Publications by authors named "Eleni Efstathiou"

116 Publications

Consistent survival benefit of enzalutamide plus androgen deprivation therapy in men with nonmetastatic castration-resistant prostate cancer: PROSPER subgroup analysis by age and region.

Eur J Cancer 2021 Nov 13;159:237-246. Epub 2021 Nov 13.

Englander Institute for Precision Medicine, Weill Cornell Medicine, Meyer Cancer Center, New York, NY, USA. Electronic address:

Background: Enzalutamide combined with androgen deprivation therapy (ADT) significantly prolonged metastasis-free survival and overall survival (OS) versus ADT alone in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) with rapidly rising prostate-specific antigen (PSA). The objective of this post hoc analysis of the PROSPER trial is to evaluate OS benefit and safety of enzalutamide in patients across age and regional subgroups.

Patients And Methods: Eligible men with nmCRPC, PSA doubling time ≤10 months and PSA ≥2 ng/mL with continued ADT use were randomised 2:1 to enzalutamide 160 mg or placebo. OS and safety were examined by age (<70 vs ≥70 years) and region (North America, Europe, Asia or the rest of the world). The impact of prior and subsequent therapy was also examined.

Results: In total, 1401 men were enrolled (median age, 74 years). Enzalutamide plus ADT reduced the risk of death, independent of age or region. Multivariate analyses identified Eastern Cooperative Oncology Group (ECOG) status (P < 0.0001), log (PSA; P = 0.0002) and subsequent therapy (P < 0.0001) as statistically significant factors impacting OS. Safety was consistent across age and regional subgroups. Any grade treatment-emergent adverse events were similar across age groups, were more common in the placebo group and had regional variation.

Conclusions: In men with nmCRPC and rapidly rising PSA, the benefit and safety of enzalutamide were consistent across age and regional subgroups. Variables impacting OS included ECOG status, log (PSA) and subsequent therapy. CLINICALTRIALS.

Gov Identifier: NCT02003924.
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http://dx.doi.org/10.1016/j.ejca.2021.10.015DOI Listing
November 2021

Apalutamide plus abiraterone acetate and prednisone versus placebo plus abiraterone and prednisone in metastatic, castration-resistant prostate cancer (ACIS): a randomised, placebo-controlled, double-blind, multinational, phase 3 study.

Lancet Oncol 2021 11 30;22(11):1541-1559. Epub 2021 Sep 30.

Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York, NY, USA.

Background: The majority of patients with metastatic castration-resistant prostate cancer (mCRPC) will have disease progression of a uniformly fatal disease. mCRPC is driven by both activated androgen receptors and elevated intratumoural androgens; however, the current standard of care is therapy that targets a single androgen signalling mechanism. We aimed to investigate the combination treatment using apalutamide plus abiraterone acetate, each of which suppresses the androgen signalling axis in a different way, versus standard care in mCRPC.

Methods: ACIS was a randomised, placebo-controlled, double-blind, phase 3 study done at 167 hospitals in 17 countries in the USA, Canada, Mexico, Europe, the Asia-Pacific region, Africa, and South America. We included chemotherapy-naive men (aged ≥18 years) with mCRPC who had not been previously treated with androgen biosynthesis signalling inhibitors and were receiving ongoing androgen deprivation therapy, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a Brief Pain Inventory-Short Form question 3 (ie, worst pain in the past 24 h) score of 3 or lower. Patients were randomly assigned (1:1) via a centralised interactive web response system with a permuted block randomisation scheme (block size 4) to oral apalutamide 240 mg once daily plus oral abiraterone acetate 1000 mg once daily and oral prednisone 5 mg twice daily (apalutamide plus abiraterone-prednisone group) or placebo plus abiraterone acetate and prednisone (abiraterone-prednisone group), in 28-day treatment cycles. Randomisation was stratified by presence or absence of visceral metastases, ECOG performance status, and geographical region. Patients, the investigators, study team, and the sponsor were masked to group assignments. An independent data-monitoring committee continually monitored data to ensure ongoing patient safety, and reviewed efficacy data. The primary endpoint was radiographic progression-free survival assessed in the intention-to-treat population. Safety was reported for all patients who received at least one dose of study drug. This study is completed and no longer recruiting and is registered with ClinicalTrials.gov, number NCT02257736.

Findings: 982 men were enrolled and randomly assigned from Dec 10, 2014 to Aug 30, 2016 (492 to apalutamide plus abiraterone-prednisone; 490 to abiraterone-prednisone). At the primary analysis (median follow-up 25·7 months [IQR 23·0-28·9]), median radiographic progression-free survival was 22·6 months (95% CI 19·4-27·4) in the apalutamide plus abiraterone-prednisone group versus 16·6 months (13·9-19·3) in the abiraterone-prednisone group (hazard ratio [HR] 0·69, 95% CI 0·58-0·83; p<0·0001). At the updated analysis (final analysis for overall survival; median follow-up 54·8 months [IQR 51·5-58·4]), median radiographic progression-free survival was 24·0 months (95% CI 19·7-27·5) versus 16·6 months (13·9-19·3; HR 0·70, 95% CI 0·60-0·83; p<0·0001). The most common grade 3-4 treatment-emergent adverse event was hypertension (82 [17%] of 490 patients receiving apalutamide plus abiraterone-prednisone and 49 [10%] of 489 receiving abiraterone-prednisone). Serious treatment-emergent adverse events occurred in 195 (40%) patients receiving apalutamide plus abiraterone-prednisone and 181 (37%) patients receiving abiraterone-prednisone. Drug-related treatment-emergent adverse events with fatal outcomes occurred in three (1%) patients in the apalutamide plus abiraterone-prednisone group (2 pulmonary embolism, 1 cardiac failure) and five (1%) patients in the abiraterone-prednisone group (1 cardiac failure and 1 cardiac arrest, 1 mesenteric arterial occlusion, 1 seizure, and 1 sudden death).

Interpretation: Despite the use of an active and established therapy as the comparator, apalutamide plus abiraterone-prednisone improved radiographic progression-free survival. Additional studies to identify subgroups of patients who might benefit the most from combination therapy are needed to further refine the treatment of mCRPC.

Funding: Janssen Research & Development.
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http://dx.doi.org/10.1016/S1470-2045(21)00402-2DOI Listing
November 2021

Prostate cancer castrate resistant progression usage of non-canonical androgen receptor signaling and ketone body fuel.

Oncogene 2021 Nov 28;40(44):6284-6298. Epub 2021 Sep 28.

Laboratorio de Inflamación y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.

Prostate cancer (PCa) that progresses after androgen deprivation therapy (ADT) remains incurable. The underlying mechanisms that account for the ultimate emergence of resistance to ADT, progressing to castrate-resistant prostate cancer (CRPC), include those that reactivate androgen receptor (AR), or those that are entirely independent or cooperate with androgen signaling to underlie PCa progression. The intricacy of metabolic pathways associated with PCa progression spurred us to develop a metabolism-centric analysis to assess the metabolic shift occurring in PCa that progresses with low AR expression. We used PCa patient-derived xenografts (PDXs) to assess the metabolic changes after castration of tumor-bearing mice and subsequently confirmed main findings in human donor tumor that progressed after ADT. We found that relapsed tumors had a significant increase in fatty acids and ketone body (KB) content compared with baseline. We confirmed that critical ketolytic enzymes (ACAT1, OXCT1, BDH1) were dysregulated after castrate-resistant progression. Further, these enzymes are increased in the human donor tissue after progressing to ADT. In an in silico approach, increased ACAT1, OXCT1, BDH1 expression was also observed for a subset of PCa patients that relapsed with low AR and ERG (ETS-related gene) expression. Further, expression of these factors was also associated with decreased time to biochemical relapse and decreased progression-free survival. Our studies reveal the key metabolites fueling castration resistant progression in the context of a partial or complete loss of AR dependence.
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http://dx.doi.org/10.1038/s41388-021-02008-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8566229PMC
November 2021

Abiraterone acetate plus prednisone in non-metastatic biochemically recurrent castration-naïve prostate cancer.

Eur J Cancer 2021 11 15;157:259-267. Epub 2021 Sep 15.

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Background: Intermittent androgen deprivation therapy (ADT) in biochemically recurrent castration-naïve prostate cancer is non-inferior to continuous therapy. We hypothesised that finite-duration abiraterone acetate plus prednisone (Abi +P) added to ADT will further reduce the duration of treatment exposure by prolonging time to prostate-specific antigen (PSA) recurrence without impacting eugonad state recovery.

Methods: This phase II, randomised, open-label trial enrolled patients with rising PSA ≥ 0.2 ng/ml after radical prostatectomy and/or a PSA ≥ 1 following radiotherapy. Patients were randomised 1:1 to receive Abi (1 g PO daily) + P (5 mg PO daily) + ADT or ADT alone for 8 months. The primary end-point was PSA-free survival difference at 1 year following completion of therapy.

Results: Between February 2013 and July 2016, 200 patients were enrolled. Of 100 patients randomised to each arm, 99 in the Abi +P arm and 98 in the ADT arm were evaluable. Median follow-up was 64.4 months. Median PSA-free survival was 27.0 months for the Abi +P-treated group versus 19.9 months for the ADT-treated group (hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.47-0.87). The PSA-free survival at 1 year post-treatment completion was 98% for the Abi +P group and 88% for the ADT group. Median time to eugonad state was 13.1 months for the abiraterone-treated group and 12.8 months for the ADT-treated group. Median eugonad PSA-free survival was 12.5 months for the abiraterone-treated group versus 9.0 for the ADT-treated group (HR 0.72, 95% CI 0.53-0.98). There were no significant between-group differences in androgen deprivation-related adverse events.

Conclusions: In men with biochemically recurrent prostate cancer following definitive treatment of the primary, finite duration treatment with ADT and Abi +P results in a significantly longer PSA relapse-free interval than treatment with ADT alone.
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http://dx.doi.org/10.1016/j.ejca.2021.06.017DOI Listing
November 2021

The protein arginine methyltransferases (PRMTs) PRMT1 and CARM1 as candidate epigenetic drivers in prostate cancer progression.

Medicine (Baltimore) 2021 Sep;100(36):e27094

Department of Pathology, School of Medicine, University of Patras, Patras, Greece.

Abstract: Epigenetic changes are implicated in prostate cancer (PCa) progression and resistance to therapy. Arginine residue methylation is an understudied histone post-translational modification that is increasingly associated with cancer progression and is catalyzed by enzymes called protein arginine methyltransferases (PRMTs). The molecular consequences of aberrant expression of PRMTs in PCa and the relationship between PRMTs and PCa progression are largely unknown. Using immunohistochemistry, we examined the expression of PRMT1 and CARM1, two of the best-studied PRMTs, in 288 patients across the spectrum of PCa and correlated them with markers of androgen receptor (AR) signaling, and milestones of carcinogenesis. Our findings indicate that PRMT1 and CARM1 are upregulated early in PCa progression, and that CARM1 is further upregulated after therapy. In addition, a correlation of CARM1 with AR post-translational modifications was noted in the setting of therapy resistance, highlighting CARM1 as one of the adaptation mechanisms of PCa cells in an androgen-depleted environment. Finally, CARM1 correlated with markers of cell cycle regulation, and both CARM1 and PRMT1 correlated with markers of epithelial-to-mesenchymal transition signaling. Taken together these findings indicate that an epigenetic network drives PCa progression through enhancement of milestone pathways including AR signaling, the cell cycle, and epithelial-to-mesenchymal transition.
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http://dx.doi.org/10.1097/MD.0000000000027094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428700PMC
September 2021

Estrogen receptor β and treatment with a phytoestrogen are associated with inhibition of nuclear translocation of EGFR in the prostate.

Proc Natl Acad Sci U S A 2021 03;118(13)

Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204;

Knockout of ERβ in the mouse leads to nuclear expression of epidermal growth factor receptor (EGFR) in the prostate. To examine whether ERβ plays a similar role in the human prostate, we used four cohorts of men: 1) a Swedish cohort of normal prostates and PCa (prostate cancer) of different Gleason grades; 2) men with benign prostatic hyperplasia (BPH) treated with the 5α-reductase inhibitor, finasteride, and finasteride together with the ERβ agonists, soy isoflavones; 3) men with PCa above Gleason grade 4 (GG4), treated with ADT (androgen deprivation therapy) and abiraterone (AA), the blocker of androgen synthesis for different durations; and 4) men with GG4 PCa on ADT or ADT with the AR (androgen receptor) blocker, enzalutamide, for 4 mo to 6 mo. In men with BPH, finasteride treatment induced EGFR nuclear expression, but, when finasteride was combined with isoflavones, EGFR remained on the cell membrane. In GG4 patients, blocking of AR for 4 mo to 6 mo resulted in loss of ERβ and PTEN expression and increase in patients with nuclear EGFR from 10 to 40%. In the men with GG4 PCa, blocking of adrenal synthesis of testosterone for 2 mo to 7 mo had the beneficial effect of increasing ERβ expression, but, on treatment longer than 8 mo, ERβ was lost and EGFR moved to the nucleus. Since nuclear EGFR is a predictor of poor outcome in PCa, addition of ERβ agonists together with abiraterone should be considered as a treatment that might sustain expression of ERβ and offer some benefit to patients.
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http://dx.doi.org/10.1073/pnas.2011269118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020780PMC
March 2021

Radium-223 Treatment Increases Immune Checkpoint Expression in Extracellular Vesicles from the Metastatic Prostate Cancer Bone Microenvironment.

Clin Cancer Res 2021 Jun 22;27(11):3253-3264. Epub 2021 Mar 22.

Department of GU Medical Oncology, MD Anderson Cancer Center, Houston, Texas.

Purpose: Radium-223 prolongs survival in a fraction of men with bone metastatic prostate cancer (PCa). However, there are no markers for monitoring response and resistance to Radium-223 treatment. Exosomes are mediators of intercellular communication and may reflect response of the bone microenvironment to Radium-223 treatment. We performed molecular profiling of exosomes and compared the molecular profile in patients with favorable and unfavorable overall survival.

Experimental Design: We performed exosomal transcriptome analysis in plasma derived from our preclinical models (MDA-PCa 118b tumors, TRAMP-C2/BMP4 PCa) and from the plasma of 25 patients (paired baseline and end of treatment) treated with Radium-223. All samples were run in duplicate, and array data analyzed with fold changes +2 to -2 and < 0.05.

Results: We utilized the preclinical models to establish that genes derived from the tumor and the tumor-associated bone microenvironment (bTME) are differentially enriched in plasma exosomes upon Radium-223 treatment. The mouse transcriptome analysis revealed changes in bone-related and DNA damage repair-related pathways. Similar findings were observed in plasma-derived exosomes from patients treated with Radium-223 detected changes. In addition, exosomal transcripts detected immune-suppressors (e.g., PD-L1) that were associated with shorter survival to Radium-223. Treatment of the Myc-CaP mouse model with a combination of Radium-223 and immune checkpoint therapy (ICT) resulted in greater efficacy than monotherapy.

Conclusions: These clinical and coclinical analyses showed that RNA profiling of plasma exosomes may be used for monitoring the bTME in response to treatment and that ICT may be used to increase the efficacy of Radium-223.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172463PMC
June 2021

Neuroendocrine and Aggressive-Variant Prostate Cancer.

Cancers (Basel) 2020 Dec 16;12(12). Epub 2020 Dec 16.

Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

In prostate cancer, neuroendocrine (NE) differentiation may rarely present de novo or more frequently arises following hormonal therapy in patients with castration-resistant prostate cancer (CRPC). Its distinct phenotype is characterized by an aggressive clinical course, lack of responsiveness to hormonal therapies and poor prognosis. Importantly, a subset of CRPC patients exhibits an aggressive-variant disease with very similar clinical and molecular characteristics to small-cell prostate cancer (SCPC) even though tumors do not have NE differentiation. This aggressive-variant prostate cancer (AVPC) also shares the sensitivity of SCPC to platinum-based chemotherapy albeit with short-lived clinical benefit. As optimal treatment strategies for AVPC remain elusive, currently ongoing research efforts aim to enhance our understanding of the biology of this disease entity and improve treatment outcomes for our patients. This review is an overview of our current knowledge on prostate cancer with NE differentiation and AVPC, with a focus on their clinical characteristics and management, including available as well as experimental therapeutic strategies.
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http://dx.doi.org/10.3390/cancers12123792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765615PMC
December 2020

Prostate Cancer Liver Metastases Presenting as Relatively Photopenic Lesions on 18F-Fluciclovine PET/CT.

Clin Nucl Med 2021 Apr;46(4):e240-e241

From the Division of Diagnostic Imaging.

Abstract: A 66-year-old man with prostate adenocarcinoma status post radical retropubic prostatectomy and bilateral pelvic lymph node dissection, followed by salvage external beam radiation therapy to the prostate bed 1 year after surgery. Over the course of 17 years, the patient underwent multiple lines of systemic treatment for recurrent disease. He was referred for restaging 18F-fluciclovine PET/CT due to rising serum prostate-specific antigen levels. Contrast-enhanced 18F-fluciclovine PET/CT images demonstrated multiple new liver metastases, which were relatively photopenic in comparison with the physiologic radiotracer activity in the surrounding normal liver parenchyma.
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http://dx.doi.org/10.1097/RLU.0000000000003377DOI Listing
April 2021

Prostate-specific Antigen Progression in Enzalutamide-treated Men with Nonmetastatic Castration-resistant Prostate Cancer: Any Rise in Prostate-specific Antigen May Require Closer Monitoring.

Eur Urol 2020 12 1;78(6):847-853. Epub 2020 Oct 1.

Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA.

Background: There is no universally accepted definition for prostate-specific antigen (PSA) progression. However, changes in PSA in patients with castration-resistant prostate cancer (CRPC) are used to inform treatment decisions.

Objective: To determine whether the Prostate Cancer Working Group 2 (PCWG2) definition of PSA progression is adequate to predict radiographic or clinical progression in enzalutamide-treated men with nonmetastatic CRPC (nmCRPC).

Design, Setting, And Participants: A post hoc, retrospective analysis of men with nmCRPC from PROSPER (NCT02003924) was performed.

Intervention: Continued androgen deprivation therapy; patients randomized 2:1 to enzalutamide 160 mg/d or placebo.

Outcome Measurements And Statistical Analysis: Metastasis-free survival (MFS) in men with and without PSA progression, defined by PCWG2, and PSA at the time of radiographic progression were assessed.

Results And Limitations: As of June 28, 2017, in enzalutamide-treated patients, the risk of metastasis or death was increased significantly in those with PSA progression versus those without (hazard ratio [HR] 3.99; 95% confidence interval [CI], 2.95-5.41; p < 0.0001). Median MFS was not reached (NR; 95% CI, NR-NR) in patients without PSA progression and was 22.6 mo (95% CI, 21.9-29.0) in those with PSA progression. In placebo-treated patients, PSA progression was not significantly associated with MFS (HR 1.72; 95% CI, 0.86-3.45; p = 0.1). Median MFS was NR (95% CI, 25.6-NR) in patients without PSA progression and 18.3 mo (95% CI, 14.9-19.4) in those with PSA progression. The median PSA increase from nadir at the time of radiographic progression was 1.4 ng/mL in enzalutamide-treated men and 25.6 ng/mL for the placebo arm.

Conclusions: In men with nmCRPC and rapidly rising PSA, radiographic progression often occurred without PCWG2-defined PSA progression, suggesting that any increase in PSA may warrant closer monitoring. While PCWG2-defined PSA progression was associated with radiographic progression in enzalutamide-treated men, our findings argue for prospective re-evaluation of this threshold.

Patient Summary: In this report, we looked at changes in prostate-specific antigen (PSA) in enzalutamide-treated men with nonmetastatic castration-resistant prostate cancer who no longer respond to testosterone-lowering treatment. We found that even very small changes in PSA while on treatment could be an early indication of disease progression and should trigger closer monitoring.
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http://dx.doi.org/10.1016/j.eururo.2020.08.025DOI Listing
December 2020

A Phase 2 Trial of Abiraterone Followed by Randomization to Addition of Dasatinib or Sunitinib in Men With Metastatic Castration-Resistant Prostate Cancer.

Clin Genitourin Cancer 2021 02 30;19(1):22-31.e5. Epub 2020 May 30.

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Background: Resistance to novel androgen signaling inhibition and metastatic castration-resistant prostate cancer (mCRPC) progression is likely dependent on tumor microenvironment interactions. The Src pathway and neoangiogenesis have been implicated in prostate cancer progression. We studied the effect of adding the targeted agents dasatinib and sunitinib to abiraterone acetate (AA) in men with mCRPC.

Patients And Methods: In this open-label randomized phase 2 study, mCRPC patients received AA. At resistance to AA, they were randomized 1:1 to combination with dasatinib or sunitinib. At second progression, patients crossed over. The primary end point was time to treatment failure (TTF), defined as time to progression or death. Secondary end points included overall survival and safety.

Results: From March 2011 to February 2015, a total of 179 patients were enrolled and 132 subsequently randomized. Median TTF was 5.7 months in the dasatinib group and 5.5 months in the sunitinib group. There was no difference between the two groups in terms of TTF (hazard ratio, 0.85; 95% confidence interval, 0.59-1.22). Median overall survival from study entry was 26.3 months in the dasatinib group and 27.7 months in the sunitinib group (hazard ratio, 1.02; 95% confidence interval, 0.71-1.47). Grade 3 or higher adverse events related to study medication were more frequent with sunitinib (n = 44, 46%) compared to dasatinib (n = 26, 24%). At data cutoff, 7 patients were experiencing a continuous response to AA, with a median duration of treatment of 5.7 years.

Conclusion: There is no difference in overall survival and TTF between dasatinib and sunitinib combined with abiraterone in the treatment of patients with bone mCRPC.
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http://dx.doi.org/10.1016/j.clgc.2020.05.013DOI Listing
February 2021

The MD Anderson Prostate Cancer Patient-derived Xenograft Series (MDA PCa PDX) Captures the Molecular Landscape of Prostate Cancer and Facilitates Marker-driven Therapy Development.

Clin Cancer Res 2020 09 23;26(18):4933-4946. Epub 2020 Jun 23.

Department of Genitourinary Medical Oncology and the David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Advances in prostate cancer lag behind other tumor types partly due to the paucity of models reflecting key milestones in prostate cancer progression. Therefore, we develop clinically relevant prostate cancer models.

Experimental Design: Since 1996, we have generated clinically annotated patient-derived xenografts (PDXs; the MDA PCa PDX series) linked to specific phenotypes reflecting all aspects of clinical prostate cancer.

Results: We studied two cell line-derived xenografts and the first 80 PDXs derived from 47 human prostate cancer donors. Of these, 47 PDXs derived from 22 donors are working models and can be expanded either as cell lines (MDA PCa 2a and 2b) or PDXs. The histopathologic, genomic, and molecular characteristics (androgen receptor, ERG, and loss) maintain fidelity with the human tumor and correlate with published findings. PDX growth response to mouse castration and targeted therapy illustrate their clinical utility. Comparative genomic hybridization and sequencing show significant differences in oncogenic pathways in pairs of PDXs derived from different areas of the same tumor. We also identified a recurrent focal deletion in an area that includes the speckle-type POZ protein-like () gene in PDXs derived from seven human donors of 28 studied (25%). is a paralog, and mutations define a molecular subclass of prostate cancer. deletions are found in 7% of The Cancer Genome Atlas prostate cancers, which suggests that our cohort is a reliable platform for targeted drug development.

Conclusions: The MDA PCa PDX series is a dynamic resource that captures the molecular landscape of prostate cancers progressing under novel treatments and enables optimization of prostate cancer-specific, marker-driven therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501166PMC
September 2020

An evaluation of apalutamide for the treatment of prostate cancer.

Expert Opin Pharmacother 2020 Sep 16;21(13):1537-1546. Epub 2020 Jun 16.

Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center , Houston, TX, USA.

Introduction: Novel androgen signaling inhibitors are currently standard of care in the treatment of patients with prostate cancer. Second-generation androgen receptor antagonists have demonstrated efficacy in earlier disease settings, fulfilling an unmet need in the treatment of patients with advanced prostate cancer.

Areas Covered: The present article focuses on the development and establishment of apalutamide among the available treatment options for prostate cancer. A literature search was performed in Pubmed/Medline for past studies and reviews of the drug. Ongoing clinical trials were also examined in the Clinicaltrials.gov online database.

Expert Opinion: Apalutamide has demonstrated benefit for patients with non-metastatic castration resistant and metastatic hormone naive prostate cancer. It is an efficacious, tolerable, and convenient oral agent, thus a valuable addition in the armamentarium of prostate cancer therapeutics for both non-metastatic castrate resistant and metastatic hormone naïve prostate cancer. Ongoing trials are investigating the drug as monotherapy and in combinations in other disease settings. Results are expected to further expand the drug's indications and shape the future landscape of prostate cancer therapy.
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http://dx.doi.org/10.1080/14656566.2020.1770726DOI Listing
September 2020

Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer.

N Engl J Med 2020 06 29;382(23):2197-2206. Epub 2020 May 29.

From the Englander Institute for Precision Medicine, Weill Cornell Medicine, New York (C.N.S.); the University of Paris Saclay, Villejuif, France (K.F.); the University of Montreal Hospital Center, Montreal (F.S.), and Cross Cancer Institute, University of Alberta, Edmonton (M.P.K.) - both in Canada; the Carolina Urologic Research Center, Myrtle Beach, SC (N.D.S.); Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy (U.D.); Vanderbilt University, Nashville (D.F.P.); the State University of Campinas (Unicamp), Campinas (U.F.), and the ABC Foundation School of Medicine, Santo André (D.I.G.C.) - both in Brazil; M.D. Anderson Cancer Center, Houston (E.E.); Wroclaw Medical University, Wroclaw, Poland (K. Madziarska); Sygehus Lillebælt, Vejle, Denmark (B.N.); Pfizer, La Jolla (F.Z., X.L.), and Pfizer, San Francisco (K. Modelska) - both in California; and Astellas Pharma, Northbrook (J. Sugg, J. Steinberg), and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago (M.H.) - both in Illinois.

Background: Preliminary trial results showed that enzalutamide significantly improved metastasis-free survival among men who had nonmetastatic, castration-resistant prostate cancer and rapidly increasing prostate-specific antigen (PSA) levels while taking androgen-deprivation therapy. Results from the final analysis of overall survival have not yet been reported.

Methods: In this double-blind, phase 3 trial, men with nonmetastatic, castration-resistant prostate cancer (defined on the basis of conventional imaging and a PSA doubling time of ≤10 months) who were continuing to receive androgen-deprivation therapy were randomly assigned (in a 2:1 ratio) to receive enzalutamide at a dose of 160 mg or placebo once daily. Overall survival was assessed with a group sequential testing procedure and an O'Brien-Fleming-type alpha-spending function.

Results: As of October 15, 2019, a total of 288 of 933 patients (31%) in the enzalutamide group and 178 of 468 (38%) in the placebo group had died. Median overall survival was 67.0 months (95% confidence interval [CI], 64.0 to not reached) in the enzalutamide group and 56.3 months (95% CI, 54.4 to 63.0) in the placebo group (hazard ratio for death, 0.73; 95% CI, 0.61 to 0.89; P = 0.001). The exposure-adjusted rate of adverse events of grade 3 or higher was 17 per 100 patient-years in the enzalutamide group and 20 per 100 patient-years in the placebo group. Adverse events in the enzalutamide group were consistent with those previously reported for enzalutamide; the most frequently reported events were fatigue and musculoskeletal events.

Conclusions: Enzalutamide plus androgen-deprivation therapy resulted in longer median overall survival than placebo plus androgen-deprivation therapy among men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level. The risk of death associated with enzalutamide was 27% lower than with placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, NCT02003924.).
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http://dx.doi.org/10.1056/NEJMoa2003892DOI Listing
June 2020

Management of Patients with Advanced Prostate Cancer: Report of the Advanced Prostate Cancer Consensus Conference 2019.

Eur Urol 2020 04 27;77(4):508-547. Epub 2020 Jan 27.

Division of Medical Oncology, National Cancer Centre, Singapore.

Background: Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence.

Objective: To present the results from the APCCC 2019.

Design, Setting, And Participants: Similar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naïve prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions.

Outcome Measurements And Statistical Analysis: The panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process.

Results And Limitations: Panellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material.

Conclusions: These voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be individualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials.

Patient Summary: The Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making.
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http://dx.doi.org/10.1016/j.eururo.2020.01.012DOI Listing
April 2020

A candidate androgen signalling signature predictive of response to abiraterone acetate in men with metastatic castration-resistant prostate cancer.

Eur J Cancer 2020 03 24;127:67-75. Epub 2020 Jan 24.

Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Centre, Houston, TX, USA. Electronic address:

Background: The unmet need for predictive biomarkers emerged from the unpredictable pattern of response to androgen signalling inhibition in metastatic castration-resistant prostate cancer (mCRPC). Here, we report on the testing of a previously identified candidate androgen signalling signature associated with response to androgen signalling inhibition.

Patients And Methods: We report on the outcome of the first module of a phase II trial on abiraterone acetate (AA) followed by combination with dasatinib or sunitinib. Bone marrow biopsies (BMBs) with matched bone marrow aspirate and blood samples were collected at baseline and upon progression. End-points included assessment of a prespecified molecular signature consisting of nuclear androgen receptor (AR) overexpression, cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17) expression, and AR-C-/N terminal expression ratio of ≥0.8 by immunohistochemistry (IHC) in patients with benefit versus primary resistance to AA (i.e. progression within 4 months). Tumour markers also included v-ets avian erythroblastosis virus E26 oncogene homologue (ERG), androgen receptor splice variant (ARV7) by IHC and steroids by liquid chromatography-tandem mass spectrometry.

Results: Of 170 patients accrued from 03/2011 to 02/2015, 44 (26%) were primary resistant to AA. Forty-eight patients had tumour infiltrated BMB at baseline. Pretreatment androgen signalling signature was linked to benefit from AA (p < 0.001). Presence of ERG was associated with benefit (p = 0.05), whereas nuclear ARV7 presence and 20 or more bone lesions at baseline with primary resistance (p = 0.04 and p = 0.0006, respectively).

Conclusion: Testing of a prespecified androgen signalling signature was highly supportive of its predictive value in maximal androgen deprivation strategies in mCRPC. Further validation is under way.

Trial Registration: ClinicalTrials.gov NCT01254864.
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http://dx.doi.org/10.1016/j.ejca.2019.12.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350510PMC
March 2020

A Phase II Study of Cabozantinib and Androgen Ablation in Patients with Hormone-Naïve Metastatic Prostate Cancer.

Clin Cancer Res 2020 03 15;26(5):990-999. Epub 2020 Jan 15.

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Cabozantinib, an oral inhibitor of c-MET/VEGFR2 signaling, improved progression-free survival (mPFS) but not overall survival (OS) in metastatic castrate-resistant prostate cancer. We evaluated cabozantinib plus androgen deprivation therapy (ADT) in hormone-naïve metastatic prostate cancer (HNMPCa).

Patients And Methods: Patients received ADT plus cabozantinib starting at 60 mg daily. The primary endpoint was castrate-resistant PFS by radiographic criteria, clinical progression, or receipt of additional therapy. Secondary endpoints included OS, safety, radiographic responses, and biomarker modulation.

Results: Sixty-two patients received treatment. With a median follow-up of 31.2 months, the mPFS was 16.1 months (95% CI, 14.6-22.7 months), and mOS was not reached. Reductions in PSA ≥ 90%, bone-specific alkaline phosphatase ≥ 50%, and urine N-telopeptides ≥ 50% occurred in 83%, 87%, and 86% of evaluable patients, respectively. Responses in bone scan and measurable disease were observed in 81% of and 90% of evaluable patients, respectively. Most common grade 3 adverse events were hypertension (19%), diarrhea (6%), and thromboembolic events (6%), and dose reductions occurred in 85% of patients. Analysis of baseline cytokine and angiogenic factors (CAFs) revealed that higher plasma concentrations of Lumican, CXCL5, CD25, and CD30 were associated with shorter PFS as was high tumor expression of pFGFR1.

Conclusions: Cabozantinib plus ADT has promising clinical activity in HNMPCa. CAF profiles and tissue markers suggest candidate prognostic and predictive markers of cabozantinib benefit and provide insights for rational therapy combinations.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2389DOI Listing
March 2020

Epigenetics and prostate cancer: defining the timing of DNA methyltransferase deregulation during prostate cancer progression.

Pathology 2020 Feb 18;52(2):218-227. Epub 2019 Dec 18.

Department of Pathology, Medical School, University of Patras, Greece.

DNA methyltransferases (DNMTs) regulate gene expression by methylating cytosine residues within CpG dinucleotides. Aberrant methylation patterns have been shown in a variety of human tumours including prostate cancer. However, the expression of DNMTs in clinical samples across the spectrum of prostate cancer progression has not been studied before. Tissue microarrays were constructed from the prostatectomy specimens of 309 patients across the spectrum of prostate cancer progression: hormone-naïve low-grade prostate cancer (n=49), hormone-naïve high-grade prostate cancer (n=151), hormonally treated high-grade prostate cancer (n=65), and castrate-resistant prostate cancer (CRPC) including neuroendocrine carcinoma (n=44). Adjacent non-neoplastic parenchyma was also available in 100 patients. In 71 patients with high-grade carcinoma and lymph node metastasis, tissue from the metastasis was also available for analysis. Immunohistochemical staining was performed with antibodies against DNMT1, DNMT2, DNMT3A, DNMT3B, and DNMT3L. Our results showed that DNMT1 and DNMT3L were upregulated early in prostate cancer progression, whereas DNMT2 was upregulated as a response to androgen ablation. DNMT1, DNMT3A, and DNMT3B were higher in the late stages of prostate cancer progression, i.e., the emergence of castrate resistance and androgen-independent growth. Lastly, DNMT1, DNMT2, and DNMT3L were upregulated in lymph node metastases compared to primary carcinomas. Our results highlight a cascade of epigenetic events in prostate cancer progression.
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http://dx.doi.org/10.1016/j.pathol.2019.10.006DOI Listing
February 2020

Clinical progression is associated with poor prognosis whatever the treatment line in metastatic castration resistant prostate cancer: The CATS international database.

Eur J Cancer 2020 01 29;125:153-163. Epub 2019 Nov 29.

Hôpital Civil, Strasbourg, France.

Aim Of The Study: Our goal was to evaluate the impact of progression type (prostate-specific antigen [PSA] only, radiological or clinical) at initiation of first-, second- and third life-extending therapy (LET) on treatment outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients, by performing a post-hoc analysis using data from the CATS international registry.

Methods: The 669 consecutive mCRPC patients of the CATS registry were classified according to their type of progression at initiation of each LET: PSA only (PSA-p), radiological (±PSA) (Radio-p); or clinical (±PSA, ±radiological) progression (Clin-p). Overall survival (OS), the primary endpoint, was calculated from initiation of the first-, second- and third-LET to death for each sequence.

Results: Median OS was shorter in the Clin-p group compared with the PSA-p group (14-month difference in first line; around 7-month difference in second- and third line). Shorter progression-free survival (PFS) was also observed in Clin-p patients, whatever the treatment is. Clinical progression seemed to be associated with a shorter duration of therapy with androgen receptor-targeted therapy (ART) compared with taxanes.

Conclusions: Clinical progression at initiation of a LET is associated with poor outcomes including shorter PFS and OS as well as clinical and biological features of aggressive disease. Stratifying patients in clinical trials according to disease progression type may prevent selection bias and data heterogeneity. In daily practice, first signs of clinical progression may prompt physicians to consider starting a new LET, independently of PSA levels.
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http://dx.doi.org/10.1016/j.ejca.2019.10.030DOI Listing
January 2020

Cabazitaxel plus carboplatin for the treatment of men with metastatic castration-resistant prostate cancers: a randomised, open-label, phase 1-2 trial.

Lancet Oncol 2019 10 9;20(10):1432-1443. Epub 2019 Sep 9.

Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Background: Taxane-platinum combinations have shown promising activity in metastatic castration-resistant prostate cancers in single-group clinical studies but not in randomised trials. Distinct biological subsets of the disease might derive the greatest benefit from the addition of platinum. We aimed to determine whether adding carboplatin to cabazitaxel would improve the outcomes of men with metastatic castration-resistant prostate cancer.

Methods: We did a phase 1-2, open label, randomised study at two centres in men with progressive metastatic castration-resistant prostate cancer. In phase 1, patients received intravenous cabazitaxel 20-25 mg/m and intravenous carboplatin area under the curve (AUC) 3-4 mg/mL per min every 21 days. The maximum tolerated dose was defined as the highest dose cohort studied in which one of six or fewer patients experienced a dose-limiting toxicity. In phase 2, patients were randomly assigned (1:1) centrally by a computerised algorithm to intravenous cabazitaxel 25 mg/m with or without intravenous carboplatin AUC 4 mg/mL per min. All patients received growth factor support and oral prednisone 10 mg daily. The primary endpoints were the maximum tolerated dose of the combination in phase 1 and investigator-assessed progression-free survival in phase 2. This trial is registered at ClinicalTrials.gov, number NCT01505868.

Findings: Between Aug 17, 2012, and May 11, 2015, nine patients completed phase 1 as planned, and 160 were randomly assigned to cabazitaxel (n=79) or cabazitaxel plus carboplatin (n=81) in phase 2. During phase I, grade 3 adverse events were anaemia (n=2), fatigue (n=1), thrombocytopenia (n=1), hypomagnesaemia (n=1), diarrhoea (n=1), hypokalaemia (n=1), anorexia (n=1), and dehydration (n=1), and no grade 4 adverse events occurred. No dose-limiting toxicities were observed, therefore, a maximum tolerated dose of cabazitaxel of 25 mg/m and carboplatin of AUC 4 mg/mL per min was selected for phase 2. At a median follow-up of 31·0 months (IQR 20·5-37·1), the combination improved the median progression-free survival from 4·5 months (95% CI 3·5-5·7) to 7·3 months (95% CI 5·5-8·2; hazard ratio 0·69, 95% CI 0·50-0·95, p=0·018). In the phase 2 study, the most common grade 3-5 adverse events were fatigue (7 [9%] of 79 in the cabazitaxel group vs 16 [20%] of 81 in the combination group), anaemia (3 [4%] vs 19 [23%]), neutropenia (3 [4%] vs 13 [16%]), and thrombocytopenia (1 [1%] vs 11 [14%]). There were no treatment-related deaths.

Interpretation: Carboplatin added to cabazitaxel showed improved clinical efficacy compared with cabazitaxel alone for men with metastatic castration-resistant prostate cancer. Although adverse events were more common with the combination, the treatment was safe and generally well tolerated. Our data suggest that taxane-platinum combinations have a clinically beneficial role in advanced prostate cancer and a randomised phase 3 study is planned.

Funding: Sanofi Genzyme, University of Texas MD Anderson Cancer Center Prostate Cancer Moon Shot Program, and Solon Scott III Prostate Cancer Research Fund.
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http://dx.doi.org/10.1016/S1470-2045(19)30408-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858999PMC
October 2019

Enzalutamide in Combination with Abiraterone Acetate in Bone Metastatic Castration-resistant Prostate Cancer Patients.

Eur Urol Oncol 2020 02 20;3(1):119-127. Epub 2019 Apr 20.

Department of Genitourinary Medical Oncology, Stanford Alexander Tissue Derivatives Laboratory, David H. Koch Center for Applied Research of Genitourinary Cancers, Houston, TX, USA.

Background: It is hypothesised that cotargeting the androgen receptor (AR) and paracrine androgen biosynthesis with enzalutamide and abiraterone acetate in metastatic castration-resistant prostate cancer (mCRPC) will dissipate adaptive feedback loops observed with either agent alone.

Objective: To assess the safety, efficacy, androgen signalling/metabolome, and drug-drug interactions (DDIs) of enzalutamide with abiraterone acetate in progressive bone mCRPC (bmCRPC).

Design, Setting, And Participants: This open-label, single-centre interventional study was conducted in bmCRPC patients.

Intervention: Enzalutamide 160mg and abiraterone acetate 1000mg once daily; prednisone 5mg twice daily.

Outcome Measurements And Statistical Analysis: Adverse events (AEs), prostate-specific antigen (PSA) response, progression-free survival (PFS), tumour biomarker/metabolite expression, and C plasma concentrations were evaluated.

Results And Limitations: Sixty patients were enrolled. Common AEs independent of grade/causality included fatigue (72%), hyperglycaemia (67%), alkaline phosphatase (ALP) elevation (53%), and hot flush (43%). Grade 3 AEs included hypertension (17%), alanine aminotransferase elevation (12%), ALP elevation (5%), and arthralgia (5%). No treatment-related grade 4 AEs or deaths were reported. Median treatment-discontinuation time was 312d (95% confidence interval [CI] 196.0-483.0). Maximal PSA decline ≥50% and ≥90% occurred in 46 (77%) and 29 (48%) patients, respectively. Median PFS was 251d (95% CI 147-337). At week 9, median tumour microenvironment androgens, precursors, and nuclear AR expression decreased (p<0.001). The baseline tumour AR C/N terminal ratio of ≥80% was associated with treatment benefit. At enzalutamide steady state, abiraterone acetate C was ∼23% lower (range 14.05-200.5ng/ml) than when given alone.

Conclusions: Enzalutamide combined with abiraterone acetate has a manageable safety profile, without a meaningful DDI. Both agents are pharmacodynamically active with no feedback. Efficacy findings do not support significant benefit of combined treatment for unselected bmCRPC.

Patient Summary: This is the first study combining enzalutamide plus abiraterone in bone metastatic castration-resistant prostate cancer. Results show that this combination is safe.
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http://dx.doi.org/10.1016/j.euo.2019.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204265PMC
February 2020

Prostate Cancer: Quo Vadis?

Eur Urol 2019 Dec 9;76(6):709-711. Epub 2019 Jul 9.

Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Utility measures are urgently needed for clinical application of new, more sensitive diagnostics to reduce the risk of excessive intervention.
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http://dx.doi.org/10.1016/j.eururo.2019.06.031DOI Listing
December 2019

Clinical and Biological Characterisation of Localised High-risk Prostate Cancer: Results of a Randomised Preoperative Study of a Luteinising Hormone-releasing Hormone Agonist with or Without Abiraterone Acetate plus Prednisone.

Eur Urol 2019 10 6;76(4):418-424. Epub 2019 Jun 6.

Department of Genitourinary Medical Oncology, David H. Koch Center for Applied Research of GU Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Optimal therapeutic strategy remains an unmet need in localised high-risk prostate cancer (LHRPC). Androgen biosynthesis inhibition in the preoperative setting may improve outcomes. In this single-centre randomised trial, we looked at therapy outcomes of preoperative treatment with abiraterone acetate+prednisone (AAP)+luteinising hormone-releasing hormone agonist (LHRHa) or LHRHa alone followed by radical prostatectomy in 65 men. We did not see a significant difference of organ-confined carcinoma (p=0.27). However, tumour volume measures were significantly lower for AAP+LHRHa treatment (p≤0.001). Of note, lower tumour epithelium volume correlated with improved biochemical recurrence-free survival at ≥4-yr follow-up (p=0.0014). Tumours pretreated with AAP+LHRHa had lower proliferation and androgen signalling expression than LHRHa. On multivariate analysis, glucocorticoid receptor (GR) overexpression correlated with persistent tumours in AAP+LHRHa (p=0.018). The presence of nuclear androgen receptor splice variant (nARV7) correlated with persistent tumours in both arms. No new safety signals were observed. This is the first study investigating the role of preoperative AAP+LHRHa versus LHRHa alone in LHRPC. We report significant cytoreduction by tumour volume measures inversely correlating with biochemical relapse. Validation of these proposed tumour volume measures is planned. A potential role of GR in resistance to androgen biosynthesis inhibition warrants further study. PATIENT SUMMARY: This is the first study of abiraterone acetate plus leuprolide versus leuprolide alone in high-risk localised prostate cancer followed by prostatectomy. Patients in the combination arm had a significantly smaller tumour size.
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http://dx.doi.org/10.1016/j.eururo.2019.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205516PMC
October 2019

Systemic Treatment of Prostate Cancer in Elderly Patients: Current Role and Safety Considerations of Androgen-Targeting Strategies.

Drugs Aging 2019 08;36(8):701-717

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1155 Pressler Street, Houston, TX, 77030, USA.

Prostate cancer commonly affects older men, with one out of five patients being diagnosed at 75 years or older. Elderly patients are more likely to have reduced performance and nutritional status, increased comorbidities, polypharmacy, and altered host-dependent pharmacokinetics and pharmacodynamics. Moreover, elderly patients are often underrepresented in clinical trials, mainly because of comorbidities and decline in performance status. The International Society of Geriatric Oncology recommends management of elderly patients according to fitness and personal preference, rather than chronological age. Since androgen signaling has a nodal role in prostate cancer progression, androgen-targeting agents remain the mainstay of systemic therapy for this disease. However, the potential benefit of these treatments may be compromised by toxicity, especially in elderly patients. Hence, management decisions require evidence-based consideration of both potential benefits and risks on an individualized basis. Furthermore, especially elderly patients should undergo geriatric screening and must be actively monitored during treatment to detect adverse events early and prevent complications. A personalized and vigilant approach could provide the elderly patient with the optimal benefits of existing and emerging prostate cancer treatments, while sparing them the risks of excessive toxicity and avoiding overtreatment.
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http://dx.doi.org/10.1007/s40266-019-00677-6DOI Listing
August 2019

Sequencing of Taxanes and New Androgen-targeted Therapies in Metastatic Castration-resistant Prostate Cancer: Results of the International Multicentre Retrospective CATS Database.

Eur Urol Oncol 2018 12 8;1(6):467-475. Epub 2018 Jun 8.

Hôpital Civil, Strasbourg, France.

Background: The optimal sequence of life-extending therapies in metastatic castration-resistant prostate cancer (mCRPC) is unknown.

Objective: To evaluate outcomes among mCRPC patients treated with docetaxel (DOC), cabazitaxel (CABA), and a novel androgen receptor-targeted agent (ART; abiraterone acetate or enzalutamide) according to three different sequences.

Design, Setting, And Participants: Data from 669 consecutive mCRPC patients were retrospectively collected between November 2012 and October 2016.

Outcome Measurements And Statistical Analysis: The primary endpoint was the prostate-specific antigen (PSA) response (decrease ≥50% from baseline) to each therapy. Secondary endpoints included best clinical benefit, time to PSA progression, radiological progression-free survival (rPFS), overall survival (OS), and toxicity.

Results And Limitations: A total of 158 patients received DOC→CABA→ART (group 1), 456 received DOC→ART→CABA (group 2), and 55 received ART→DOC→CABA (group 3). At baseline, PSA progression only and Gleason <8 were more common in group 3. PSA response on DOC was lower in group 3 than in other groups (p=0.02) and PSA response on CABA was higher in the second than in the third line (p=0.001). In Group 3, rPFS on ART (6.6 mo) and DOC (9.2 mo) was also shorter than in the other groups. OS calculated from the first life-extending therapy reached 34.8, 35.8, and 28.9 mo in groups 1, 2 and 3, respectively (p=0.007). Toxicity was comparable between the arms. The main limitations of the trial are its retrospective design and the low number of patients in group 3.

Conclusions: In this retrospective trial, sequencing of DOC, CABA, and one ART, was associated with median OS of up to 35.8 mo. CABA seemed to retain its activity regardless of treatment sequence. DOC activity after ART appeared to be reduced, but the data are insufficient to conclude that cross-resistance occurs.

Patient Summary: The order of drugs administered to patients with metastatic castration-resistant prostate cancer could impact their efficacy, with cabazitaxel appearing to retain its activity whatever the therapeutic sequence.
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http://dx.doi.org/10.1016/j.euo.2018.05.009DOI Listing
December 2018

AR-V7 and AR-FL expression is associated with clinical outcome: a translational study in patients with castrate resistant prostate cancer.

BJU Int 2019 May 4. Epub 2019 May 4.

Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Objectives: To investigate if full-length androgen receptor (AR-FL) is associated with resistance to AR-directed therapy independently and/or combined with AR splice variant 7 (AR-V7).

Patients And Methods: Plasma samples were prospectively collected from 73 patients with CRPC before first or second-line AR-directed therapy. mRNA was isolated from exosomes and AR-FL and AR-V7 were analyzed by ddPCR.

Results: AR-FL was detected in all patients while 22% were AR-V7+ at baseline. AR-FL expression was significantly higher in AR-V7+ vs AR-V7- patients (p<0.0001). Stratifying patients by tertiles for AR-FL expression, PFS was 22 vs 18 vs 4 months for lower vs intermediate vs higher tertile, respectively (p=0.0003). Median PFS and OS were significantly longer in AR-V7- vs AR-V7+ patients (20 vs 4 months, p<0.0001; not reached vs 9 months, p<0.0001, respectively).

Conclusions: Resistance to AR-directed therapy is associated with the presence of AR-V7; however, AR-FL expression may help better refine response and survival of patients to AR-directed therapy. Both biomarkers, if validated in prospective trials, may be used to select the best treatment strategy. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/bju.14792DOI Listing
May 2019

B7-H3 Expression in Merkel Cell Carcinoma-Associated Endothelial Cells Correlates with Locally Aggressive Primary Tumor Features and Increased Vascular Density.

Clin Cancer Res 2019 06 26;25(11):3455-3467. Epub 2019 Feb 26.

Department of Pathology, the University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy whose pathogenesis and prognosis are related to the integrity of the host immune system. Despite promising clinical responses to immune-checkpoint blockade, response and resistance remain unpredictable, underscoring a critical need to delineate novel prognostic biomarkers and/or therapeutic targets for this disease. Expression of immune-regulatory markers (PD-L2, B7-H3, B7-H4, IDO-1, ICOS, TIM3, LAG3, VISTA, and OX-40) was assessed using singlet chromogenic IHC in 10 primary MCCs. Multiplex immunofluorescence quantified CD31 and B7-H3 expression in 52 primary and 25 metastatic MCCs. B7-H3 and CD31 expressions were tabulated as a series of independent (X,Y) cell centroids. A spatial G-function, calculated based on the distribution of distances of B7-H3+ (X,Y) cell centroids around the CD31 (X,Y) cell centroids, was used to estimate a colocalization index equivalent to the percentage of CD31-positive cell centroids that overlap with a B7-H3-positive cell centroid.

Results: Primary and metastatic MCCs exhibit a dynamic range of colocalized CD31 and B7-H3 expression. Increasing colocalized expression of B7-H3 with CD31 significantly associated with increased tumor size ( = 0.0060), greater depth of invasion ( = 0.0110), presence of lymphovascular invasion ( = 0.0453), and invasion beyond skin ( = 0.0428) in primary MCC. Consistent with these findings, increasing colocalized expression of B7-H3 and CD31 correlated with increasing vascular density in primary MCC, but not metastatic MCC.

Conclusions: Our results demonstrate that colocalized expression of B7-H3/CD31 is a poor prognostic indicator and suggest therapies targeting B7-H3 may represent an effective approach to augmenting immune-activating therapies for MCC.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211110PMC
June 2019

Movember GAP1 PDX project: An international collection of serially transplantable prostate cancer patient-derived xenograft (PDX) models.

Prostate 2018 12 2;78(16):1262-1282. Epub 2018 Aug 2.

Monash University, Melbourne, Australia.

Background: While it has been challenging to establish prostate cancer patient-derived xenografts (PDXs), with a take rate of 10-40% and long latency time, multiple groups throughout the world have developed methods for the successful establishment of serially transplantable human prostate cancer PDXs using a variety of immune deficient mice. In 2014, the Movember Foundation launched a Global Action Plan 1 (GAP1) project to support an international collaborative prostate cancer PDX program involving eleven groups. Between these Movember consortium members, a total of 98 authenticated human prostate cancer PDXs were available for characterization. Eighty three of these were derived directly from patient material, and 15 were derived as variants of patient-derived material via serial passage in androgen deprived hosts. A major goal of the Movember GAP1 PDX project was to provide the prostate cancer research community with a summary of both the basic characteristics of the 98 available authenticated serially transplantable human prostate cancer PDX models and the appropriate contact information for collaborations. Herein, we report a summary of these PDX models.

Methods: PDX models were established in immunocompromised mice via subcutaneous or subrenal-capsule implantation. Dual-label species (ie, human vs mouse) specific centromere and telomere Fluorescence In Situ Hybridization (FISH) and immuno-histochemical (IHC) staining of tissue microarrays (TMAs) containing replicates of the PDX models were used for characterization of expression of a number of phenotypic markers important for prostate cancer including AR (assessed by IHC and FISH), Ki67, vimentin, RB1, P-Akt, chromogranin A (CgA), p53, ERG, PTEN, PSMA, and epithelial cytokeratins.

Results: Within this series of PDX models, the full spectrum of clinical disease stages is represented, including androgen-sensitive and castration-resistant primary and metastatic prostate adenocarcinomas as well as prostate carcinomas with neuroendocrine differentiation. The annotated clinical characteristics of these PDXs were correlated with their marker expression profile.

Conclusion: Our results demonstrate the clinical relevance of this series of PDXs as a platform for both basic science studies and therapeutic discovery/drug development. The present report provides the prostate cancer community with a summary of the basic characteristics and a contact information for collaborations using these models.
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http://dx.doi.org/10.1002/pros.23701DOI Listing
December 2018
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