Japanese P2 study shows potential of combined vaccine and steroid drug in castration-resistant PCa

"Since the anti-tumour effects of peptide vaccination are driven by different mechanisms as those from ADT and chemotherapy, we may circumvent many of the pitfalls experienced with the current therapies. We believe that this treatment approach will be key in order to achieve a breakthrough as a new therapeutic option for CRPC," he said.
Prostate cancer remains the most common noncutaneous malignancy among men in the United States. In 2010, it is estimated that 220 000 men were newly diagnosed with prostate cancer and 32 050 men died of the disease. Prostate cancer is a biologically heterogeneous disease that produces variable clinical outcomes. Since the advent of prostate-specific antigen (PSA) testing, most patients diagnosed with prostate cancer have disease confined to the prostate gland (organ-confined disease). For some men, prostate cancer follows a relatively indolent clinical course that does not require immediate treatment or in some cancer cases, any treatment at all. In contrast, up to 75% of newly diagnosed patients present with potentially aggressive prostate cancers that warrant treatment. For these patients with clinically significant disease, tumor progression occurs in a well-recognized anatomical pattern. Tumors that are initially organ confined can spread to locoregional lymph nodes but more commonly disseminate hematogenously to distant organs with a striking predilection for the skeleton. Prostate cancer that progresses despite castrate levels of serum testosterone is defined as “castrate resistant”. Over the past decade, insights into the biological basis of prostate cancer development and progression have influenced our approach to treating patients with advanced disease. Although research efforts have historically focused on the prostate cancer epithelial cell to identify genetic alterations associated with malignant transformation, there is growing evidence that the host tissue microenvironment is critical for the progression from localized disease to distant metastases. For example, prostate cancer epithelial cells preferentially metastasize to bone. This is a multistep nonrandom process that involves 1) dissemination of cancer cells into the vascular system, 2) adhesion of cancer cells to the skeletal microvasculature, 3) extravasation of cancer cells into bone marrow, and 4) survival and proliferation of prostate cancer cells within the bone microenvironment. The normal bone microenvironment is composed of multiple types of stromal cells including hematopoietic cells, fibroblasts, endothelial cells, adipocytes, macrophages, osteoblasts, osteoclasts, and mesenchymal stem cells. In addition, the bone marrow microenvironment contains a soluble extracellular matrix rich in growth factors and cytokines.
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Prostate cancer is a progressive disease. Over time, the cancer cells start to become resistant to hormonal therapies that are designed to block the release and/or uptake of androgen. In the past, patients were considered to have reached the state of metastatic CRPC after failing first-line hormonal therapy and were often immediately started on chemotherapy. However, we’ve learned over the last decade or so that demonstrating resistance to one kind of hormonal therapy does not mean these patients cannot be successfully treated with a second or even third trial of hormonal manipulation. Clinical trials with 2 new oral agents have shown them to be effective in patients who have failed conventional hormonal therapy. The first is an antiandrogen, developed by Dr. Charles Sawyers, called MDV3100. An antiandrogen given in concert with gonadotropin-releasing hormone (GnRH) analogues has been the standard of care for a long time; MDV3100 is a novel antiandrogen that has a much higher binding affinity to the androgen receptor compared with other antiandrogens. So far, data show that patients who already failed treatment with a GnRH analogue in concert with bicalutamide or nilutamide respond well to MDV3100 with only minimal toxicities. We’ve seen significant declines in prostate-specific antigen (PSA) levels with this agent, and although it’s too early to determine whether it will have an effect on survival outcomes, any oral agent that provides an immediate biochemical response without significantly affecting quality of life in patients who have already failed standard hormonal therapy is very promising. The second new agent in this area of research is called abiraterone; it is being developed by Dr. Johann de Bono. Ketoconazole is an antifungal agent that is often used as a second- or third-line hormonal treatment in metastatic prostate cancer. It works at the level of the adrenal gland, which plays an important role in the manufacture of estrogen or testosterone via steroidogenesis. Although the drug can be effective in some patients, it causes significant nausea, vomiting, rash, and fatigue. Abiraterone is an oral medication that also targets steroidogenesis by the adrenal glands, but by a different pathway. Dr. de Bono and colleagues have seen some dramatic declines in PSA as well as on radiographic scans in patients who have failed prior hormonal therapy, including those who failed ketoconazole and/or docetaxel, but with considerably lower rates of toxicity compared with ketoconazole. There is great interest in moving this agent into phase 3 trials, especially considering its ability to elicit a response in patients who have already failed multiple hormonal therapies. ### Susan F. Slovin, MD, PhD
Ivanka Moerkerken .(JavaScript must be enabled to view this email address) 31-026-389-0680 European Association of Urology

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