PSMA Radioligands for Diagnostics and Treatment of Advanced Prostate Cancer

SOMATOSTATIN ANALOGUES AND ESTROGENS IN THE TREATMENT OF ANDROGEN ABLATION REFRACTORY PROSTATE ADENOCARCINOMA

At present there is no cure for advanced prostate cancer once it progresses to an androgen independent stage. Hormonal therapy, radiotherapy, and chemotherapy all have limited durations of efficacy for men diagnosed with androgen independent disease and patients will succumb over a period of several months to two years. The androgen receptor (AR) has been suspected to play an important role in the mechanism of progression to androgen independence. This is because the AR is a transcription factor that 'normally' mediates the effects of androgen to regulate expression of genes involved in proliferation and survival of prostate cells. Thus identifying and characterizing the proteins that interact with the AR to facilitate an activated receptor is of critical importance. Proteomic approaches such as isotope-coded affinity tags (ICAT), isotope Tags for Relative and Absolute Quantification (iTRAQ)(TM), Stable Isotope Labeling with Amino acids in Cell culture (SILAC), Tandem Affinity Purification (TAP) of tagged proteins (TAP-tag) and Multidimensional Protein Identification Technology (MudPIT) provide large scale unbiased strategies and have not been previously applied to identify proteins that interact with the AR. Here an example of the power of these proteomic approaches to identify potential therapeutic targets for prostate cancer is provided. Application of MudPIT identified 82 peptides in endogenous complexes immunoprecipitated with the AR from prostate cancer cells. Identification of these novel proteins may ultimately lead to the development of better therapies for the treatment or prevention of advanced prostate cancer.

Present highlights from recent research examining treatment of advanced prostate cancer. Data are emerging that combining androgen deprivation, docetaxel, and additional androgen-receptor-targeted therapies in treatment naïve metastatic prostate cancer may be an effective strategy to improve outcomes. Genomically targeted therapies and radiopharmaceuticals continue to be evaluated in the treatment of advanced castration-resistant prostate cancer. Although no clear consensus has emerged regarding the best sequencing of available therapeutics, trial results continue to support moving available therapies earlier in the disease course. Data continue to build for novel radiopharmaceuticals soon to likely be approved for treatment of castration-resistant disease.

Hormonal treatment is effective for only a limited time in primary treatment of advanced prostate cancer, because of the development of hormone-resistant cells. It is unknown whether these cells were present in small numbers from the beginning or developed later by mutation of hormone-sensitive cells. Cytotoxic therapy has, up to now, mainly been used as second-line treatment when virtually all cells are hormone-resistant. Because 20% of all advanced prostate cancers do not respond to hormonal treatment even when given as primary therapy, hormone-resistant cells may have been present from the beginning. Trials using a combined hormonal and cytotoxic treatment as primary therapy would, therefore, be interesting. However, there is a lack of active compounds that do not show major toxicity. Estramustine phosphate (EMP) may be an exception. It is unusual because it combines hormonal and cytotoxic effects. Second-line treatment with chemotherapy has led to subjective improvement over a very short period of time only. EMP may be of benefit to patients who have had previous radiotherapy as it does not suppress the bone marrow. Although primary treatment of advanced prostate cancer with a combination of hormone and chemotherapy does not lead to a cure, it may extend time to progression, particularly in patients with poor prognostic factors at the onset. In future phase III studies, the role of prognostic factors must be further classified in order to obtain meaningful results.

COMPLETE ANDROGEN BLOCKADE FOR PROSTATE CANCER: WHAT WENT WRONG?

152 Background: The mediator complex plays a pivotal role in the regulation of gene transcription. The subunits CDK8 and CDK19 are overexpressed in advanced prostate cancer (PCa) and promote migration and invasion, as shown previously by our group. The aim of this study was to analyze if CDK8/CDK19 inhibition can impede PCa progression. Methods: Immunohistochemistry for CDK8 and CDK19 was performed on a large PCa cohort (376 radical prostatectomy (RP) specimens, 39 locally advanced tumors, 32 lymph node metastases, 24 distant metastases, 73 benign prostatic specimens). PCa cell lines (DU145, PC3) were treated with CDK8/CDK19 small molecule inhibitors followed by MTT assay, wound healing assay, and Western Blot for epithelial/mesenchymal markers. Results: CDK19 is higher expressed in primary PCa vs. benign specimens and locally advanced PCa/distant metastases vs. primary PCa. CDK8 and CDK19 are higher expressed in castration-resistant specimens vs. hormone-naive specimens. CDK19 significantly correlates with grade group in RP specimens. Biochemical recurrence free survival rates are lower for patients with high vs. medium vs. no/low CDK19 expression in the tumor. CDK19 predicts recurrence free survival independently from grade group and PSA. CDK8/CDK19 inhibition results in decreased migration, while there is no effect on proliferation. Mesenchymal markers are reduced while epithelial markers are induced following CDK8/CDK19 inhibition. Conclusions: CDK19 qualifies as a prognostic marker predicting biochemical recurrence following RP. CDK8/CDK19 inhibition leads to decreased migratory potential and mesenchymal phenotype. CDK8/19 expression increases during progression to castration-resistance. Collectively, CDK8/CDK19 represents a new target for treatment of advanced and/or castration-resistant PCa.

Prostate cancer is the second leading cause of cancer death in men. Screening and advances in the treatment of localized disease may help reduce the burden of this disease. Unfortunately, despite progress in these areas, a significant number of men continue to present with advanced disease or to develop advanced disease at some time after treatment for their local disease. The treatment of advanced or metastatic prostate cancer is systemic therapy. The mainstay of systemic therapy for prostate cancer has been hormonal therapy for many years. Orchiectomy and estrogens were the initial hormonal therapies used. Over the past several years a number of agents have been shown to produce similar rates of disease control with improved tolerability profiles. The luteinizing hormone releasing hormone (LHRH) agonists are the most frequently used hormonal agents in prostate cancer. Antiandrogens have also been used as single agents, or in combination with LHRH agonists. Soon LHRH antagonists may come into clinical practice. When hormone therapy fails to control this disease, chemotherapy is the next line of treatment. Over the past several years, several newer chemotherapy agents have renewed enthusiasm for this avenue of treatment in prostate cancer. Novel agents utilizing a variety of recently identified mechanisms of action are likely to become clinically relevant in the treatment of prostate cancer over the next few years. This review seeks to address the major issues relating to the pharmacological treatment of advanced prostate cancer.

BackgroundPatient preference studies can inform decision-making across all stages of the medical product life cycle (MPLC). The treatment landscape for advanced prostate cancer (APC) treatment has substantially changed in recent years. However, the most patient-relevant aspects of APC treatment remain unclear. This systematic review of patient preference studies in APC aimed to summarize the evidence on patient preferences and patient-relevant aspects of APC treatments, and to evaluate the potential contribution of existing studies to decision-making within the respective stages of the MPLC.MethodsWe searched MEDLINE and EMBASE for studies evaluating patient preferences related to APC treatment up to October 2020. Two reviewers independently performed screening, data extraction and quality assessment in duplicate. We descriptively summarized the findings and analyzed the studies regarding their contribution within the MPLC using an analytical framework.ResultsSeven quantitative preference studies were included. One study each was conducted in the marketing approval and the health technology assessment (HTA) and reimbursement stage, and five were conducted in the post-marketing stage of the MPLC. While almost all stated to inform clinical practice, the specific contributions to clinical decision-making remained unclear for almost all studies. Evaluated attributes related to benefits, harms, and other treatment-related aspects and their relative importance varied relevantly between studies. All studies were judged of high quality overall, but some methodological issues regarding sample selection and the definition of patient-relevant treatment attributes were identified.ConclusionThe most patient-relevant aspects regarding the benefits and harms of APC treatment are not yet established, and it remains unclear which APC treatments are preferred by patients. Findings from this study highlight the importance of transparent reporting and discussion of study findings according to their aims and with respect to their stage within the MPLC. Future research may benefit from using the MPLC framework for analyzing or determining the aims and design of patient preference studies.

Racial disparities in prostate cancer treatment and survival in the U.S. have been attributed to differences in access to care and medical insurance. We aimed to compare treatment and survival of advanced prostate cancers between White and Black men in the equal access Military Health System (MHS). We accessed the MilCanEpi database to study a cohort of non-Hispanic White and Black men diagnosed with stage III or IV prostate cancer between 1998 and 2014 in the MHS. The racial groups were compared in receiving curative treatment of radical prostatectomy (RP) only, RP with (neo)adjuvant radiation or hormone therapy, radiation only, or combination radiation and hormone therapy; and overall survival using multivariable regression models. The study included 1476 White and 531 Black men. Overall, there was no racial difference in receiving any curative treatment (AOR = 0.85, 95% CI = 0.67, 1.08 for Black vs. White). By treatment type, Black men were statistically as likely to receive RP only (AOR = 0.87, 95% CI = 0.67, 1.14), radiation only (AOR = 0.81, 95% CI = 0.49, 1.34), or combination radiation and hormone therapy (AOR = 1.12, 95% CI = 0.71, 1.78) but statistically less likely to receive RP with (neo)adjuvant treatment (AOR = 0.56, 95% CI = 0.37, 0.86) relative to no curative treatment compared to White men. The difference in RP with (neo)adjuvant treatment was also statistically significant among patients with stage III tumors, but not stage IV. Survival was similar overall (AHR = 1.12, 95% CI = 0.88, 1.42 for Black vs. White) and when evaluated by tumor stage. In the MHS, the overall likelihood to receive any treatment for advanced prostate cancers and survival was similar between races, which might result from universal health care. Racial differences in receipt of RP with (neo)adjuvant treatment, especially for patients with stage III prostate cancer, may be related to factors other than access to care and warrants further research.

ABSTRACTBackground and scope: Leuprorelin is a well known luteinising hormone releasing hormone (LHRH) agonist. The drug is effective in the treatment of advanced prostate cancer and is well tolerated. This article reviews published literature (based on a search of PubMed, EMBASE and Biosis databases to the end of 2005) and other sources of data on a new formulation of leuprorelin acetate (Eligard) for use in the treatment of hormone-dependent advanced prostate cancer. This product takes advantage of a novel delivery system (Atrigel) which forms an implant in situ that is capable of delivering double doses of leuprorelin consistently to provide better, more sustained testosterone suppression compared with a microsphere leuprolide acetate formulation. Two formulations, 7.5 mg and 22.5 mg, are currently available with duration of action of 1 and 3 months, respectively. The 2-week stability at room temperature prior to mixing facilitates its use and reduces the potential for waste.* Eligard is a registered trade name of Astellas pharma in Europe and the sanofi-aventis group of companies in the USA† Atrigel is a registered trade mark of QLT USA, Inc., Fort Collins, CO, USAFindings: In clinical studies of the new leuprorelin acetate formulation reviewed here, all patients achieved testosterone levels ≤ 50 ng/dL and up to 98% of patients showed levels comparable to those resulting from surgical bilateral orchidectomy (≤ 20 ng/dL). Both formulations showed minimal breakthroughs, defined as a rise in testosterone levels after reaching levels of 50 ng/dL. The safety profile is typical of LHRH agonists, with mild to moderately severe ‘hot flushes’ being the most common adverse event. The higher dose of 22.5 mg, with a volume of 0.375 mL is administered subcutaneously via a small 20G needle, causing little local discomfort.Conclusion: Prostate cancer remains a major cause of morbidity and mortality in older men. In the majority of cases, suppression of serum testosterone levels is very effective. The level of testosterone suppression is currently under debate, with ideal suppression levels ranging from 20 to 50 ng/dL. Not all LHRH agonist therapy achieves the same degree of testosterone suppression as bilateral orchidectomy. The new leuprorelin acetate (Eligard) appears to achieve a testosterone suppression of 20 ng/dL in 98% of patients, while maintaining a side effect profile comparable to other products in its class.

Objectives To investigate clinical efficacy of the plasma electtonics resection (PKRP) for the treatment of advanced prostate cancer with bladder outlet obstruction.Methods Retrospective analysis of 2008 August to 2011 August 24 cases treated by PKRP in patients with PCa,collected from patients with clinical data,followed up for 6 months,before and after operation on the patients with the International Prostate Symptom Score (IPSS),quality of life score(QOL),maximal urinary flow rate (Qmax),residual urine volume(RV) were compared.Results 24 cases of patients with lower urinary tract symptoms were significantly reduced,IPSS preoperatively by (18.96 ± 4.28) to (8.51 ±2.52) divided into(P ＜0.05),QOL preoperatively by (4.51 ± 0.52) to (1.51 ±0.01) divided into(P ＜0.05),Qmax by operation before(9.2 ±0.6) ml/s to (19.3 ±2.3) ml/s (P ＜0.05),RV preoperatively by (201.4 ± 12.4) ml to (42.6 ± 4.6) ml (P ＜ 0.05),during the follow-up period no deaths.Conclusions Conclusion:the late with BOO PCa patients,plasma electtonics resection therapy is a safe,effective treatment,can improve the life quality of the patients. Key words: Prostatic Neoplasms; Prostatectomy

To review the pharmacology, pharmacokinetics, efficacy, and adverse effects of nilutamide and to compare this agent with the currently marketed nonsteroidal antiandrogens (i.e., bicalutamide, flutamide) by critically analyzing the published literature. MEDLINE (1980-1995) and CANCERLIT (1991-1995) were searched for English-language publications using the terms nilutamide, bicalutamide, and flutamide alone, and either nilutamide or androgen antagonists in combination with prostatic neoplasms. All articles with subject matter on nilutamide, bicalutamide, and flutamide were considered for inclusion. For studies published in more than one journal, the first publication was used unless a subsequent publication included additional or follow-up data, in which case the latter publication was cited instead. Nilutamide was effective in combination with orchiectomy in improving responses in patients with advanced prostate cancer. However, patient survival was not improved in these trials, and improvements in bone pain did not usually result in improved performance status in these patients. The few trials of nilutamide monotherapy or nilutamide in combination with a luteinizing hormone-releasing hormone analog are too small to draw meaningful conclusions regarding its efficacy or its role in the treatment of advanced prostate cancer. No comparative trials of nilutamide with other antiandrogens and no analysis of the impact of nilutamide on patient quality of life are currently available. Nilutamide appears to produce a higher frequency of adverse effects than the other currently marketed nonsteroidal antiandrogens, bicalutamide and flutamide. Nilutamide does not appear to represent a major advance in the treatment of advanced prostate cancer and appears to be somewhat inferior to both flutamide and bicalutamide with regard to adverse effects. Nilutamide should not be considered the antiandrogen of choice in the treatment of advanced prostate cancer.

Combination immunotherapy is emerging as a promising approach for the treatment of advanced prostate cancer. This research highlight discusses the combination of a PSA-directed poxviral vaccine and a monoclonal antibody blocking an important immune checkpoint molecule to treat men with metastatic castration-resistant prostate cancer. The results demonstrate feasibility and safety, as well as intriguing clinical responses to this combination therapy.

Androgen ablation therapy remains the gold standard for the treatment of advanced prostate cancer, but unfortunately, it is not curative and eventually the disease will return as lethal castration-resistant prostate cancer (CRPC). There is evidence supporting the concept that development of CRPC is causally related to continued transactivation of androgen receptor (AR). Suspected mechanisms for continued AR activity in spite of castrate levels of androgen include: amplification or overexpression of AR; gain-of-function mutations allowing AR to be activated by steroids or antiandrogens; ligand-independent activation by growth factors, cytokines, or kinases; overexpression of AR coactivators; intracrine signaling by increased intratumoral androgens; and/or expression of constitutively active splice variants of AR that lack the C-terminal ligandbinding domain (LBD). All current therapies that target the AR are dependent on the presence of its C-terminal LBD. However, it is the N-terminal domain (NTD) of the AR that is the “Achilles Heel” of AR activity, with activation function-1 (AF-1) being essential for AR activity regardless of androgen. Our efforts have been focused upon developing drugs to the AR NTD and have yielded EPI-001 a small molecule, sintokamide peptides, and decoys to the AR NTD. Of these, EPI-001 is the best characterized as previously shown to inhibit essential protein-protein interactions that are required for AR transcriptional activity. EPI-001 and its analogues (generally referred to as “EPI”) have great promise for clinical development based upon its unique mechanism of action, specificity, low toxicity, and cytoreductive antitumor activity. EPI blocked transcriptional activity of full-length and AR variants as well as specifically inhibited AR-dependent cell proliferation. EPI directly and specifically interacted with AF1 and did not interact with denatured AF1 as shown using in vitro binding assays. Specific and direct interaction of EPI with the endogenous AR occurred in living cells as shown using click chemistry. EPI-001 had 86% oral bioavailability, a half-life of 3.4 hours, and plasma levels at the effective concentration of 10 ug/ml were achieved with oral dosing. Consistent with excellent oral bioavailability, oral dosing of EPI inhibited VCaP tumor growth in castrated animals. VCaP human prostate cancer cells express an abundance of full-length AR as well as constitutively active AR splice variant lacking LBD. Evidence for EPI targeting the AR transcriptional program in vivo, was provided by reduced transcripts of UBE2C, CDC20, cyclinA2, and AKT1 in harvested VCaP xenografts from animals treated orally with EPI. In conclusion, EPI is an antagonist of AR NTD that blocks the activity of AR, including constitutively active AR splice variants, by a mechanism that involves direct interaction with the NTD. Oral dosing of EPI has antitumor activity in prostate cancer xenografts that express AR variant. Together these data support the clinical development of EPI for the treatment of CRPC. Funding: NIH (2R01 CA105304) and US Army Medical Research and Materiel Command Prostate Cancer Research Program (PC100761). Note: This abstract was not presented at the conference because the presenter was unable to attend. Citation Format: Marianne D. Sadar, Jae-Kyung Myung, Iain McEwan, Stephen Plymate, Raymond J. Andersen, Carmen A. Banuelos, Nasrin R. Mawji, Jun Wang, Javier Garcia Fernandez, Amy Tien, Iran Tavakoli, Yu Chi Yang, Simon Haile. Developing small-molecule inhibitors to the androgen receptor N-terminus domain for the treatment of advanced prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr B14.

Over the past decade, the treatment of advanced prostate cancer has developed significantly, and perhaps the most dramatic shift came in 2004 with the demonstration that docetaxel-based chemotherapy significantly improved overall survival in patients with castration-resistant prostate cancer. This led to a significant expansion of the role of chemotherapy in the management of prostate cancer. In addition, there is now considerable progress being made in the development of more effective antiandrogens, cytochrome P17 inhibitors, novel chemotherapy regimens, targeted therapies, and immunotherapies that can complement existing therapies and may soon become integrated into the treatment paradigm. Progress in our understanding of molecular signalling pathways that play an important role in prostate cancer has stimulated the investigation of targeted therapies, including antiangiogenic agents, bone-targeted agents, and specific inhibitors of key signalling molecules and chaperone proteins. For the most part, targeted agents are being combined with chemotherapy, similar to the approach taken in other solid tumours. Various therapeutic vaccine strategies also appear to have potential in the treatment of advanced prostate cancer. However, the development of new approaches to the treatment of prostate cancer presents many challenges that will demand collaboration and consensus building with respect to biomarkers for patient selection, clinical endpoints, and trial designs.