Median PSA Progression-free Survival Research Articles

Design of phase Ib/II study of oral VERU-111, an α and β-tubulin inhibitor, for the treatment of metastatic castration- and androgen-blocking-agent-resistant prostate cancer.

TPS330 Background: VERU-111 is a novel oral small molecule (NCE) that targets α and β-tubulin subunits of microtubules resulting in the inhibition of tubulin polymerization. Agents that target microtubules are among the most effective for the treatment of metastatic cancers. However, these currently available agents target only the β-tubulin subunit and are administered IV. VERU-111 has high oral bioavailability and does not interact with MDR proteins. In nonclinical models, VERU-111 has high activity against many tumor types as well as against prostate cancers that have become resistant to taxanes and novel androgen blocking agents (abiraterone and enzalutamide). In 28-day dog and rat toxicity studies, no neutropenia, myelosuppression, or liver function test changes were observed at oral daily doses in blood concentrations that resulted in antitumor activity in preclinical models. Based on these unique properties, VERU-111 has advanced into a Phase1b/2 clinical trial. Methods: V1011101 is a Phase 1b/2 study, being conducted in at least three sites in the US, evaluating the safety and preliminary efficacy of VERU-111 in men with metastatic castration and androgen blocking agent resistant prostate cancer (mCARPC). The Phase 1b portion of the study consists of 21-day cycles where VERU-111 is taken daily, orally for 7-days followed by a 14-day hiatus (dose cycle). Safety/tolerability of VERU-111 and MTD of VERU-111 will be determined. The Phase 2 will use the selected dose cycle from the Phase 1b and the primary endpoint will be the PSA50 response rate, defined as a decline in PSA to > 50% of baseline level, confirmed with a second measurement at least 3 weeks apart (PCWG3) and determine the pharmacokinetic profile of VERU-111. The secondary endpoints include determining the safety/tolerability of VERU-111 as defined as incidence of CTCAE v5.0 grade ≥3 toxicities; estimating the median PSA progression-free survival (PCWG3); estimating the median progression-free survival (PCWG3); and estimating the objective response rate. It is anticipated that based upon the Phase 1b/2 clinical findings VERU-111 will also be expanded into other cancer types.

Effect of Adding Docetaxel to Androgen-Deprivation Therapy in Patients With High-Risk Prostate Cancer With Rising Prostate-Specific Antigen Levels After Primary Local Therapy

Androgen-deprivation therapy (ADT) plus docetaxel is the standard of care in hormone-naive metastatic prostate cancer but is of uncertain benefit in a nonmetastatic, high-risk prostate cancer setting. To assess the benefit of ADT plus docetaxel in patients presenting with rising prostate-specific antigen (PSA) levels after primary local therapy and high-risk factors but no evidence of metastatic disease. This open-label, phase 3, randomized superiority trial comparing ADT plus docetaxel vs ADT alone enrolled patients from 28 centers in France between June 4, 2003, and September 25, 2007; final follow-up was conducted April 12, 2017, and analysis was performed May 2 to July 31, 2017. Patients had undergone primary local therapy for prostate cancer, were experiencing rising PSA levels, and were considered to be at high risk of metastatic disease. Stratification was by prior local therapy and PSA-level doubling time (≤6 vs >6 months), and intention-to-treat analysis was used. Patients were randomly assigned to receive ADT (1 year) plus docetaxel, 70 mg/m2 (every 3 weeks [6 cycles]), or ADT alone (1 year). The primary outcome was PSA progression-free survival (PSA-PFS). Secondary end points were PSA response, radiologic PFS, overall survival, safety, and quality of life. Overall, 254 patients were randomized (1:1) to the trial; median age, 64 years in the ADT plus docetaxel arm, 66 years in the ADT alone arm. At a median follow-up of 30.0 months, the median PSA-PFS was 20.3 (95% CI, 19.0-21.6) months in the ADT plus docetaxel arm vs 19.3 (95% CI, 18.2-20.8) months in the ADT alone arm (hazard ratio [HR], 0.85; 95% CI, 0.62-1.16; P = .31). At a median follow-up of 10.5 years, there was no significant between-arm difference in radiologic PFS (HR, 1.03; 95% CI, 0.74-1.43; P = .88). Overall survival data were not mature. The most common grade 3 or 4 hematologic toxic effects in the ADT plus docetaxel arm were neutropenia (60 of 125 patients [48.0%]), febrile neutropenia (10 [8.0%]), and thrombocytopenia (4 [3.0%]). There was no significant between-arm difference in overall quality of life. Compared with ADT alone, combined ADT plus docetaxel therapy with curative intent did not significantly improve PSA-PFS in patients with high-risk prostate cancer and rising PSA levels and no evidence of metastatic disease. French Health Products Safety Agency identifier: 030591; ClinicalTrials.gov identifier: NCT00764166.

Permanent 125I prostate brachytherapy for castration‐resistant prostate cancer

To evaluate the clinical significance of permanent 125 I prostate brachytherapy in patients with castration-resistant prostate cancer. A retrospective study of 45 patients with castration-resistant prostate cancer from the Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu, China was carried out. Patients were divided into two groups according to different treatments: 21 patients received endocrine therapy alone (control group), and 24 patients underwent brachytherapy combined with endocrine therapy (treatment group). Prostate-specific antigen progression-free survival, cancer-specific survival, overall survival and quality of life of the two groups were compared. The median prostate-specific antigen progression-free survival and cancer-specific survival of the treatment group were 29months (interquartile range 25-37months) and 37months (interquartile range 30-50months), respectively. These were significantly longer than those of the control group (both P<0.05). Prostate-specific antigen (before androgen deprivation therapy and before brachytherapy), prostate volume, Gleason score, clinical stage and brachytherapy were associated with prostate-specific antigen progression-free survival and cancer-specific survival on univariate analysis. For the quality of life after treatment, urinary symptoms/problems at 1month after brachytherapy compared with the control group had a statistically significant difference and clinically relevant deterioration, but after 6months there were no statistically significant differences and clinically relevant deterioration. Compared with the control group, the physical functioning, social functioning, global health and general physical discomfort of the treatment group were significantly improved. Brachytherapy with 125 I seed implantation can effectively prolong survival of patients with castration-resistant prostate cancer and, to a certain extent, improve patients' quality of life.

Clinical activity of abiraterone plus prednisone in docetaxel-naοve and docetaxel-resistant Chinese patients with metastatic castration-resistant prostate cancer.

This study investigated the clinical activity of abiraterone plus prednisone in docetaxel-naïve and docetaxel-resistant Chinese patients with metastatic castration-resistant prostate cancer (mCRPC). A total of 146 patients with docetaxel-naïve group (103 cases) and docetaxel-resistant group (43 cases) were enrolled from the Shanghai Cancer Center (Shanghai, China) in this retrospective cohort study. The efficacy endpoints were prostate-specific antigen response rate, prostate-specific antigen progression-free survival, clinical/radiographic progression-free survival, and overall survival in response to abiraterone plus prednisone. Significantly higher prostate-specific antigen response rate was found in docetaxel-naïve group (54.4%, 56/103) compared to docetaxel-resistant group (34.9%, 15/43) (P = 0.047). In addition, significantly higher median prostate-specific antigen progression-free survival (14.0 vs 7.7 months, P = 0.005), clinical or radiographic progression-free survival (17.0 vs 12.5 months, P = 0.003), and overall survival (27.0 vs 18.0 months, P = 0.016) were found in docetaxel-naïve group compared to docetaxel-resistant group, respectively. The univariate and multivariate analyses indicated that lower albumin and visceral metastases were independent significant predictors for shorter overall survival. To sum up, our data suggested that abiraterone plus prednisone was efficient in both docetaxel-naïve and docetaxel-resistant Chinese patients. Moreover, higher PSA response rate and longer overall survival were observed in the docetaxel-naïve group, which suggested that abiraterone was more effective for docetaxel- naïve patients than for docetaxel failures.

Abstract 2593: AR-V7 and AR-V9 expression is not predictive of response to AR-axis targeting agents in metastatic castration-resistant prostate cancer

Abstract In 2014, a landmark study was published demonstrating that androgen receptor splice variant (AR-V) AR-V7 expression was a negative predictive biomarker for response to abiraterone acetate and enzalutamide in metastatic castration-resistant prostate cancer (mCRPC) patients. However, these results were not supported by the recently reported ARMOR3-SV phase III clinical trial, which employed an identical circulating tumor cell assay to assess AR-V7 expression. Therefore, the predictive utility of AR-V7 expression in mCRPC remains uncertain, as does any potential association between other AR splice variants and treatment response. To further investigate, we designed a highly sensitive and specific whole blood assay for detecting AR-V7 and AR-V9. We then examined for a correlation between baseline AR-V7/V9 status and treatment outcome in 37 mCRPC patients commencing abiraterone or enzalutamide. Blood was taken in a PAXgene RNA tube at baseline prior to the commencement of therapy and at end of treatment (if applicable). 24% (9/37) of patients were AR-V-positive. Notably, PSA response rates did not significantly differ between AR-V-positive (6/9) and AR-V-negative (18/28) patients (66% vs. 64%, p=0.896). Likewise, median PSA progression-free survival was not significantly different between AR-V-positive and AR-V-negative patients (9.2 months vs. not reached; p=0.894). Additionally, we identified 2 patients who were AR-V7 negative at baseline but had converted to AR-V7 positive in their end-of-treatment sample. This was associated with much shorter PSA-PFS than those that remained negative (2.58 months vs. no reached), suggesting gain of AR-V expression may be a marker of acquired resistance. These data, which support the findings of the pivotal ARMOR3-SV clinical trial, suggest that baseline AR-V expression does not predict outcomes in mCRPC patients receiving abiraterone or enzalutamide. Citation Format: Sarah Q. To, Edmond Kwan, Heidi Fettke, Andrew Mant, Maria Docanto, Luciano Martelotto, Patricia Bukczynska, Nicole Ng, Lisa-Jane Graham, Phillip Parente, Carmel Pezaro, Kate Mahon, Lisa Horvath, Tilman Todenhöfer, Arun Azad. AR-V7 and AR-V9 expression is not predictive of response to AR-axis targeting agents in metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2593.

Prostate-Specific Membrane Antigen in Circulating Tumor Cells is a New Predictive Marker for Castration-Resistant Prostate Cancer

Purpose: The aim of this study is to elucidate the clinical significance of prostate-specific membrane antigen (PSMA) expression in circulating tumor cells (CTCs) from castration-resistant prostate cancer (CRPC) patients. Experimental Design: We analyzed total of 167 CTC samples from 68 CRPC patients to investigate the proportion of positive mRNA expressions at a different treatment phase. Among them, we next focused on 39 CRPC patients who had their CTC samples collected at the time of recurrence and thereafter were given new treatments (treatment-failure cohort). First, in this cohort, we assessed whether the presence of CTC per se affects treatment response. Then, we investigated the association between PSMA expression in CTCs and treatment response. Results: CTCs were detected in 105/167 samples (63%) and among 105 CTC-positive samples, 62% of them were positive for PSMA. PSMA was significantly more expressed in samples derived from heavily treated patients. In the treatment-failure cohort of 39 patients, 27 of them were positive for CTCs. Among them, 13 patients were positive for PSMA in CTCs. PSMA expression was inversely correlated with percentage of change in prostate-specific antigen (PSA) by treatment with a statistical significance. The median PSA progression-free survival was significantly shorter in the PSMA-positive cohort. Furthermore, PSMA expression in CTCs was predictive of poor treatment response. Conclusions: PSMA was significantly more expressed in CTCs derived from heavily treated patients. PSMA expression in CTCs was significantly associated with poor treatment response in CRPC. PSMA expression in CTCs can be a novel biomarker for CRPC. Funding: This work was supported by Astellas; and Sanofi Aventis. Declaration of Interests: Shigeo Horie has research grants from Astellas and Sanofi Aventis, honorarium from Astellas, Takeda, Astra Zeneca and Sanofi Aventis and Janssen. Other authors have declared no conflicts of interest. Ethical Approval Statement: This study was approved by the institutional review board of Juntendo hospital (admission number: 14-052), and all experiments were carried out in accordance with approved guidelines.

Ipilimumab plus nivolumab and DNA-repair defects in AR-V7-expressing metastatic prostate cancer.

AR-V7-expressing metastatic prostate cancer is an aggressive phenotype with poor progression-free survival (PFS) and overall survival (OS). Preliminary evidence suggests that AR-V7-positive tumors may be enriched for DNA-repair defects, perhaps rendering them more sensitive to immune-checkpoint blockade. We enrolled 15 metastatic prostate cancer patients with AR-V7-expressing circulating tumor cells into a prospective phase-2 trial. Patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses, then maintenance nivolumab 3 mg/kg every 2 weeks. Targeted next-generation sequencing was performed to determine DNA-repair deficiency (DRD) status. Outcomes included PSA response rates, objective response rates (ORR), PSA progression-free survival (PSA-PFS), clinical/radiographic PFS and OS. Median age of participants was 65, median PSA was 115 ng/mL, 67% had visceral metastases, and 60% had ≥4 prior systemic therapies. Six of 15 men (40%) had DRD mutations (three in BRCA2, two in ATM, one in ERCC4; none had microsatellite instability). Overall, the PSA response rate was 2/15 (13%), ORR was 2/8 (25%) in those with measurable disease, median PSA-PFS was 3.0 (95%CI 2.1–NR) months, PFS was 3.7 (95%CI 2.8–7.5) months, and OS was 8.2 (95%CI 5.5–10.4) months. Outcomes appeared generally better in DRD+ vs. DRD– tumors with respect to PSA responses (33% vs. 0%; P=0.14, nonsignificant), ORR (40% vs. 0%; P=0.46, nonsignificant), PSA-PFS (HR 0.19; P<0.01, significant), PFS (HR 0.31; P=0.01, significant), and OS (HR 0.41; P=0.11, nonsignificant). There were no new safety concerns. Ipilimumab plus nivolumab demonstrated encouraging efficacy in AR-V7-positive prostate cancers with DRD mutations, but not in the overall study population.

Expression of Androgen Receptor Splice Variant 7 or 9 in Whole Blood Does Not Predict Response to Androgen-Axis–targeting Agents in Metastatic Castration-resistant Prostate Cancer

Detection of androgen receptor splice variants (AR-Vs) in circulating tumour cells of advanced prostate cancer patients has been linked to resistance to abiraterone and enzalutamide. We designed a blood test to detect AR-Vs that can be performed more routinely than tests involving circulating tumour cells and found that patients with AR-Vs still benefit from these effective treatments.

Serum levels of neuroendocrine differentiation markers predict the prognosis of patients with metastatic castration resistant prostate cancer treated with abiraterone acetate

Objective To determine the influence of abiraterone acetate (AA) on neuroendocrine differentiation (NED) in metastatic castration-resistant prostate cancer (mCRPC) and the prognostic predicting value of the serum NED markers in mCRPC patients treated with AA. Methods We conducted an analysis in 115 chemotherapy-naive mCRPC patients who were treated with chemotherapy in Renji hospital from 2013 to 2017. The median age was 70, ranged from 65 to 76 years old. The median CgA, NSE and PSA levels were 101.1 ng/ml(78.5-150.0 ng/ml), 13.4 ng/ml(10.5-17.6 ng/ml)and 38.8 ng/ml(11.2-123.2 ng/ml), respectively. Among them, 48 cases were classified as the group without AA treatment. The other 67 cases were classified as group after AA failure. In group without AA treatment, the median CgA, NSE and PSA levels were 109.1 ng/ml(80-151.5 ng/ml); 13.8 ng/ml(10.8-18.2 ng/ml)and 39.2 ng/ml(8.6-200 ng/ml), respectively. In group after AA failure, the median CgA, NSE and PSA levels were 105.4 ng/ml(78.8-175.5 ng/ml), 13.8 ng/ml(10.8-17.6 ng/ml)and 39.0 ng/ml(8.4-219.8 ng/ml), respectively. In the group with serial evaluation of NED markers during AA treatment, the median serum CgA, NSE levels at baseline were 115.9 ng/ml(90.1-201.5 ng/ml), 13.3 ng/ml(10.4-18.1 ng/ml), respectively. The endpoints were PSA PFS(progression-free survival) and radiographic PFS(rPFS). Results In 34 patients with serial evaluation, serum NED markers level in 19 patients increased after the failure of AA treatment. Median serum CgA and NSE levels were 115.9 ng/ml(90.1-201.5 ng/ml) and 13.25 ng/ml (10.37-18.14 ng/ml)at baseline. Median serum CgA and NSE levels were 129.6 ng/ml (75.5-230.5 ng/ml) and 14.7 ng/ml(11.8-19.1 ng/ml) after 6 months treatment, respectively. The median serum CgA and NSE levels were 130.4 ng/ml (95.7-205.7 ng/ml) and 15.2 ng/ml(12.4-18.7 ng/ml) at the time of failure of AA treatment, respectively. There was no significant difference of NED markers between baseline and failure of AA treatment (P=0.243). In logistic univariate analysis, AA treatment and its duration were not independent factors influencing NED(P=0.30; P=0.52). Compared with the NED markers elevation group in the first 6 months of AA treatment and baseline supranormal NED markers group, the NED markers decline group(PSA PFS(17.1 vs. 10.4 months, P<0.001)and rPFS(17.0 vs. 10.4 months, P=0.003)) and baseline normal NED markers group(PSA PFS(14.1 vs. 9.5 months, P=0.001)and rPFS(16.4 vs. 10.5 months, P<0.001)) has a longer median PSA PFS and rPFS respectively. In multivariate Cox analysis, baseline NED markers level and NED markers variation during the first 6 months of AA treatment remained significant predictors of rPFS(P<0.05), and PSA-PFS(P<0.05). Conclusions We found there was heterogeneity in changes of NED markers in different mCRPC patients during AA treatment, and AA might not significantly lead to progression of NED of mCRPC in general. Serial CgA and NSE evaluation might help clinicians guide clinical treatment of mCRPC patients. Serum NED markers elevation during the first 6 months of AA treatment and elevated baseline NED markers levels indicated poor prognosis in mCRPC treated with AA. Key words: Abiraterone acetate; Neuroendocrine differentiation; Chemotherapy naive; Castration-resistant prostate cancer

PD14-01 CLINICAL EXPERIENCE WITH LUTETIUM 177-LABELED PSMA-I&T FOR RADIOLIGAND THERAPY IN 100 CONSECUTIVE PATIENTS WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) II1 Apr 2018PD14-01 CLINICAL EXPERIENCE WITH LUTETIUM 177-LABELED PSMA-I&T FOR RADIOLIGAND THERAPY IN 100 CONSECUTIVE PATIENTS WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER Matthias Heck, Sebastian Schwaiger, Karina Knorr, Margitta Retz, Tobias Maurer, Friederike Janssen, Calogero D`Alessandria, Hans-Jürgen Wester, Jürgen Gschwend, Markus Schwaiger, Robert Tauber, and Matthias Eiber Matthias HeckMatthias Heck More articles by this author , Sebastian SchwaigerSebastian Schwaiger More articles by this author , Karina KnorrKarina Knorr More articles by this author , Margitta RetzMargitta Retz More articles by this author , Tobias MaurerTobias Maurer More articles by this author , Friederike JanssenFriederike Janssen More articles by this author , Calogero D`AlessandriaCalogero D`Alessandria More articles by this author , Hans-Jürgen WesterHans-Jürgen Wester More articles by this author , Jürgen GschwendJürgen Gschwend More articles by this author , Markus SchwaigerMarkus Schwaiger More articles by this author , Robert TauberRobert Tauber More articles by this author , and Matthias EiberMatthias Eiber More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.787AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES To report our clinical experience with 177Lutetium-labeled prostate-specific membrane antigen-ligand (177Lu-PSMA-I&T) for systemic radioligand therapy in 100 consecutive patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS All patients were treated under a review board-approved compassionate use protocol. Eligibility criteria for 177Lu-PSMA-I&T therapy included previous treatment with abiraterone or enzalutamide, previous taxane-based chemotherapy or ineligibility to taxanes as well as positive 68Ga-PSMA tracer uptake of metastases in a prior PET-scan. Intravenous treatment with 177Lu-PSMA-I&T was given 6- to 8-weekly with an activity of 7.4GBq up to 6 cycles in patients without clinical or radiographic progression. We report prostate-specific antigen (PSA) decline, PSA progression-free survival (PSA-PFS), clinical progression-free survival (cPFS) and overall survival (OS) as well as toxicity. RESULTS Median age was 72 years (range 46-85) and median PSA level was 164 ng/ml (range 0-6178). Bone, lymph node and visceral metastases were present in 94%, 85% and 33% of patients, respectively. The median number of previous treatment regimens for mCRPC was 3 (range 1-6) and 84% of patients were pretreated with chemotherapy. At the time of evaluation, 286 cycles with 177Lu-PSMA-I&T were applied (median 2 cycles per patient, range 1-6), while treatment was still ongoing in 27% of patients. Overall, 4 and 6 cycles were applied in 33 and 15 patients, respectively. PSA decline ≥30%, ≥50% and ≥90% was achieved in 40%, 32% and 9% of patients, respectively. Median PSA-PFS was 3.4 months (95%CI 2.7-4.0), median cPFS was 4.1 months (95%CI 2.5-5.7) and median OS was 12.2 months (95%CI 8.8-15.7). Treatment-emergent hematologic grade 3/4 toxicities were anemia in 7%, thrombocytopenia in 5% and neutropenia in 4% of patients. Grade 3/4-non-hematologic toxicities were not observed. The main non-hematologic grade 1/2 toxicities were dry mouth in 18%, fatigue in 16% and loss of appetite in 9% of patients. CONCLUSIONS Radioligand therapy with 177Lu-PSMA I&T appears to be safe and active in late-stage mCRPC. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e304 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Matthias Heck More articles by this author Sebastian Schwaiger More articles by this author Karina Knorr More articles by this author Margitta Retz More articles by this author Tobias Maurer More articles by this author Friederike Janssen More articles by this author Calogero D`Alessandria More articles by this author Hans-Jürgen Wester More articles by this author Jürgen Gschwend More articles by this author Markus Schwaiger More articles by this author Robert Tauber More articles by this author Matthias Eiber More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Multicenter prospective study of switching from GnRH agonists to GnRH antagonist for patients with early stage of castration resistant prostate cancer as a second-line hormonal therapy.

183 Background: It was reported that GnRH antagonist could extend progression free survival for prostate cancer patients significantly longer than GnRH agonist in a first line hormonal therapy. However, the usefulness of switching from GnRH agonist to GnRH antagonist as a second hormonal therapy remains obscure. We performed a multicentral prospective study to investigate whether the switching from GnRH agonist to GnRH antagonist (degalerix) for patients with castration resistant prostate cancer (CRPC) as the 2nd line hormonal therapy was effective. Methods: 37 patients who were pathologically diagnosed as prostatic adenocarcinoma and developed CRPC after 1st line hormonal therapy with GnRH agonist plus anti-androgens were enrolled. After confirming anti-androgen withdrawal syndrome, they were treated with switching from GnRH agonists to degalerix. The primary endpoint was PSA response (PSA decline or up to 10% over baseline PSA). Secondary endpoints were the time to 25% PSA increase from the baseline (PSA response time), PSA progression free survival (PPFS), the time to treatment failure, cancer specific survival, radiographic PFS (rPFS), and safety. Results: Mean age was 76 years old, super high risk; 20 cases (54.1%), high risk; 11 cases (29.7%), intermediate risk; 5 cases (13.5%), low risk; one case (2.7%). PSA responder rate was 24.3% (9 cases). In responders, the median PSA response time was 5.75 months, the median PPFS was 1.77 months, and rPFS rate at 3 months was 96%. Regarding safety, only 2 cases (5.4%) showed G3 of AE. The PSA response had no relationship with the change of serum testosterone, LH nor FSH. Conclusions: The effectiveness of switching from GnRH agonist to GnRH antagonist showed to be limited. Although no predictive factor of the switching was recognized, some long-term responders were seen. We expect the possibility of switching to GnRH antagonist for patients in the early stage of CRPC, especially non-metastatic status. Clinical trial information: UNKNOWN.

Clinical experience with 100 consecutive patients treated with Lu-177-labeled PSMA-I&amp;T radioligand therapy for metastatic castration-resistant prostate cancer.

206 Background: To report our clinical experience with 177Lutetium-labeled prostate-specific membrane antigen-ligand (177Lu-PSMA-I&amp;T) for systemic radioligand therapy in 100 consecutive patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: All patients were treated under a review board-approved compassionate use protocol. Eligibility criteria for 177Lu-PSMA-I&amp;T therapy included previous treatment with abiraterone or enzalutamide, previous taxane-based chemotherapy or unsuitability for taxanes as well as positive 68Ga-PSMA tracer uptake of metastases in a prior PET-scan. Intravenous treatment with 177Lu-PSMA-I&amp;T was given 6- to 8-weekly with an activity of 7.4GBq up to 6 cycles in patients without clinical or radiographic progression. We report prostate-specific antigen (PSA) decline, PSA progression-free survival (PSA-PFS), clinical progression-free survival (cPFS) and overall survival (OS) as well as toxicity. Results: Median age was 72 years (range 46-85) and median PSA level was 164 ng/ml (range 0-6178). Bone, lymph node and visceral metastases were present in 94%, 85% and 33% of patients, respectively. The median number of previous treatment regimens for mCRPC was 3 (range 1-6) and 84% of patients were pretreated with chemotherapy. At the time of evaluation, 286 cycles with 177Lu-PSMA-I&amp;T were applied (median 2 cycles per patient, range 1-6), while treatment was still ongoing in 27% of patients. Overall, 4 and 6 cycles were applied in 33 and 15 patients, respectively. PSA decline ≥30%, ≥50% and ≥90% was achieved in 40%, 32% and 9% of patients, respectively. Median PSA-PFS was 3.4 months (95%CI 2.7-4.0), median cPFS was 4.1 months (95%CI 2.5-5.7) and median OS was 12.2 months (95%CI 8.8-15.7). Treatment-emergent hematologic grade 3/4 toxicities were anemia in 7%, thrombocytopenia in 5% and neutropenia in 4% of patients. Grade 3/4-non-hematologic toxicities were not observed. The main non-hematologic grade 1/2 toxicities were dry mouth in 18%, fatigue in 16% and loss of appetite in 9/% of patients. Conclusions: Radioligand therapy with 177Lu-PSMA I&amp;T appears to be safe and active in late-stage mCRPC.

Metronomic therapy in metastatic castrate-resistant prostate cancer: Experience from a tertiary cancer care center.

Many agents have shown survival advantage in metastatic castrate-resistant prostate cancer (mCRPC). Despite this improvement, survival is poor, especially in subgroup of elderly patients who are not fit for cytotoxic chemotherapy. This is a single-institutional data review of mCRPC treated between December 2012 and May 2016 with oral cyclophosphamide (50-100 mg/day) ± oral prednisolone. mCRPCs failed or not fit for docetaxel and/or abiraterone were included in this study. Monthly prostate-specific antigen (PSA) was monitored, and toxicity of cyclophosphamide was recorded. PSA response was defined as ≥50% reduction from precyclophosphamide value. The median follow-up was calculated from the day of starting cyclophosphamide and the last date of follow-up or death, whichever is later. Eighteen patients were included with a median age of 74.5 years (range: 59-83). The site of metastasis was bone in 15, bone and distant lymph nodes in 2, and rectum in 1 patient. The median duration of androgen deprivation was 21 months (range: 3-42.9 months). The median cyclophosphamide exposure was 2 months (range: 0.9-13.5 months) after a median follow-up of 5.8 months. Overall PSA response rate was 44%. The median PSA progression-free survival with cyclophosphamide was 4.7 months (range: 0.9-13.5 months). Five patients had durable PSA response of 9.9, 10.1, 10.5, 12.1, and 13.5 months, respectively. No Grade 3 or 4 toxicity was observed with cyclophosphamide. Oral metronomic cyclophosphamide was found to be an effective and well-tolerated therapy in mCRPC after failure or not fit for docetaxel and/or abiraterone. In few patients, cyclophosphamide induced durable PSA response. This finding needs further evaluation in a prospective manner.

Effectiveness of Deferred Combined Androgen Blockade Therapy Predicts Efficacy in Abiraterone Acetate Treated Metastatic Castration-Resistant Prostate Cancer Patients after Docetaxel.

Introduction: Conventional anti-androgen regimens were widely used as an initiation or combined androgen blockade (CAB) therapy in advanced prostate cancer patients. Currently, new androgen pathway inhibitors such as abiraterone acetate (AA) and enzalutamide had been proven effective in metastatic castration resistant prostate cancer. In this study, we attempt to analyze the role of conventional anti-androgen drugs as deferred CAB therapy in castration-resistant prostate cancer patients.Materials and Methods: From 2012 to 2017, 48 metastatic castration-resistant prostate cancer (CRPC) patients who received sequential treatments with primary androgen blockade, oral anti-androgen regimens, and docetaxel followed by AA treatment were included. We defined effective deferred CAB as any decline of PSA after add-on antiandrogen after CRPC. Patients were separated into effective and ineffective deferred CAB. Comparison between two groups in the first line androgen deprivation therapy duration, CRPC PSA level, pre-AA PSA level, chemotherapy dosages, duration, and patients progression free survival and overall survival after AA treatment were analyzed.Results: Twenty-three patients (47.9%) achieved PSA decline after deferred CAB. Among total 48 patients, 24 patients experienced PSA decline more than 50% after AA treatment. The median PSA progression-free survival and overall survival after AA treatment in the total cohort of 48 patients were 4.4 and 24.3 months, respectively. The effective deferred CAB group showed significantly lower PSA level, lower percentage of PSA progression, higher total follow-up duration, higher percentage of surviving patients, better progression free survival, and overall survival estimate after AA treatment. Of the eight variables analyzed, effectiveness in deferred CAB showed positive association to progression free survival (HR 0.29, 95% CI 0.12–0.67, p = 0.004) and overall survival (HR 0.24, 95% CI 0.07–0.81, p = 0.022). First line androgen deprivation therapy (ADT) duration also showed positive association to overall survival (HR 0.95, 95% CI 0.91–0.99, p = 0.023).Conclusions: Effectiveness of deferred CAB therapy was positively associated with progression free survival and overall survival of AA treatment after docetaxel. It can be used as a pre-treatment predictor.

Impact of prior androgen receptor-axis-targeted agents on the clinical activity of subsequent docetaxel in patients with metastatic castration-resistant prostate cancer: comparative assessment between abiraterone acetate and enzalutamide

The objective of this study was to investigate the impact of prior treatment with androgen receptor-axis-targeted (ARAT) agents, abiraterone acetate (AA) and enzalutamide (Enz), on the activity of subsequently introduced docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC). This study included a total of 114 mCRPC patients consisting of 54 and 60 who progressed following treatment with AA and Enz, respectively, prior to the introduction of docetaxel, and compared oncological outcomes with docetaxel between these two groups. There were no significant differences in the major clinicopathological characteristics before treatment with docetaxel between the AA and Enz groups. The prostate-specific antigen (PSA) response rates to docetaxel in the AA and Enz groups were 40.7 and 43.3%, respectively, with no significant differences in the rates between these two groups. Following the introduction of docetaxel, the median PSA progression-free survival (PFS) and overall survival (OS) in the 114 patients were 7.2 and 17.5months, respectively. There was no significant difference in the PSA PFS or OS between the AA and Enz groups. Despite the lack of a significant impact of the type of ARAT agent on PSA PFS or OS by univariate analysis, multivariate analyses identified the following independent prognostic predictors: performance status (PS) for PSA PFS and PS and visceral metastasis for OS. Collectively, these findings suggest that the type of ARAT agent may not have a significant impact on disease control by subsequent docetaxel therapy in mCRPC patients.

The application of CyberKnife stereotactic body radiotherapy in treatment of oligometastatic prostate cancer

Objective To determine the effectiveness and safety of stereotactic body radiotherapy (SBRT)-CyberKnife for oligometastatic prostate cancer. Methods From May 2012 to February 2017, 31 patients treated by CyberKnife were retrospectively reviewed, with a median age of 67 years(range 52 to 83 years), including 50 oligometastatic and 2 primary prostate cancer patients. The median PSA level was 8.4 ng/ml(range 0 to 300.0 ng/ml) and PSA test was performed every month. PSA progression-free survival (PSA-PFS), time to initiation of androgen deprivation therapy (ADT) and local control rate (LCR) were measured as the main outcomes. Results SBRT was well tolerated and were performed as planned in all patients. No SBRT related acute or late toxicities were observed. No bone fracture was observed in patients treated by bony targeted radiotherapy. The median follow-up after SBRT was 20.7 months (range 1.2-58.3 months). The median PSA-PFS was 5.3 months (range 0-58.3 months). 1-year, 2-year, and 4-year PSA-PFS was 52.0%, 36.7% and 36.7% respectively. PSA level decrease was observed in 21 oligometastatic prostate cancer patients after SBRT, with median PSA-PFS of 12.3 months (range 1.2-58.3 months). PSA level increase was observed in 29 oligometastatic prostate cancer patients after SBRT. Six local recurrence were observed resulting in an actuarial 1-year, 2-year and 3-year LCR of 90.4%, 86.9% and 82.6%, respectively. Twelve patients treated without ADT after SBRT, with median follow-up of 8.6 months (range 2.9-58.3 months) in this subgroup. Seven patients were added ADT after SBRT, with the median time from SBRT to initiation of ADT of 13.3 months (range 3.0-24.0 months) in this subgroup. Twelve patients were treated with ADT continuously after SBRT. Conclusions CyberKnife seems to be a safe and effective treatment with tolerated adverse events and good local control for patients with oligometastatic prostate cancer. Key words: Prostate cancer; Oligometastatic; CyberKnife; Stereotactic body radiotherapy; Prostate specific antigen(PSA)

MP53-02 SERUM TESTOSTERONE LEVEL IS A USEFUL BIOMARKER TO AID OPTIMAL TREATMENT SELECTION IN MEN WITH CASTRATION-RESISTANT PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) III1 Apr 2017MP53-02 SERUM TESTOSTERONE LEVEL IS A USEFUL BIOMARKER TO AID OPTIMAL TREATMENT SELECTION IN MEN WITH CASTRATION-RESISTANT PROSTATE CANCER Kohei Hashimoto, Tetsuya Shindo, Hidetoshi Tabata, Toshiaki Tanaka, Jiro Hashimoto, Ryuta Inoue, Takashi Shimizu, Takashi Muranaka, Hiroshi Hotta, Atsushi Takahashi, Masahiro Yanase, and Naoya Masumori Kohei HashimotoKohei Hashimoto More articles by this author , Tetsuya ShindoTetsuya Shindo More articles by this author , Hidetoshi TabataHidetoshi Tabata More articles by this author , Toshiaki TanakaToshiaki Tanaka More articles by this author , Jiro HashimotoJiro Hashimoto More articles by this author , Ryuta InoueRyuta Inoue More articles by this author , Takashi ShimizuTakashi Shimizu More articles by this author , Takashi MuranakaTakashi Muranaka More articles by this author , Hiroshi HottaHiroshi Hotta More articles by this author , Atsushi TakahashiAtsushi Takahashi More articles by this author , Masahiro YanaseMasahiro Yanase More articles by this author , and Naoya MasumoriNaoya Masumori More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1653AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Enzalutamide and abiraterone are frequently used for castration-resistant prostate cancer (CRPC), because of improved tolerability of them compared to taxanes. However, there are no predictive biomarkers to make a decision of how to best use abiraterone or enzalutamide. The aim of this study was to clarify the impact of serum testosterone in a decision-making of treatment selections (enzalutamide or abiraterone) for CRPC. METHODS We retrospectively evaluated consecutive CRPC patients treated at our institution and other satellite hospitals between 2013 and May 2016. A total of 115 patients received enzalutamide or abiraterone for CRPC and had serum testosterone measure at the initiation of the treatment were included in this study. The patients were divided into two groups by serum testosterone before enzalutamide or abiraterone: 54 in the testosterone <5 ng/dl group and 61 in the testosterone ≥5 ng/dl group. Prostate-specific antigen (PSA) response rates (defined as ≥50% PSA declines), PSA progression-free survival (PSA-PFS), and overall survival (OS) were compared between groups. RESULTS A total of 72 patients were treated with enzalutamide and 43 with abiraterone. In the testosterone <5 ng/dl group, the PSA response rates were significantly lower with enzalutamide than that with abiraterone (32% vs. 62%, p=0.033), whereas there was no difference in the testosterone ≥5 ng/dl group (81% vs. 93%, p=0.429). During the median follow-up period of 12 months, 68 men (59%) had PSA relapse. In the testosterone <5 ng/dl group, the median PSA-PFS was significantly lower with enzalutamide than that with abiraterone (2.8 months vs. 6.4 months, p=0.004) (Figure). Likewise, it was significantly lower with enzalutamide than that with abiraterone in the testosterone ≥5 ng/dl group (7.6 months vs. no available, p=0.004) (Figure). Multivariate analysis reveals that testosterone ≥5 ng/dl was an independent predictive factor for PSA-PFS (HR 3.1, p<0.001). However, there was no significant difference in the median OS according to the different testosterone groups. CONCLUSIONS This result suggests that serum testosterone level is a useful biomarker in a decision-making of treatment selections in the novel hormonal therapy for CRPC. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e713 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Kohei Hashimoto More articles by this author Tetsuya Shindo More articles by this author Hidetoshi Tabata More articles by this author Toshiaki Tanaka More articles by this author Jiro Hashimoto More articles by this author Ryuta Inoue More articles by this author Takashi Shimizu More articles by this author Takashi Muranaka More articles by this author Hiroshi Hotta More articles by this author Atsushi Takahashi More articles by this author Masahiro Yanase More articles by this author Naoya Masumori More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Exploring optimal sequence of abiraterone and enzalutamide in patients with castration-resistant prostate cancer: The Kyoto-Baltimore collaboration.

219 Background: Abiraterone (ABI) and enzalutamide (ENZA) are novel hormonal treatments for castration-resistant prostate cancer (CRPC) used before and after docetaxel (DTX) chemotherapy. We aimed to evaluate and compare the efficacy of sequential treatment with ABI followed by ENZA or vice versa in patients with CRPC, using combined data from two institutions. Methods: We retrospectively evaluated data on 352 consecutive patients who had received both ABI and ENZA for CRPC at Kyoto University Hospital and at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. Using Kaplan-Meier analysis and log-rank tests, we compared PSA progression-free survival (PSA-PFS) and overall survival (OS) in patients treated with sequential ABI-to-ENZA versus ENZA-to-ABI without intervening therapies. Results: The number of patients receiving ABI-to-ENZA and ENZA-to-ABI were 163 (pre-DTX: 116, post-DTX: 47) and 189 (pre-DTX: 85, post-DTX: 104), respectively. The &gt; 50% PSA response rates to ABI and ENZA were 47% and 52% in the first-line CRPC setting, and were 9% and 29% in the second-line setting. In the pre-DTX population, median PSA-PFS was not significantly different between ABI (median: 194 days) and ENZA (median: 126 days) in the first-line setting (p = 0.411), but there was an advantage favoring ENZA (median: 91 days) compared to ABI (median: 55 days) in the second-line setting (p = 0.008). Furthermore, the combined PSA-PFS was significantly longer in the ABI-to-ENZA sequence (median: 455 days) than in the ENZA-to-ABI sequence (median: 296 days) (p &lt; 0.001). There was no statistical difference in OS between the two sequences (p = 0.598). Conclusions: The ABI-to-ENZA sequence may have more favorable efficacy in terms of combined PSA-PFS than the ENZA-to-ABI sequence, although no differences in OS were observed. This may possibly be attributable to higher PSA response rates and longer PSA-PFS to second-line ENZA compared to ABI (i.e., ENZA retains activity after ABI but not vice versa).

First Line Androgen Deprivation Therapy Duration Is Associated with the Efficacy of Abiraterone Acetate Treated Metastatic Castration-Resistant Prostate Cancer after Docetaxel.

Introduction: We performed a chart review study in our castration-resistant prostate cancer (CRPC) patients who received Abiraterone acetate (AA) treatment after docetaxel and identified clinical markers which can predict treatment outcome.Materials and Methods: From 2012 to 2016, 64 patients who received docetaxel after CRPC followed by AA treatment were included. Clinical parameters were recorded and analysis was performed to identify associations between pre-treatment variables and treatment outcome.Results: Thirty three patients (51.6%) achieved a decrease in PSA of 50%. The median PSA progression-free survival and overall survival in the total cohort of 64 patients were 6.6 and 24 months, respectively. Adverse events (AEs) in all grades developed in 35.9% (23/64) patients and mostly were grade 1 or 2. The most common AEs were gastric upset, hypokalemia and elevated liver function tests. Of the eight variables analyzed, first line androgen deprivation therapy (ADT) duration showed positive association to progression free survival (HR 0.98, 95% CI [0.96–0.99], p = 0.012) and overall survival (HR 0.97, 95% CI [0.94–0.99], p = 0.019). Pre-AA PSA and PSA progression ratio showed negative association only to progression free survival (HR 1.0, 95% CI [1.000–1.002], p = 0.025, HR 1.01, 95% CI [1.00–1.01], p < 0.001, respectively).Conclusion: First line ADT duration was positively associated with AA treatment efficacy in progression free survival and overall survival. It can be used as a pre-treatment predictor.

Degarelix therapy for prostate cancer in a real-world setting: experience from the German IQUO (Association for Uro-Oncological Quality Assurance) Firmagon® registry.

BackgroundWe investigated the use of the gonadotropin-releasing hormone (GnRH) antagonist degarelix in everyday clinical practice using registry data from uro-oncology practices in Germany.MethodsData were analysed retrospectively from the IQUO (Association for uro-oncological quality assurance) patient registry. Data were prospectively collected from all consecutive PCa patients treated with degarelix (n = 1010) in 138 uro-oncology practices in Germany between May 2009 and December 2013.ResultsMedian overall survival had not yet been reached in the all-patient group or in subgroups who had or had not received prior hormonal therapy (HT). Cox regression analysis showed that patients who had received prior HT (n = 542) had a 58 % increased mortality risk (hazard ratio 1.58, 95 % CI 1.20–2.09) versus patients who had not (n = 468) (p = 0.001). Also, in patients who had received prior luteinizing hormone-releasing hormone (LHRH) analogue therapy (LHRH agonists or GnRH antagonists), median time to PSA progression was shorter (209 weeks) than in those who had not received prior LHRH analogues (n = 555; median PSA progression-free survival not yet reached). Degarelix was generally well tolerated.ConclusionsDegarelix was effective and well tolerated in everyday clinical practice, confirming observations from clinical studies. Patients who received prior HT appeared to have a significantly higher mortality risk.