital. Pts were divided into two groups, the first having received D followed by AA (D- > AA) and the second AA followed by D(AA- > D). Pts who received D in the non-castrate setting or enzalutamide prior to D or AA were excluded. Hormonal treatments or phase I/II investigational agents were allowed between D and AA. Cabazitaxel(C) was allowed either before or after the second part of treatment. Overall survival (OS) was defined as time from initiation of first treatment, D or AA, to death or last follow-up (LFU). Log-Rank testing was used to compare OS between the two groups and two-sided Pearson's Chi-Square and Student's t-test to compare categorical and continuous variables respectively. Results: Time between treatment stages in months. Mean; Median (Min;Max) Diagnosis to CRes CRes to D End of D to AA End of AA to C End of AA to LFU D- > AA 50.0;33.8 (2.4;190.1) 15.0;10.3 (0.0;122.1) 11.5;9.2 (0.0;47.8) -1.5;1.0 (-17.0;9.1) 9.7;6.8 (0.0;57.0) Diagnosis to CRes Cres to AA End of AA to D End of D to C End of D to LFU AA- > D 54.4;35.8 (4.8;210.7) 14.9;13.7 (0.2;71.5) 7.5; 4.0 (0.9; 28.5) 14.7;9.2 (1.6;38.8) 12.5;8.2 (0.4;51.0) CRes: Castration Resistance. Between 10/2004 and 06/2012 161 and 37 mCRPC pts were identified who received D- > AA and AA- > D respectively. Baseline mean values of prognostic parameters were comparable in the two groups: Hg was 11.9g/dl and 12.7g/dl (p = 0.04), LDH 195.2u/l and 203.6u/l(p = 0.5), ALP 252.1u/l and 156u/l(p = 0.1), albumin 35.2g/l and 36.9g/l(p = 0.06), PSA 786.3ng/ml and 118.7ng/ml (p = 0.7) –median(m)PSA 131ng/ml and 72ng/ml- in D- > AA and AA- > D group respectively. Similar proportion of pts received C in the two groups: 36 pts (22.4%) in D- > AA and 4 (10.8%) in AA- > D (p = 0.1). After a mFU of 2.7 years 18 pts (11.2%) in the D- > AA group were alive and 2 (5.4%) in the AA- > D group; mOS was 31.4 months (95%CI: 28.3-34.4) in D- > AA and 38.6months (95% CI:30.3-46.9) in AA- > D (p = 0.6). The difference was not statistically significant. Conclusions: This retrospective analysis did not identify a statistically significant difference in mOS between pts treated with D- > AA or AA- > D. Prospective studies to evaluate optimal treatment sequencing for mCRPC are warranted. Disclosure: Z. Zafeiriou: Employee at the time of manuscript preparation of the Institute of Cancer Research, Sutton, Surrey, UK, that has commercial interest in abiraterone. Z.Z has received grants from Hellenic Society of Medical Oncology; R. Ferraldeschi, A. Altavilla, S. Sideris, P. Rescigno, D. Bianchini, A. Smith, R. Perez Lopez, N. Mehra, P. Ravi, E. Grist and N. Tunariu: Employee at the time of manuscript preparation of the Institute of Cancer research, Sutton, Surrey, UK, that has commercial interest in abiraterone; A. Omlin: Employee at the time of manuscript preparation of the Institute of Cancer research, Sutton, Surrey, UK, that has commercial interest in abiraterone. Advisory role: Janssen as COI; C. Pezaro and D. Mukherji: Employee at the time of manuscript preparation of the Institute of Cancer research, Sutton, Surrey, UK, that has commercial interest in abiraterone. Has has received honoraria from Sanofi-Aventis and Janssen-Cilag; D. Lorente: Employed at the Institute of Cancer Research, which has a commercial interest in the development of abiraterone; J. Mateo: Employed at the Institute of Cancer Research when the abstract was created, which has a commercial interest in the development of this agent; G. Attard: GA is listed in the ICR co-inventors reward scheme for abiraterone acetate; J.S. de Bono: JSB has a consultant role with Johnson & Johnson, and received honoraria from Johnson & Johnson. Consultant and Chief Investigator of the Abiraterone Trial.

215 Background: Falls in prostate specific antigen (PSA) levels by 50% from the baseline at 12 weeks are currently used to assess response to treatment for mCRPC (Scher et al, 2008). However PSA decline algorithms do not provide robust intermediate endpoints of overall survival (OS) benefit in mCRPC. We evaluated the association between PSA decline at 4 weeks and OS. Methods: We identified mCRPC patients who had received treatment with abiraterone acetate (AA) plus prednisolone post-docetaxel at the Royal Marsden (London, UK) between 01.01.2006 and 30.04.14. Patients were eligible for this analysis if they had PSA levels assessed at baseline, after 4 weeks and 12 weeks of treatment. PSA response at 4 weeks was defined as a ≥30% (PSA4w30) and ≥50% (PSA4w50) decline from baseline (PSABL). Association with outcome was analyzed using multivariate Cox regression and log-rank analyses. A significant p-value of 0.0167 was pre-specified to account for multiple testing. Demographics and clinical data were retrospectively collected from the hospital electronic patient record system (EPR). Results: We identified 124 patients who had received AA post-docetaxel and were eligible for this analysis. PSA4w30 was associated with longer OS (median OS 11.1 vs. 6.8 months; HR 0.50; 95% CI 0.32-0.80; p=.004). PSA4w50 was not associated with OS. A ≥50% PSA decline at 12 weeks (PSA12w50), the standard response measure, was also associated with OS (median OS 9.3 vs. 8.2; HR 0.49; 95% CI 0.29-0.80; p=.005). PSA4w30 was significantly associated with PSA12w50 (p

278 Background: PSA decline (PSAD) in CRPC after withdrawal of antiandrogens and steroid related drugs is well established. DW responses have been anecdotal and not well characterized. In this study we investigated the frequency and magnitude of PSA changes after DW. Methods: We retrospectively identified patients treated in the Royal Marsden for CRPC with D monotherapy. Patients were considered evaluable if they had between DW and their next treatment or radiotherapy an interval of at least 7 days, no other intervention and at least one PSA reading. Patients who received radiotherapy during treatment with D or received D for palliation of symptoms were excluded. The number of patients showing PSAD was recorded together with its percentage change from baseline. Chi-square test was used to compare response rates between different groups and 95% confidence intervals (CI) for the description of frequencies. PSA progression (PSAP) was defined according to Prostate Cancer Working Group 2 criteria. Results: 200 patients were identified who had received D of which 50 were evaluable. During D treatment PSA responses were not available for 5 patients, while 16 (35%, 95%CI [20%-50%]) had a ≥ 50% PSAD which was confirmed a month later with a second reading. For the responders, the median duration of PSA response from initiation of treatment to PSAP was 293 days (range: 219 to 1063). After DW, PSAD was observed in 12 patients (24%, 95% CI [12%,36%]). PSAD ≥ 25%, ≥ 30% and ≥ 50% was observed in 6, 3 and 2 patients respectively (12%, 6% and 4%) and in only one could the ≥ 30% PSAD be confirmed with a second reading a month later. In 5 cases of ≥ 25% PSAD, next treatment was initiated despite a dropping PSA, after 8 to 43 days. In one case only was PSAP reached during DW with a response duration of 53 days from DW to PSAP. The frequency of ≥ 25% PSAW responses was not significantly different between patients with and without prior response to dexamethasone: 6% and 17% respectively, Chi-square test p = 0.29. One patient reported improvement of his urinary symptoms after DW. Conclusions: DW responses are observed in a minority of patients. This phenomenon merits further prospective characterization and needs to be considered in the design of clinical trials.

5013 Background: A prognostic model based on clinical parameters has been derived from the population of the COU-AA-301 Phase 3 trial for mCRPC patients treated with AA after docetaxel. It relies o...