Agents For Castration-resistant Prostate Cancer Research Articles

Androgen deprivation therapy increases the sensitivity of human prostate carcinoma cells to T cell-mediated lysis through an androgen receptor dependent mechanism

Despite recent advances in diagnosis and therapy, prostate cancer remains the most frequently diagnosed non-skin cancer in the United States and the third leading cause of cancer deaths. Failure of chemotherapies and hormone-deprivation therapies is the major cause of death in patients with castration-resistant prostate cancer (CRPC). Currently, the androgen inhibitors Enzalutamide and Abiraterone are approved for treatment of metastatic CRPC. Enzalutamide is a second-generation androgen antagonist with no agonist activity. Abiraterone is a cytochrome P450 inhibitor that blocks adrenal and intratumoral androgen production. Here we show for the first time that both Enzalutamide and Abiraterone induce immunogenic modulation in human prostate tumor cells, rendering them more sensitive to T cell-mediated lysis, and that these immunomodulatory activities are androgen receptor (AR)-dependent. In studies reported here, exposure in vitro and in vivo of human prostate carcinoma cells to Enzalutamide significantly down-regulated the anti-apoptotic NAIP gene. Functional analysis revealed that NAIP played a critical role in inducing CTL sensitivity. Amplification of AR is a major mechanism of resistance to androgen-deprivation therapy (ADT). Here, we show that Enzalutamide enhances sensitivity to immune-mediated killing of prostate tumor cells that overexpress AR. The immunomodulatory properties of Enzalutamide and Abiraterone provide a rationale for their use in combination with immunotherapeutic agents in CRPC, particularly for patients with minimal response to Enzalutamide or Abiraterone alone, or for patients who have developed resistance to ADT.

Treatment sequencing patterns of novel agents in patients with prostate cancer.

296 Background: The National Comprehensive Cancer Network (NCCN) guidelines recommend chemotherapy, immunotherapy or anti-androgen therapies for the treatment of advanced castration-resistant prostate cancer (CRPC). This study evaluated treatment sequencing of recently approved agents for CRPC [abiraterone (ABI), enzalutamide (ENZ), docetaxel (DOC), cabazitaxel (CAB), or sipuleucel-T (SIP)] among men with PC. Methods: This retrospective, observational study evaluated adult men with PC in the MarketScan Oncology EMR database, which includes data from over 900 contributing oncologists from over 100 community practices. Inclusion required a diagnosis of PC (ICD-9-CM diagnosis code 185) from 07/01/2011-03/31/2014, no treatment with ABI, ENZ, DOC, CAB, or SIP prior to 09/01/2012, no other primary cancers, and six months of medical record history prior to index date. The index date was the date of first prescription of ABI, ENZ, DOC, CAB or SIP between 09/01/2012 and 03/31/2014. First-, second- and subsequent-line treatments were evaluated prior to end of data availability or end of study. Results: In total, 812 PC patients were identified; mean age was 75 years and 68% had recorded metastasis. A single line of therapy was observed for 544 patients (67%). ABI was the most common first-line treatment (443; 55%), followed by DOC (167; 21%), ENZ (113; 14%), SIP (82; 10%) and CAB (7; 1%). A second line of therapy occurred in 268 patients (33%) and third line in 8%. The table below describes first-line and the two most common second-line therapies for those moving on to second-line. Conclusions: Of the five agents of interest, ABI was the most commonly prescribed first-line medication for advanced PC in this patient cohort. First-line DOC was more common than first-line CAB or SIP. Further studies with longer follow-up and other treatments are warranted. [Table: see text]

Prostate cancer in Asia: A collaborative report

The incidence of prostate cancer (PCa) within Asian population used to be much lower than in the Western population; however, in recent years the incidence and mortality rate of PCa in some Asian countries have grown rapidly. This collaborative report summarized the latest epidemiology information, risk factors, and racial differences in PCa diagnosis, current status and new trends in surgery management and novel agents for castration-resistant prostate cancer. We believe such information would be helpful in clinical decision making for urologists and oncologists, health-care ministries and medical researchers.

Androgen deprivation therapy sensitizes prostate cancer cells to T-cell killing through androgen receptor dependent modulation of the apoptotic pathway.

Despite recent advances in diagnosis and management, prostrate cancer remains the second most common cause of death from cancer in American men, after lung cancer. Failure of chemotherapies and hormone-deprivation therapies is the major cause of death in patients with castration-resistant prostate cancer (CRPC). Currently, the androgen inhibitors enzalutamide and abiraterone are approved for treatment of metastatic CRPC. Here we show for the first time that both enzalutamide and abiraterone render prostate tumor cells more sensitive to T cell-mediated lysis through immunogenic modulation, and that these immunomodulatory activities are androgen receptor (AR)-dependent. In studies reported here, the NAIP gene was significantly down-regulated in human prostate tumor cells treated in vitro and in vivo with enzalutamide. Functional analysis revealed that NAIP played a critical role in inducing CTL sensitivity. Amplification of AR is a major mechanism of resistance to androgen-deprivation therapy (ADT). Here, we show that enzalutamide enhances sensitivity to immune-mediated killing of prostate tumor cells that overexpress AR. The immunomodulatory properties of enzalutamide and abiraterone provide a rationale for their use in combination with immunotherapeutic agents in CRPC, especially for patients with minimal response to enzalutamide or abiraterone alone, or for patients who have developed resistance to ADT.

A phase 2 study of intravenous panobinostat in patients with castration-resistant prostate cancer

Panobinostat, a pan-deacetylase inhibitor, increases acetylation of proteins associated with growth and survival of malignant cells. This phase 2 study evaluated the efficacy of intravenous (IV) panobinostat in patients with castration-resistant prostate cancer (CRPC) who had previously received chemotherapy. The primary end point was 24-week progression-free survival. Secondary end points included safety, tolerability, and the proportion of patients with a prostate-specific antigen (PSA) decline. IV panobinostat (20mg/m(2)) was administered to patients on days 1 and 8 of a 21-day cycle. Tumor response was assessed by imaging every 12weeks (4 cycles) according to modified response evaluation criteria in solid tumors (Scher et al. in Clin Cancer Res 11:5223-5232, 23), and PSA response was defined as a 50% decrease from baseline maintained for ≥4weeks. Safety monitoring was routinely performed and included electrocardiogram monitoring. Of 35 enrolled patients, four (11.4%) were alive without progression of disease at 24weeks. PSA was evaluated in 34 (97.1%) patients: five (14.3%) patients demonstrated a decrease in PSA but none ≥50%; one patient (2.9%) had carcinoembryonic antigen as a marker of his prostate cancer, which declined by 43%. Toxicities regardless of relationship to panobinostat included fatigue (62.9%), thrombocytopenia (45.7%), nausea (51.4%), and decreased appetite (37.1%). Despite promising preclinical data and scientific rationale, treatment with IV panobinostat did not show a sufficient level of clinical activity to pursue further investigation as a single agent in CRPC.

Novel immunotherapeutic agents for castration-resistant prostate cancer: update from clinical trials

Immunotherapy has been recognized as a viable therapeutic approach since the regulatory approval of the autologous cell-based vaccine sipuleucel-T in 2010. Emerging preclinical evidence and early-stage clinical studies point to a potential synergy between currently available immunotherapeutic agents and standard anticancer therapies such as radiation and chemotherapy. Several other immunotherapeutic platforms, such as immune checkpoint inhibitors and DNA- and peptide-based vaccines are also in development and clinical testing. Based on the logistics of their production, these platforms are broadly categorized as patient-specific or off-the-shelf. Together, they are beginning to transform the therapeutic landscape in prostate cancer. This article reviews the rationale behind immunotherapeutic approaches in castration-resistant prostate cancer, plus the latest available clinical data.

Abstract 1741: Mitotic catastrophe and inhibition of growth of Castration Resistant Prostate Cancers by a dietary agent Withaferin-A.

Abstract Cell cycle deregulation has been strongly associated with the pathogenesis of prostate cancer. It has been well documented that an increased expression of cell cycle regulatory proteins (cyclin D1-25%, cyclin A-35% and cyclin B-75%) have been reported in castration resistant prostate cancer (CRPC) cells, when compared to normal prostate tissue. There are several cell cycle regulators undergoing clinical trials targeting either G0/G1 or G2/M phase of cell cycle to inhibit the growth of many cancers including prostate cancer. We previously published that Withaferin-A (WA); a natural compound effectively suppresses CRPC growth both in vitro and in vivo. Hence, in this study we intend to determine the cell-cycle regulatory potential of this agent on CRPC cells. WA caused irreversible G2/M arrest in both CRPC cell lines (PC-3 and C4-2B) till 72 hours . Phosphorylation of cdc2 by Wee1 and Myt1 is an important step to maintain an inactive state of cdc2 that lead to G2/M cell cycle arrest. Additionally decreased levels of phosphorylated Wee-1 and Myt1 followed by increase in the phosphorylation status of cdc2 (Tyr15 and Thr14) supported the G2/M phase of cell cycle arrest in both CRPC cell lines. Further checkpoint kinase assay showed increased activity in WA treated CRPC cells suggesting activation of CDC25C that activates cyclinB/cdc2 complex .We also observed down regulation of several cyclin family proteins in both CRPC cells. Altogether, these results conclude d that WA inhibits CRPC cell growth by induction of G2/M cell cycle arrest, highlighting the potential of WA could be a therapeutic agent for CRPC. Currently, we are investigating the effect of WA on cell cycle markers using both xenograft and TRAMP models. The outcome of our study may enable bringing WA to the mainstream of medicine for prevention and/or therapy for CRPC. Citation Format: Aditi Shirish Vadodkar, Suman Suman, Ram Vinod Roy, Chendil Damodaran. Mitotic catastrophe and inhibition of growth of Castration Resistant Prostate Cancers by a dietary agent Withaferin-A. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1741. doi:10.1158/1538-7445.AM2013-1741

922P - A Phase II Study of SB939 in Patients (PTS) with Castration Resistant Prostate Cancer (CRPC)

ABSTRACT Background SB939 is a potent oral inhibitor of class 1, 2, and 4 histone deacetylases (HDACs). These 3 HDAC classes are highly expressed in CRPC and associated with poor clinical outcomes. HDAC inhibition abrogates androgen receptor signaling via inactivation of HSP90, and may have particular relevance in prostate cancer with the TMPRSS2-ERG (T2-E) fusion. Methods Pts with locally recurrent or metastatic CRPC received SB939 60mg every other day 3 times per week x 3 weeks on a 28-day cycle. Primary endpoints were PSA response rate (RR) (>50% decline from baseline for > 4 weeks) and progression-free survival (PFS). Secondary endpoints included objective response rate and duration; overall survival; circulating tumor cell (CTC) enumeration at baseline, 6 and 12 weeks; T2-E fusion analysis; correlative analysis of archival tissue; and safety. In a 2-stage design, a planned maximum of 29 response evaluable patients were to be enrolled. Results 32 pts were enrolled and have completed study treatment. Median age was 70; 88% of pts had received no prior chemotherapy; and ECOG performance status was 0/1 in 44%/56%. Bone/lymph node/visceral metastases were present in 91%/75%/12%. The median number of SB939 cycles administered was 3 (range 1-8). Adverse events were generally grade 1-2, with 5 pts experiencing one or more grade 3 events (fatigue (5), vomiting (1), dyspnea (1)). One pt died due to myocardial infarction. A confirmed PSA response was noted in 2 pts (6%), lasting 3.0 and 9.4 mo. In 16 pts with measurable disease, there were no objective responses, 7 pts had stable disease lasting 1.6 to 8.0 months. CTC response (from ≥5 at baseline to 5 at 6 weeks correlated with PSA progression. Correlative studies to evaluate T2-E from whole blood as well as T2-E fusion and PTEN deletion status on archival tissue are ongoing. Conclusion SB939 is tolerable at the dose/schedule given, but does not merit further study as a single agent in CRPC based on PSA RR. Activity was observed in terms of CTC declines however. Study of SB939 with cytotoxic or AR targeted therapies may be warranted. Supported by grants from the Canadian Cancer Society and the Ontario Institute for Cancer Research. Disclosure All authors have declared no conflicts of interest.

Novel and bone-targeted agents for CRPC

Clearly, no neoplasm other than prostate cancer has benefited from so many breakthroughs since the beginning of this decade: the past two years can be considered exceptional due to the number of emerging agents against castration-resistant prostate cancer (CRPC), which have demonstrated positive outcomes in phase III trials. Until 2010, docetaxel (Taxotere) was the only agent capable of improving survival in patients with metastatic CRPC. Since then, positive results from phase III trials have been reported for sipuleucel-T, cabazitaxel, denosumab, abiraterone, radium-223, and enzalutamide, while other promising agents including notably orteronel, ipilimumab and cabozantinib are currently under study. Taken together, the incorporation of these agents in the routine management of patients with CRPC is likely to expand their median life expectancy, which was only ∼1 year until the early 2000, to >30 months in the near future. The availability of these agents will lead to new challenges and questions, such as: Can our societies afford the costs? Should we use these agents sequentially or in combination with an incremental benefit? Can we personalise treatment based on the biology of the individual's disease? How will we develop new active compounds in the context where a half dozen approved agents may confound their potential overall survival effect?

The 7th American Urological Association and the Japanese Urological Association International Affiliate Society Meeting

The 7th American Urological Association and the Japanese Urological Association International Affiliate Society Meeting

A multi-centre randomised phase III trial of Dexamethasone vs Dexamethasone and diethylstilbestrol in castration-resistant prostate cancer: immediate vs deferred Diethylstilbestrol

Background:The role of further hormone therapy in castration-resistant prostate cancer (CRPC) remains unclear. We performed a multi-centre randomised phase III study comparing the use of Dexamethasone, Aspirin, and immediate addition of Diethylstilbestrol (DAiS) vs Dexamethasone, Aspirin, and deferred (until disease progression) addition of Diethylstilbestrol (DAdS).Methods:From 2001 to 2008, 270 men with chemotherapy-naive CRPC were randomly assigned, in a 1 : 1 ratio, to receive either DAiS or DAdS. They were stratified for performance status, presence of bone metastases, and previous normalisation of prostate-specific antigen (PSA) to androgen deprivation. The study end points were the proportion of patients achieving a 50% PSA response, progression-free survival (PFS), overall survival, and quality of life. Intention-to-treat analysis was carried out. The effect of treatment was studied first by Kaplan–Meier curves and log-rank test, and finally through multivariable stratified Cox's proportional hazards model adjusting for the effects of possible baseline prognostic factors. Quality of life was analysed using multivariate analysis of variance.Results:At study entry, the median age was 76 years (inter-quartile range: 70–80 years), the median PSA was 79 ng ml−1, and 76% of the cohort had metastatic disease. The response rates for DAiS (68%) and DAdS (64%) were not significantly different (P=0.49). Similar to the response rate, neither the PFS (median=8.1 months for both arms) nor the overall survival (19.4 vs 18.8 months) differed significantly between the DAiS and DAdS groups (P>0.20). However, the response rate for the DAiS (68%) was significantly higher than the response rate of DA (before adding Diethylstilbestrol) (50%) (P=0.002). Similarly, the median time to progression for DAiS (8.6 months) was significantly longer than that of DA (4.5 months) (P<0.001). Multivariable analysis showed that patients with previous haemoglobin ⩾11 g dl−1 decreased the risk of death significantly (hazard ratio: 0.44, 95% CI: 0.25–0.77). Patients treated with previous anti-androgens alone had more than 5 times more risk of death compared with patients treated with gonadorelin analogues throughout their castration-sensitive phase. Treatment sequencing did not affect the quality of life but pre-treatment performance status did. The incidence of veno–thromboembolic events was 22% (n=28) in DAiS and 11% (n=14) in the DA arm (P=0.02). Painful gynaecomastia occurred in only 1% on DA, whereas in 40% on DAiS (P=0.001).Conclusion:Dexamethasone and immediate Diethylstilbestrol resulted in neither higher PSA response rate nor higher PFS compared with Dexamethasone with deferred Diethylstilbestrol. There was no suggestion of significantly improved overall survival or quality of life. Given the significantly higher toxicity of Diethylstilbestrol, deferring Diethylstilbestrol until failure of Dexamethasone is the preferred strategy when using these agents in CRPC.

Castration-Resistant Prostate Cancer

Until very recently, docetaxel was the only approved agent in castration-resistant prostate cancer (CRPC) and other effective therapeutic options are urgently needed. In recent years, several new agents with promising activity and a favourable toxicity profile have been developed and clinically investigated in the fields of hormonal, cytotoxic, targeted and immune therapy. In particular, recent results from two large phase III trials of sipuleucel-T and cabazitaxel show that these two agents significantly prolong overall survival in CRPC. Indeed, sipuleucel-T has recently been approved by the US FDA for the treatment of CRPC. Many other pharmaceuticals, which are presented in this review, have been investigated recently or are being investigated in phase III trials and might prove to be effective in the future. Reviewed articles are discussed in light of the innovations in study design brought by the Prostate Cancer Clinical Trials Working Group (PCWG2), which updated the Prostate-Specific Antigen Working Group (PCWG1) guidelines, in order to allow better identification of potentially active drugs in clinical trials.

Recent Progress and Pitfalls in Testing Novel Agents in Castration-Resistant Prostate Cancer

Despite docetaxel’s approval as systemic therapy for metastatic castration-resistant prostate cancer (CRPC) and its adoption as the standard of care for CRPC patients, median progression-free survival remains about 6 mo, and overall survival remains <2 yr. Multiple efforts have been directed at improving its efficacy, as extensively reviewed by Chi et al [1]. In current drug development for CRPC, docetaxel is either a comparator or a backbone on which to build. Another development strategy is to test new agents in the docetaxel pretreated or refractory patient, for which there are no standard options. Recent insights into novel pathways involved in PCa (prostate cancer) progression have allowed significant progress to be made in the understanding of the biology of CRPC. Advances in immunology, angiogenesis, apoptosis, and bone metastasis research have all significantly contributed to the field. This has led to the development of many novel agents that show promise in the management of patients with advanced PCa. Some of these agents appear to have significant activity as single agents; others appear to be best deployed in combination with chemotherapy. Combining cytotoxic chemotherapy with the newer targeted agents raises the appealing possibility of parallel or possibly complementary therapeutic effects. Unfortunately, none of the newer treatment modalities or the addition of one of these modalities to docetaxel has yet been shown to be more effective than standard docetaxel treatment. Some very promising new agents, such as the anti-BCL2 trial mentioned in the Chi et al review [1], have failed to achieve their goal. As molecularly targeted agents enter the clinical arena, well-designed clinical trials are imperative. The assessment