First-line Androgen Deprivation Therapy Research Articles

Macroscopic locoregional relapse from prostate cancer: which role for salvage radiotherapy?

Salvage radiotherapy (SRT) after radical prostatectomy for prostate cancer (PCa) is recommended as soon as PSA rises above 0.20ng/ml, but many patients (pts) still experience local macroscopic relapse. The aim of this multicentric retrospective analysis was to evaluate the role of SRT in pts with macroscopic relapse. From 2001 to 2016, 105 consecutive pts with macroscopic PCa relapse underwent SRT ± androgen deprivation therapy (ADT). Mean age was 72years. At time of relapse, 29 pts had a PSA value < 1.0ng/mL, 50 from 1.1 to 5, and 25 pts > 5. Before SRT, 23 pts had undergone 18F-choline PET and 15 pts pelvic MRI. Ninety-four pts had prostatic bed relapse only, and four nodal involvement. Fifty-one pts were previously submitted to first-line ADT, while 6 pts received ≥ 2 lines. At a median follow-up of 52months, 89 pts were alive, while 16 were dead. Total RT dose to macroscopic lesions was > 70Gy in 58 pts, 66-70Gy in 43, and < 66Gy in 4 pts. In 72 pts, target volume encompassed only the prostatic bed with sequential boost to macroscopic site; 33 pts received prophylactic pelvic RT. Ten-year overall survival was 76.1%, while distant metastasis-free survival was 73.3%. No grade 4-5 toxicities were found. SRT ± ADT for macroscopic relapse showed a favorable oncological outcome supporting its important role in this scenario. Data from this series suggest that SRT may either postpone ADT or improve results over ADT alone in appropriately selected pts.

A noninvasive prognostic biomarker for metastatic castration-resistant prostate cancer: Very small nuclear circulating tumor cells.

179 Background: Circulating tumor cells (CTCs) have arisen as a contemporary biomarker for prostate cancer (PC). A subgroup of PC CTCs, with particularly small nuclei ( &lt; 8.54 μm), were found to be correlated with poor prognosis and the emergence of visceral metastases (VM). This subgroup was named very-small nuclear CTCs (vsnCTCs). The findings led us to explore vsnCTCs as an aggressive biomarker in metastatic castration-resistant PC (mCRPC). We also explored a biological pathway that potentially drives this morphologic phenomenon. Studies showed that the disruption of the linker of nucleoskeleton and cytoskeleton (LINC) complex proteins, such as emerin, results in nuclear envelope instability and drives cancer cells to an amoeboid phenotype with increasing capacity of migration and invasion. We hypothesized that emerin mislocalization is associated with vsnCTC formation and may be a critical step of metastasis. Methods: Using our NanoVelcro CTC assay, we are able to capture and enumerate CTCs from patients' blood and correlate this data with clinical outcomes. We collected samples from 35 mCRPC patients who failed first-line androgen deprivation therapy and started treatment with abiraterone, enzalutamide, or taxane-based chemotherapy. Survival analyses were performed to exam the correlation between vsnCTC counts and patients’ prognosis. Concurrently, emerin staining was performed and the distribution and expression levels were analyzed in selected vsnCTC samples. Results: The presence of one or more vsnCTCs correlated with worse overall survival (P = 0.00013), progression free survival (PSA progression: P = 0.012; radiographic progression: P = 0.0015), and faster time to VM (P = 0.024). We also observed lower emerin content in vsnCTCs compared to WBC, and more prominent emerin mislocalization in vsnCTCs compared to CTCs with larger nuclei. Conclusions: Our study demonstrated the importance of morphologic characterization of CTCs and suggested that vsnCTCs is a putative biomarker for prediction of worse outcome. Additionally, our findings of emerin mislocalization in vsnCTCs suggested a potential biological pathway behind this nuclear morphologic phenomenon.

Three May Be Better Than Two: A Proposal for Metformin Addition to PI3K/Akt Inhibitor-antiandrogen Combination in Castration-resistant Prostate Cancer.

Prostate cancer is a prevalent malignant disease. Castration-resistant prostate cancer (CRPC) is a poor prognosis form that develops upon resistance to first-line androgen deprivation therapy. Intensive research is ongoing to find efficient therapeutics for this refractory state. Actually, the combination of PI3K/Akt inhibitors with new-generation antiandrogens is among the most promising therapeutic schemes, although not yet at the optimal level. Metformin effects on prostate cancer, notably its therapeutic targets shared with antiandrogens and/or PI3K/Akt inhibitors, are reviewed in this article. From that, the hypothesis of PI3K/Akt-antiandrogens dual blockade optimization by metformin addition in CRPC will be deduced.

Detection Efficacy of 18F-PSMA-1007 PET/CT in 251 Patients with Biochemical Recurrence of Prostate Cancer After Radical Prostatectomy.

Prostate-specific membrane antigen (PSMA)–targeted PET imaging recently emerged as a new method for the staging and restaging of prostate cancer. Most published studies investigated the diagnostic potential of 68Ga-labeled PSMA agents that are excreted renally. 18F-PSMA-1007 is a novel PSMA ligand that has excellent preclinical characteristics and that is only minimally excreted by the urinary tract, a potential advantage for pelvic imaging. The aim of this study was to investigate the diagnostic efficacy of 18F-PSMA-1007 for biochemical recurrence (BCR) after radical prostatectomy. Methods: From 3 academic centers, 251 patients with BCR after radical prostatectomy were evaluated in a retrospective analysis. Patients who had received second-line androgen deprivation therapy (ADT) or chemotherapy were excluded, but prior first-line ADT exposure was allowed. The median prostate-specific antigen (PSA) level was 1.2 ng/mL (range, 0.2–228 ng/mL). All patients underwent PSMA PET/CT at 92 ± 26 min after injection of 301 ± 46 MBq of 18F-PSMA-1007. The rate of detection of presumed recurrence sites was correlated with the PSA level and original primary Gleason score. A comparison to a subset of patients treated previously with ADT was undertaken. Results: Of the 251 patients, 204 (81.3%) had evidence of recurrence on 18F-PSMA-1007 PET/CT. The detection rates were 94.0% (79/84), 90.9% (50/55), 74.5% (35/47), and 61.5% (40/65) for PSA levels of greater than or equal to 2, 1 to less than 2, 0.5 to less than 1, and 0.2 to less than 0.5 ng/mL, respectively. 18F-PSMA-1007 PET/CT revealed local recurrence in 24.7% of patients (n = 62). Lymph node metastases were present in the pelvis in 40.6% of patients (n = 102), in the retroperitoneum in 19.5% of patients (n = 49), and in supradiaphragmatic locations in 12.0% of patients (n = 30). Bone and visceral metastases were detected in 40.2% of patients (n = 101) and in 3.6% of patients (n = 9), respectively. In tumors with higher Gleason scores (≤7 vs. ≥8), detection efficacy trended higher (76.3% vs. 86.7%) but was not statistically significant (P = 0.32). However, detection efficacy was higher in patients who had received ADT (91.7% vs. 78.0%) within 6 mo before imaging (P = 0.0179). Conclusion: 18F-PSMA-1007 PET/CT offers high detection rates for BCR after radical prostatectomy that are comparable to or better than those published for 68Ga-labeled PSMA ligands.

Treatment strategy for metastatic prostate cancer with extremely high PSA level: reconsidering the value of vintage therapy.

The prognostic significance of initial prostate-specific antigen (PSA) level for metastatic prostate cancer remains uncertain. We investigated the differences in prognosis and response to hormonal therapies of metastatic prostate cancer patients according to initial PSA levels. We analyzed 184 patients diagnosed with metastatic prostate cancer and divided them into three PSA level groups as follows: low (<100 ng ml−1), intermediate (100–999 ng ml−1), and high (≥1000 ng ml−1). All patients received androgen deprivation therapy (ADT) immediately. We investigated PSA progression-free survival (PFS) for first-line ADT and overall survival (OS) within each of the three groups. Furthermore, we analyzed response to antiandrogen withdrawal (AW) and alternative antiandrogen (AA) therapies after development of castration-resistant prostate cancer (CRPC). No significant differences in OS were observed among the three groups (P = 0.654). Patients with high PSA levels had significantly short PFS for first-line ADT (P = 0.037). Conversely, patients in the high PSA level group had significantly longer PFS when treated with AW than those in the low PSA level group (P = 0.047). Furthermore, patients with high PSA levels had significantly longer PFS when provided with AA therapy (P = 0.049). PSA responders to AW and AA therapies had significantly longer survival after CRPC development than nonresponders (P = 0.011 and P < 0.001, respectively). Thus, extremely high PSA level predicted favorable response to vintage sequential ADT and AW. The current data suggest a novel aspect of extremely high PSA value as a favorable prognostic marker after development of CRPC.

Prediction of Time to Castration-Resistant Prostate Cancer Using Bone Scan Index in Men with Metastatic Hormone-Sensitive Prostate Cancer

Introduction: We evaluated bone scan index (BSI) as a predictive biomarker for time to castration-resistant prostate cancer (CRPC) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). Materials and Methods: We identified 85 consecutive mHSPC patients treated with first-line androgen deprivation therapy. We analyzed the correlations between time to CRPC and clinicopathological characteristics, including age, prostate-specific antigen (PSA) level, Gleason score, clinical TNM stage, hemoglobin, lactate dehydrogenase, C-reactive protein, and BSI. Results: The median BSI was 2.7%. Progression to CRPC occurred in 55 (64.7%) patients and the median time to CRPC was 12.9 months. In multivariate analysis, 3 significant risk factors for time to CRPC were identified: age (>73 vs. ≤73 years; hazard ratio [HR] 0.53), p = 0.038, PSA level (>270 vs. ≤270 ng/mL; HR 0.53, p = 0.038), and BSI (>2.7 vs. ≤2.7%; HR 2.97, p < 0.001). Conclusion: Age, PSA level, and BSI were found to be significant predictive factors for time to CRPC in patients with mHSPC.

Predictors for survival with cabazitaxel (CBZ) in metastatic, castration-resistant prostate cancer (mCRPC): Long term follow-up of the Spanish registry.

e602 Background: The clinical experience with CBZ in mCRPC patients (pts) has enriched notably since its approval for clinical use, but there is still a lack of well-defined prognostic/predictive factors to better characterize the profile of pts that could achieve the best therapeutic benefit. Analysis of the final expanded cohort and mature long-term follow-up are presented. Methods: Medical records from mCRPC pts progressing during or after docetaxel and treated with CBZ at 21 centres in Spain were reviewed retrospectively. Baseline characteristics, overall survival (OS), radiographic progression-free survival (rPFS), and toxicity were collected. Univariate and multivariate analysis of a variety of factors predicting OS were conducted. Results: 187 consecutive pts (median age 69) with intermediate-poor prognostic baseline characteristics (Table 1) received a median of 6 cycles (range 2-59) of CBZ. Median OS from first CBZ cycle was 15.3 [CI: 11.7; 18.0] months (mo) and median clinical and/or rPFS was 7.9 mo [CI: 6.8; 10.3]. Gleason score (GS) &lt; 8 (vs ≥ 8), time under first-line androgen deprivation therapy (ADT) ( &gt; 16.1 (median) vs &lt; 16.1 mo) and the number of chemotherapy lines before CBZ did not significantly influence OS. Median follow-up was 9.5 mo. Febrile neutropenia occurred in 4 pts and 1 pt had neutropenic infection. Main nonhematologic grade ≥ 3 toxicities were asthenia (2.7%) and diarrhea (1.6%). Alopecia, nails disorders and peripheral neuropathy were uncommon. Conclusions: CBZ administered in the daily clinical practice is associated with consistent OS, similar to that observed in pivotal clinical trials. GS, median time under first-line ADT and number of chemotherapy lines before CBZ did not influence clinical benefit. CBZ has an acceptable safety profile. Funding: Sanofi [Table: see text]

Survival Outcomes in Octogenarian and Nonagenarian Patients Treated with First-line Androgen Deprivation Therapy for Organ-confined Prostate Cancer

BackgroundThe use of primary androgen deprivation therapy (PADT) is common in elderly men with early-stage prostate cancer (PCa), despite the absence of guideline recommendations. ObjectiveTo examine survival patterns of octo- and nonagenarian men with organ-confined PCa exposed to PADT, to assess whether their life expectancy warrants androgen deprivation therapy use. Design, setting, and participantsIn the Surveillance, Epidemiology, and End Results-Medicare-linked database, we identified 14 785 octo- and nonagenarian organ-confined PCa patients treated with PADT between 1991 and 2009. Outcome measurements and statistical analysisThe smoothed cumulative incidence method was used to examine 10-yr overall mortality, cancer-specific mortality (CSM), and other-cause mortality (OCM) rates. Multivariable Cox regression analyses focused on the combined effect of age and Charlson comorbidity index (CCI) after adjusting for different confounders. Results and limitationsOf all the deaths observed during the study period, 80% were due to non-cancer causes and 20% were due to PCa. The 10-yr overall survival (OS) rate in the overall population was 15.4%. The 10-yr OS rates ranged from 19.9% in patients aged 80–84 yr to 3.1% in those aged ≥90 yr. Similarly, the 10-yr OS rates ranged from 18.7% in patients with CCI=0 to 11.5% in those with CCI≥2. The 10-yr OCM rate in the overall population was 68.2%. The 10-yr OCM rates ranged from 64.6% in patients aged 80–84 yr to 77.2% in patients aged ≥90 yr. Similarly, the 10-yr OCM rates ranged from 62.1% in patients with CCI=0 to 75.2% in those with CCI≥2. The 10-yr CSM rate in the overall population was 16.4%. The 10-yr CSM rates ranged from 15.5% in patients aged 80–84 yr to 19.7% in those aged ≥90 yr, and from 19.2% in patients with CCI=0 to 13.3% in those with CCI≥2. ConclusionsOf the elderly patients with organ-confined PCa exposed to PADT, only 15% survive at 10-yr follow-up. Mortality related to non-cancer causes is the leading cause of death in the same follow-up period. These figures question the rationale for PADT in elderly men with organ-confined PCa. Patient summaryIn this study, we looked at the survival patterns of octo- and nonagenarians treated with primary androgen deprivation therapy for organ-confined prostate cancer. We found that a small proportion of patients who received primary androgen deprivation therapy remain alive at 10-yr follow-up, and the leading cause of death was not attributable to prostate cancer.

Duration of response to first androgen deprivation therapy, time to castration resistance prostate cancer, and outcome of metastatic castration resistance prostate cancer patients treated with abiraterone acetate.

Abiraterone acetate (AA) demonstrated its efficacy in the treatment of patients with metastatic castration resistance prostate cancer (mCRPC) in predocetaxel and postdocetaxel setting. However, we learn from pivotal studies that forms of primary and acquired resistance to this drug exist. Patient selection becomes so crucial to optimize treatment results. Potential predictive biomarkers have been identified but are not yet validated. In this scenario, clinical features and disease characteristics may still be of value in selecting patients for different treatments. The objective of this retrospective study was to assess whether or not a correlation between duration of response to first androgen deprivation therapy (ADT), time to castration-resistant prostate cancer (TTCRPC), and outcome of AA therapy exists. A retrospective analysis of clinical data of mCRPC patients treated with AA at two Italian cancer centers was carried out. The Kaplan-Meier method and Cox proportional hazard model were used to analyze survival data. Correlation between median duration of response to first ADT or median TTCRPC and the outcome of patients treated with AA was analyzed. From January 2015 to November 2015, data of 59 patients with mCRPC were collected. We observed no differences in patient's median progression-free survival (PFS) and biochemical progression-free survival (bPFS), according to both median duration of response to first-line ADT (duration of first ADT<13 months: median PFS and bPFS were 11 and 5 months, respectively; duration of ADT≥13 months: median PFS and bPFS were 9 and 6 months, respectively) and median TTCRPC (TTCRPC<28 months: median PFS and bPFS were 8 and 5 months, respectively; TTCRPC≥28 months: median PFS and bPFS were 10 and 9 months, respectively). Overall survival, in the same group, did not differ between patients with a duration of response to first ADT over or under 13 months (P=0.90) but in patients with a TTCRPC of 28 months or more, there was a trend toward longer survival than patients with TTCRPC less than 28 months (5-year overall survival was 74 vs. 50%; P=0.14). The duration of response to first-line ADT and the TTCRPC showed no significant association with outcome of AA therapy in patients with mCRPC. However, large prospective trials are desirable to confirm these data.

WS-1-2 - Pros and cons of docetaxel used to treat metastatic hormone-sensitive prostate cancer: The cons

Recent advances in treatments for castration-resistant prostate cancer (CRPC) have proven to be effective. Clinical trials using novel agents targeting the androgen axis, and chemotherapeutic agents including docetaxel and cabazitaxel, have shown that such agents significantly prolong survival. Emerging trends in terms of the use of such agents include up-front prescription in settings of hormone-sensitive prostate cancer. Three landmark studies on first-line docetaxel combined with androgen deprivation therapy (ADT) have appeared. The CHAARTED study the STAMPEDE study, significant prolongation of overall survival was evident when docetaxel was combined with ADT (compared to ADT alone). Based on these results, the first-line use of docetaxel combined with ADT in patients with metastatic prostate cancer has become a standard of care recognized in both the NCCN and ESMO guidelines. The research findings are robust, and it is thus necessary to reconsider the optimal treatment strategy for hormone-sensitive metastatic prostate cancer occurring in Japanese patients. Study of a large-scale Japanese database detailing patient outcomes after hormone treatment (the J-CAP database) reveals that the overall survival rates were excellent. The clinical outcomes after ADT vary by race; Japanese patients enjoy better outcomes than do Caucasians. A response to first-line ADT was a strong predictor of clinical outcome in patients with metastatic hormone-sensitive prostate cancer. Considering such findings, initiation of up-front docetaxel would be controversial in Japanese populations. It is necessary to define biomarkers indicating that the early use of docetaxel would be warranted, or other predictors of optimal results after such treatment. For example, predictors of early recurrence after primary ADT would certainly support a decision to prescribe docetaxel up-front when treating hormone-sensitive metastatic prostate cancers in Japanese populations.

Abstract 4947: Branched chain RNA in situ hybridization for the detection of androgen receptor splice variants within archival prostate cancer tissue

Abstract Introduction: Androgen receptor (AR) mRNA splice variants have emerged as predictive biomarkers for response to AR targeted therapies. There are no commercially available assays to detect AR splice variants. The branched chain RNA in situ hybridization (ISH) platform enables the highly sensitive detection of RNA transcripts in formalin-fixed, paraffin-embedded (FFPE) tissues. In this pilot study, we developed an RNA ISH assay to detect the constitutively active AR-V7 splice variant, and we correlated AR-V7 expression with clinical outcomes after first-line androgen deprivation therapy (ADT) for metastatic prostate cancer. Methods: We designed a branched chain RNA ISH probe to target the unique cryptic exon CE3 of AR-V7 using multiple tiling probes (Affymetrix). Automated ISH assays were performed using ViewRNA eZl Detection Kit on the BOND RX IHC and ISH Staining System. A semiquantitative scoring method was used to score the RNA ISH signal in FFPE tissue. We analyzed AR-V7 and full length AR within two prostate cancer cohorts that we hypothesized to represent “low likelihood” and “high likelihood” to have detectable AR-V7. “Low likelihood” men had undergone prostatectomy for Gleason 6 adenocarcinoma, and “high likelihood” men had metastatic castration resistant prostate cancer with tumor tissue obtained after disease progression despite at least one subsequent line of hormonal therapy (abiraterone, enzalutamide, or bicalutamide). We then analyzed two additional cohorts who experienced a “sustained response” (&amp;gt;2.5 years; n = 13) or “brief response” (&amp;lt;9 months; n = 9) to first-line ADT for metastatic prostate cancer and for whom baseline tumor tissue was available. Results: “High likelihood” cohort samples had detectable AR-V7 with a score of 1+ to 3+ in all samples (n = 12). “Low likelihood” cohort samples had no detectable AR-V7 (n = 10). Given the apparent binary distinction of AR-V7 signal among the above groups, we analyzed pre-treatment AR-V7 status as a predictive and prognostic biomarker in men with treatment-naive metastatic disease. Detectable AR-V7 was more common among “brief response” samples (6 of 9) than among “sustained response” samples (4 of 13) (not significant; P = 0.19). Patients without detectable AR-V7 RNA had significantly longer overall survival (OS, logrank P = 0.044), with a non-significant trend toward superior progression-free survival (PFS, logrank P = 0.055). Conclusions: Within an institutional cohort, the RNA ISH assay identified AR-V7 in all tested samples of high clinical likelihood for the splice variant RNA and no tested samples of low clinical likelihood. AR-V7 RNA was detectable in some pretreatment samples, and its presence was associated with significantly shorter overall survival. The potential prognostic and predictive utility of AR-V7 status as determined by RNA ISH from conventionally prepared FFPE tissue warrants further study in larger cohorts. Citation Format: Philip J. Saylor, Richard J. Lee, Kshitij S. Arora, David T. Ting, Vikram Deshpande, Miguel N. Rivera, Rong Hu, Chin-Lee Wu, David T. Miyamoto. Branched chain RNA in situ hybridization for the detection of androgen receptor splice variants within archival prostate cancer tissue. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4947.

Randomised phase 3 trial of enzalutamide in first-line androgen deprivation therapy for metastatic prostate cancer: The ANZUP ENZAMET Trial (ANZUP 1304).

TPS5077 Background: Androgen deprivation therapy (ADT) with a luteinising hormone releasing hormone analogue (LHRHA) or surgical castration, either alone or combined with conventional non-steroidal...

PD28-01 TESTOSTERONE LOWERING, PSA RESPONSE AND QUALITY OF LIFE IN PATIENTS WITH ADVANCED HORMONE SENSITIVE PROSTATE CANCER RECEIVING TAK-385, AN ORAL GNRH ANTAGONIST: PHASE 2 INTERIM ANALYSIS

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) I1 Apr 2016PD28-01 TESTOSTERONE LOWERING, PSA RESPONSE AND QUALITY OF LIFE IN PATIENTS WITH ADVANCED HORMONE SENSITIVE PROSTATE CANCER RECEIVING TAK-385, AN ORAL GNRH ANTAGONIST: PHASE 2 INTERIM ANALYSIS Neal D. Shore, James L. Bailen, Christopher Pieczonka, Daniel R. Saltzstein, Paul R. Sieber, David B. MacLean, Hongliang Shi, Hélène M. Faessel, Huamao Mark Lin, Yanyan Zhu, and Fred Saad Neal D. ShoreNeal D. Shore More articles by this author , James L. BailenJames L. Bailen More articles by this author , Christopher PieczonkaChristopher Pieczonka More articles by this author , Daniel R. SaltzsteinDaniel R. Saltzstein More articles by this author , Paul R. SieberPaul R. Sieber More articles by this author , David B. MacLeanDavid B. MacLean More articles by this author , Hongliang ShiHongliang Shi More articles by this author , Hélène M. FaesselHélène M. Faessel More articles by this author , Huamao Mark LinHuamao Mark Lin More articles by this author , Yanyan ZhuYanyan Zhu More articles by this author , and Fred SaadFred Saad More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.388AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES TAK-385 is an investigational, oral, non-peptide GnRH antagonist in late phase 2 evaluation for the management of hormone sensitive prostate cancer (HSPC). Two trials are ongoing: TAK-385 120 mg daily (QD) vs degarelix for patients (pts) requiring 6-mos neoadjuvant/adjuvant to EBRT (NCT02135445) and continuous TAK-385 80 or 120 mg QD vs leuprorelin (LEU) for advanced PC (relapse post local treatment or M1; NCT02083185; reported here). METHODS Pts aged ≥18 yrs with biopsy-confirmed PC, baseline testosterone (T) >150 ng/dL and PSA >2 ng/mL, and candidates for first-line androgen deprivation therapy, were randomized to receive oral TAK-385, 80 or 120 mg, QD or LEU 22.5 mg SC Q12 wks, for 48 wks. The primary endpoint was effective castration rate (T <50 ng/dL) at all scheduled visits from wk 5-24. Secondary endpoints included safety, PK, PSA response and quality of life (QoL). RESULTS At the second interim analysis (May 2015), 92% of 75 pts in the 2 TAK-385 arms (median age 73 yrs) achieved sustained castration rates (wk 5-24) vs 95% of 20 pts in the LEU arm (median age 68.5 yrs). Median T levels after 3 days of TAK-385 fell to castrate levels (36.9 ng/dL) vs the expected T flare (648.1 ng/dL) with LEU. After 2 wks, median T with TAK-385 achieved castration levels of <20 ng/dL and from wk 5-24 most pts in all arms maintained median T~10 ng/ dL. Consistent with the onset and depth of T lowering, PSA50 after 4 wks was 81% (TAK-385) and 20% (LEU). After 24 wks, median PSA reduction was 97.3% (0.1 ng/mL, TAK-385) vs 92.4% (0.2 ng/mL, LEU). Global QoL scores after 24 wks were similar across arms (mean decrease of 6.9 points [p=0.004] from baseline score of 81.4 for TAK-385 vs 7.4 points [p=0.131] from 79.6 for LEU. Most pronounced, significant changes from baseline occurred in 2 EORTC QLQ-PR25 subscales (sexual activity and hormonal-treatment related symptoms) and were similar across arms. TAK-385 safety profile is consistent with medical castration with to date no identified significant off-target toxicity. All-grade adverse events occurred in 91% vs 95% pts (TAK-385 vs LEU); the most common were hot flush (59/60%) and fatigue (21/15%). PK analysis showed dose-proportional plasma trough levels over >6 mos consistent with phase 1 results. CONCLUSIONS As a GnRH antagonist with rapid T and PSA response, the long term tolerability, efficacy and QoL of TAK-385 appear comparable to LEU. A phase 3 study of TAK-385, as an option to injectable GnRH therapies for PC pts, is planned. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e654 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Neal D. Shore More articles by this author James L. Bailen More articles by this author Christopher Pieczonka More articles by this author Daniel R. Saltzstein More articles by this author Paul R. Sieber More articles by this author David B. MacLean More articles by this author Hongliang Shi More articles by this author Hélène M. Faessel More articles by this author Huamao Mark Lin More articles by this author Yanyan Zhu More articles by this author Fred Saad More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

844 Survival outcomes in octogenarian and nonagenarian patients treated with first-line androgen deprivation therapy for localized prostate cancer

844 Survival outcomes in octogenarian and nonagenarian patients treated with first-line androgen deprivation therapy for localized prostate cancer

Should We Try Antiandrogen Withdrawal in Castration-Resistant Prostate Cancer Patients? Insights From a Retrospective Study

BackgroundIt remains uncertain whether those with response to antiandrogen withdrawal (AAW) have a better prognosis. We investigated the predictors of a better response to AAW and overall survival after acquiring resistance to first-line androgen deprivation therapy inpatients with castration-resistant prostate cancer (CRPC). Patients and MethodsWe retrospectively reviewed the medical records of 87 CRPC patients treated at Keio University Hospital. Sixty-seven of 87 CRPC patients underwent AAW. We analyzed clinicopathologic parameters to identify predictors of survival in CRPC patients and investigated predictors of good response to AAW. ResultsYounger age, longer duration of androgen deprivation therapy before CRPC development, and better response to AAW were independent favorable prognostic factors for overall survival. Although better response to AAW was a favorable prognostic factor in this study, trying AAW was not significantly related to overall survival. Duration of hormone therapy was significantly longer in those whose disease responded to AAW (69.9 ± 11.0 months) than those with no response (45.3 ± 5.2 months). ConclusionThe prognostic benefit of AAW was not clearly determined in this study. However, AAW might be beneficial in patients who have favorable prognostic factors for a response to AAW—that is, those who have received hormone therapy for a long period. However, AAW should not be done in patients who do not have favorable factors and who had a high prostate-specific antigen level at the time of their prostate cancer diagnosis.

Second interim analysis (IA2) results from a phase II trial of TAK-385, an oral GnRH antagonist, in prostate cancer patients (pts).

200 Background: Gonadotropin-releasing hormone (GnRH) antagonists achieve rapid decrease in testosterone (T) without transient T surge seen with GnRH agonists and thus may avoid clinical flare symptomatology. TAK-385 is an investigational, oral, non-peptide GnRH antagonist highly selective for the human GnRH receptor (IC50 0.12 nM). We report IA2 results from a phase 2, randomized, open label, parallel group study of TAK-385 in pts with advanced prostate cancer (NCT02083185). Methods: Pts aged ≥ 18 yrs with histologically confirmed prostate cancer, baseline T &gt; 150 ng/dL and prostate-specific antigen (PSA) &gt; 2 ng/mL, who were candidates for first-line androgen deprivation therapy, were randomized to receive oral TAK-385, 80 or 120 mg, once daily (QD) or leuprorelin (LEU) 22.5 mg subcutaneously every 12 wks, for 48 wks. The primary endpoint was effective castration rate of TAK-385 (T &lt; 50 ng/dL) from wk 5–24. Secondary endpoints included: safety, pharmacokinetics (PK), and PSA. Results: At data cut-off, 75 pts had received TAK-385 (39 at 80 mg, 36 at 120 mg QD); 20 pts received LEU. Median age was 73 yrs with TAK-385 and 68.5 yrs with LEU; median treatment duration was 35.1 wks and 37.8 wks. After 3 days/4 wks/24 wks of treatment, median T was 36.9/10.6/8.9 ng/dL with TAK385 vs 648.1/13.0/11.5 ng/dL with LEU. T &lt; 50 ng/dL was sustained over 5–24 wks in 92% vs 95% of pts (TAK-385 vs LEU). After 24 wks, PSA was reduced by 97.3% to a median of 0.1 ng/mL with TAK-385 vs 92.4% to 0.2 ng/mL with LEU. All-grade adverse events occurred in 91% vs 95% of pts (TAK-385 vs LEU); the most common were hot flush (59/60%), fatigue (21/15%), elevated alanine aminotransferase (9/10%), nasopharyngitis (8/5%), and elevated aspartate aminotransferase (5/10%). Initial analysis of pooled phase 1/2 data showed similar PK in the phase 2 pts and in previously studied healthy men, with dose-proportional plasma trough levels over &gt; 6 mos. Conclusions: At IA2, the efficacy of TAK-385 was consistent with the GnRH antagonist mechanism of action and the safety profile was good. TAK-385 rapidly reduced T and sustained castration ( &lt; 50 ng/dL) over 24 wks. Further investigation of TAK-385, as an option to injectable GnRH therapies, is warranted. Clinical trial information: NCT02083185.

Upon failure of first-line ADT, should second-line hormonal manipulation without survival benefit data still be used?

The androgen receptor (AR) is an important target in castrationresistant prostate cancer (CRPC) as the progression of the disease is still largely dependent on androgen signalling. The recommendation to continue with androgen deprivation therapy is reasonable, as cessation and restoration of testosterone levels may have an adverse impact on survival. Antiandrogen withdrawal may also be attempted in all patients, as some patients are long-term responders. In one study, 19% of patients showed no signs of progression 1 year after antiandrogen withdrawal.1 Bissada et al. reported on a case in which the duration of response was for more than 3 years after antiandrogen withdrawal.2 First-generation antiandrogens such as flutamide, bicalutamide, and nilutamide have shown to be effective against prostate cancer relapse after failure of first-line androgen deprivation therapy (ADT). Studies have indicated PSA responses of 14e48% with bicalutamide and up to 50% with nilutamide.3e9 Among patients with minimal or no bone scan involvement and low baseline prostate-specific antigen (PSA) who were started on high-dose ketoconazole, PSA levels decreased by at least 75%.10 But high doses of ketoconazole have been linked to clinically significant toxicity. Therefore, as shown in a small, retrospective study, lowdose ketoconazole may be an option for patients with biochemical failure who have failed ADT.11 With second-line hormonal manipulation using ketoconazole, response rates of between 11% and 13% were reported. There was also a marked palliation of pain in a subset of patients. Low-dose ketoconazole appears to be well

Serial blood-based analysis of AR-V7 in men with advanced prostate cancer

We previously showed that pretreatment detection of androgen receptor splice variant-7 (AR-V7) in circulating tumor cells (CTCs) from men with castration-resistant prostate cancer is associated with resistance to abiraterone and enzalutamide, but not to taxane chemotherapies. Here, we conducted serial measurements of AR-V7 and evaluated patterns of longitudinal AR-V7 dynamics over the course of multiple sequential therapies. Metastatic prostate cancer patients treated at Johns Hopkins with AR-directed therapies or taxane chemotherapies underwent serial liquid biopsies for CTC-based AR-V7 analysis at baseline, during therapy, and at progression. We used a CTC enrichment platform followed by multiplexed reverse-transcription polymerase chain reaction analysis to detect full-length androgen receptor and AR-V7 transcripts. Patients selected for inclusion in this report were those who provided ≥4 CTC samples, at least one of which was AR-V7 positive, over the course of ≥2 consecutive therapies. We identified 14 patients who received a total of 37 therapies and contributed 70 CTC samples for AR-V7 analysis during a median follow-up period of 11 months. Three patients remained AR-V7 positive during the entire course of therapy. The remainder underwent transitions in AR-V7 status: there were eight instances of 'conversions' from AR-V7-negative to -positive status (during treatment with first-line androgen deprivation therapy, abiraterone, enzalutamide, and docetaxel), and six instances of 'reversions' from AR-V7-positive to -negative status (during treatment with docetaxel and cabazitaxel). AR-V7 is a dynamic marker, and transitions in AR-V7 status may reflect selective pressures on the tumor exerted by therapeutic interventions. While 'conversions' to AR-V7-positive status were observed with both AR-directed therapies and taxane chemotherapies, 'reversions' to AR-V7-negative status only occurred during taxane therapies. Serial blood-based AR-V7 testing is feasible in routine clinical practice, and may provide insights into temporal changes in tumor evolution.

The predictive value of ERG protein expression for development of castration-resistant prostate cancer in hormone-naïve advanced prostate cancer treated with primary androgen deprivation therapy.

Biomarkers predicting response to primary androgen deprivation therapy (ADT) and risk of castration-resistant prostate cancer (CRPC) is lacking. We aimed to analyse the predictive value of ERG expression for development of CRPC. In total, 194 patients with advanced and/or metastatic prostate cancer (PCa) treated with first-line castration-based ADT were included. ERG protein expression was analysed in diagnostic specimens using immunohistochemistry (anti-ERG, EPR3864). Time to CRPC was compared between ERG subgroups using multiple cause-specific Cox regression stratified on ERG-status. Risk reclassification and time-dependent area under the ROC curves were used to assess the discriminative ability of ERG-status. Time to PSA-nadir, proportion achieving PSA-nadir ≤0.2 ng/ml, and risk of PCa-specific death were secondary endpoints. Median follow-up was 6.8 years (IQR: 4.9-7.3). In total, 105 patients (54.1%) were ERG-positive and 89 (45.9%) were ERG-negative. No difference in risk of CRPC was observed between ERG subgroups (P = 0.51). Median time to CRPC was 3.9 years (95%CI: 3.2-5.1) and 4.5 years (95%CI: 2.3-not reached) in the ERG-positive and ERG-negative group, respectively. Compared to a model omitting ERG-status, the ERG-stratified model showed comparable AUC values 1 year (77.6% vs. 78.0%, P = 0.82), 2 years (71.7% vs. 71.8%, P = 0.85), 5 years (68.5% vs. 69.9%, P = 0.32), and 8 years (67.9% vs. 71.4%, P = 0.21) from ADT initiation. No differences in secondary endpoints were observed. ERG expression was not associated with risk of CRPC suggesting that ERG is not a candidate biomarker for predicting response to primary ADT in patients diagnosed with advanced and/or metastatic PCa.

A randomised, double-blind study comparing the addition of bicalutamide with or without dutasteride to GnRH analogue therapy in men with non-metastatic castrate-resistant prostate cancer

BackgroundBicalutamide blocks androgen action and is frequently used in men with non-metastatic, castration-resistant prostate cancer (CRPC). By reducing intracellular dihydrotestosterone, dutasteride (dual 5-alpha reductase inhibitor) could increase the effectiveness of bicalutamide in this setting. The objective of the study is therefore to prospectively evaluate dutasteride plus bicalutamide in men with asymptomatic, non-metastatic CRPC with rising prostate-specific antigen (PSA). MethodsProstate cancer patients with rising PSA whilst on first-line androgen deprivation therapy (ADT) were randomised (1:1) in a double-blind trial to receive bicalutamide 50mg plus placebo or bicalutamide 50mg plus dutasteride 3.5mg once daily for 18months.Randomisation was stratified by centre; treatment assignments were generated using GlaxoSmithKline’s RandAll System. Subjects who completed 18months could participate in the 2-year extension. Central laboratory and study sites/monitors remained treatment-blinded.Primary end-point was time to disease progression (TDP) up to 42months (defined as PSA progression from baseline or nadir, radiographic disease progression, death from prostate cancer or receipt of rescue medication). FindingsThere was no statistically significant difference in TDP in 127 men treated with bicalutamide/dutasteride (n=62) compared with bicalutamide/placebo (n=65) (hazard ratio (HR)=0.94 [95% confidence interval (CI) 0.61, 1.46]; p=0.79). The estimated median TDP was 425days (95% CI 302, 858) in the bicalutamide/placebo group and 623days (95% CI 369, 730) in the bicalutamide/dutasteride group. There was no statistically significant difference between the treatment groups for any secondary efficacy end-points, including time to treatment failure or PSA response. In the multivariate analysis, age, non-White race, higher baseline testosterone and lower baseline PSA were associated with longer TDP. Adverse events were comparable between treatment groups. InterpretationIn men with non-metastatic CRPC, adding dutasteride to bicalutamide did not significantly prolong TDP. Prospective data are provided concerning the common practice of using bicalutamide in this setting.