Tumor Volume on PSMA PET as a Prognostic Biomarker in Prostate Cancer Patients Treated With Cabazitaxel.

PURPOSE: The aim of this study was to evaluate the prognostic value of 68 Ga-labeled prostate-specific membrane antigen (PSMA) PET/CT in metastatic castration-resistant prostate cancer patients receiving second-line chemotherapy with cabazitaxel. METHODS: All patients with metastatic castration-resistant prostate cancer who underwent a PSMA PET/CT within 8 weeks before initiating the cabazitaxel treatment were retrospectively evaluated. The whole-body PSMA total tumor volume (PSMA-TV) was measured for each patient. Other factors such as prostate-specific antigen, hemoglobin, lactate dehydrogenase, and alkaline phosphatase were recorded. A log-rank cutoff finder was used to define the PSMA-TV optimal cutoff. Survival analyses were performed using Cox regression and Kaplan-Meier methods. RESULTS: In total, 32 patients were included, receiving a median of 6 cycles of cabazitaxel (range, 2-10). After a median follow-up of 12 months, 28 patients presented disease progression, and 18 died. Baseline PSMA-TV presented a significant association with progression-free survival (PFS) and overall survival (OS; P = 0.035 and P = 0.002, respectively). Optimal PSMA-TV cutoffs were 515 mL for PFS and 473 mL for OS. Patients with low volume presented longer PFS and OS than those with high volume: median PFS, 21 versus 12 weeks, respectively (hazard ratio, 0.33; P = 0.017); and median OS, 24 versus 8.5 months, respectively (hazard ratio, 0.21; P = 0.002). On the multivariable analyses, PSMA-TV remained an independent predictor of OS ( P = 0.016). CONCLUSION: Our results show that total tumor volume measured on PSMA PET/CT is a prognostic biomarker in patients treated with cabazitaxel. High PSMA-TV before treatment initiation is associated with shorter PFS and OS.

Prevalence and clinical impact of tumor BRCA1 and BRCA2 mutations in patients presenting with localized or metastatic hormone-sensitive prostate cancer.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

68Ga-PSMA PET/CT for Response Assessment and Outcome Prediction in Metastatic Prostate Cancer Patients Treated with Taxane-Based Chemotherapy.

We aimed to evaluate the role of PET targeting the prostate-specific membrane antigen (PSMA) for response assessment in metastatic prostate cancer (PCa) 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 PCa or metastatic castration-resistant PCa (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 at least 50% decreased level of prostate-specific antigen, compared with baseline. Associations between BR and different PET parameters were tested. A cutoff of at least a 30% decrease in PSMA total tumor volume (PSMA-TV) was used to define a PSMA response (PSMA-R) versus a PSMA nonresponse (PSMA-NR). Correlations between PSMA PET/CT response and BR were evaluated using the ϕ-coefficient. Associations between PET response and overall survival (OS) was tested using Cox regression and the Kaplan-Meier method. Results: Our cohort comprised 8 (22%) metastatic hormone-sensitive PCa and 29 (78%) mCRPC patients. Twenty-one patients received docetaxel treatment, and 16 received cabazitaxel (median, 6 cycles; interquartile range, 5-8 cycles). BR was found in 18 of 37 patients. Using PSMA total tumor volume, PSMA PET/CT response was concordant with BR in 35 of 37 patients (ϕ = 0.89, P < 0.0001). Eighteen of 37 patients had PSMA-R (6, complete response; 12, partial response), and 19 had PSMA-NR (17, progressive disease; 2, stable disease). After a median follow-up of 23 mo, there was a statistically significant longer OS for PSMA-R than for PSMA-NR (median OS not reached vs. 12 mo, respectively; hazard ratio, 0.10; 95% CI, 0.03-0.39; P = 0.001) for the entire population. Among the mCRPC subgroup, differences in OS were also observed (median, 22 vs. 12 mo, respectively; hazard ratio, 0.22; 95% CI, 0.06-0.82; P = 0.023), with a 12-mo OS rate of 100% for PSMA-R and 52% for PSMA-NR (P = 0.011). Conclusion: This retrospective analysis suggests that 68Ga-PSMA-11 PET/CT is a promising imaging modality for assessing response to taxane-based chemotherapy in metastatic PCa. Changes in PSMA expression might be used as a predictive biomarker for OS to help tailor individual therapy and select eligible patients for clinical trials.

Safety and efficacy of immune checkpoint inhibitors in advanced urological cancers with pre-existing autoimmune disorders: a retrospective international multicenter study.

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.

Early Post-treatment Prostate-specific Antigen at 4 Weeks and Abiraterone and Enzalutamide Treatment for Advanced Prostate Cancer: An International Collaborative Analysis.

BACKGROUND: Declines in prostate-specific antigen (PSA) levels at 12wk are used to evaluate treatment response in metastatic castration-resistant prostate cancer (mCRPC). PSA fall by ≥30% at 4wk (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 12wk 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 4wk, and 948 at both 4 and 12wk). 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 4wk had a PSA12w30 (1% of the overall population). CONCLUSIONS: PSA changes in the first 4wk 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 4wk after abiraterone/enzalutamide treatment are important to determine patients' outcome and should be taken into consideration in clinical practice.

Early Detection of Metastatic Prostate Cancer Relapse on 68Ga-PSMA-11 PET/CT in a Patient Still Exhibiting Biochemical Response.

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.

Evaluation of PSMA expression changes on PET/CT before and after initiation of novel antiandrogen drugs (enzalutamide or abiraterone) in metastatic castration-resistant prostate cancer patients.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Docetaxel Treatment in PTEN- and ERG-aberrant Metastatic Prostate Cancers.

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.

Autoimmune paraneoplastic syndromes associated to lung cancer: A systematic review of the literature Part 4: 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 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.

Autoimmune paraneoplastic syndromes associated to lung cancer: A systematic review of the literature: Part 5: Neurological auto-antibodies, discussion, flow chart, conclusions.

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.

Autoimmune paraneoplastic syndromes associated to lung cancer: A systematic review of the literature: Part 2: Hematologic, cutaneous and vascular syndromes.

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.

Clinical impact of 68 Ga-prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) in patients with prostate cancer with rising prostate-specific antigen after treatment with curative intent: preliminary analysis of a multidisciplinary approach.

OBJECTIVE: To assess the impact of a novel molecular imaging technique, 68 Ga-(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 68 Ga-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 68 Ga-(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, 68 Ga-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 68 Ga-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.

Phenotypic diversity of circulating tumour cells in patients with metastatic castration-resistant prostate cancer.

OBJECTIVES: 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. PATIENTS AND METHODS: 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. RESULTS: Traditional CTCs (CD45- /CK+ /morphologically distinct) were identified in all patients with mCRPC and we also identified CTC clusters and non-traditional CTCs in patients with mCRPC, including CK- and apoptotic CTCs. Small CTCs (≤white blood cell size) were identified in 98% of patients with mCRPC. Total, traditional and non-traditional CTCs were significantly increased in patients who were deceased vs alive after 18 months; however, only non-traditional CTCs were associated with overall survival. Traditional and total CTC counts according to the Epic platform in the mCRPC cohort were also significantly correlated with CTC counts according to the CellSearch system. CONCLUSIONS: Heterogeneous non-traditional CTC populations are frequent in mCRPC and may provide additional prognostic or predictive information.

Testicular germ cell tumor: Short and long-term side effects of treatment among survivors.

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.

Efficacy of weekly paclitaxel treatment as a single agent chemotherapy following first-line cisplatin treatment in urothelial bladder cancer.

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.

Prostate-specific Antigen Decline After 4 Weeks of Treatment with Abiraterone Acetate and Overall Survival in Patients with Metastatic Castration-resistant Prostate Cancer.

BACKGROUND: 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). OBJECTIVE: To evaluate the association between early PSA decline and OS following abiraterone acetate (AA) treatment. DESIGN, SETTING, AND PARTICIPANTS: 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. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: 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. RESULTS AND LIMITATIONS: 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, p<0.001), 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; p<0.001). 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. CONCLUSIONS: 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. PATIENT SUMMARY: 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.

Checkpoint inhibitors in bladder and renal cancers: results and perspectives.

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.

PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate.

BACKGROUND: Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) occurs frequently in prostate cancers. Preclinical evidence suggests that activation of PI3K/AKT signaling through loss of PTEN can result in resistance to hormonal treatment in prostate cancer. OBJECTIVE: To explore the antitumor activity of abiraterone acetate (abiraterone) in castration-resistant prostate cancer (CRPC) patients with and without loss of PTEN protein expression. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively identified patients who had received abiraterone and had hormone-sensitive prostate cancer (HSPC) and/or CRPC tissue available for PTEN immunohistochemical analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was overall survival from initiation of abiraterone treatment. Relationship with outcome was analyzed using multivariate Cox regression and log-rank analyses. RESULTS AND LIMITATIONS: A total of 144 patients were identified who had received abiraterone post-docetaxel and had available tumor tissue. Overall, loss of PTEN expression was observed in 40% of patients. Matched HSPC and CRPC tumor biopsies were available for 41 patients. PTEN status in CRPC correlated with HSPC in 86% of cases. Loss of PTEN expression was associated with shorter median overall survival (14 vs 21 mo; hazard ratio [HR]: 1.75; 95% confidence interval [CI], 1.19-2.55; p=0.004) and shorter median duration of abiraterone treatment (24 vs 28 wk; HR: 1.6; 95% CI, 1.12-2.28; p=0.009). PTEN protein loss, high lactate dehydrogenase, and the presence of visceral metastases were identified as independent prognostic factors in multivariate analysis. CONCLUSIONS: Our results indicate that loss of PTEN expression was associated with worse survival and shorter time on abiraterone treatment. Further studies in larger and prospective cohorts are warranted. PATIENT SUMMARY: PTEN is a protein often lost in prostate cancer cells. In this study we evaluated if prostate cancers that lack this protein respond differently to treatment with abiraterone acetate. We demonstrated that the survival of patients with loss of PTEN is shorter than patients with normal PTEN expression.

External validation of a prognostic model predicting overall survival in metastatic castrate-resistant prostate cancer patients treated with abiraterone.

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<0.001; area under the curve [AUC]: 0.71). Analysis of group B confirmed the ability of the model to prognosticate for survival in the prechemotherapy setting: (good: n=44, mOS: 45.6 mo; intermediate or poor: n=20, mOS: 34.5 mo; p=0.042; AUC: 0.61). These results serve to validate the prognostic model in an independent population treated with abiraterone after docetaxel and support clinical implementation of the score. Calibration of the model was poorer in patients receiving abiraterone prechemotherapy. Prospective evaluation of this model in clinical trials is needed.