Laurie Barclay, MD, March 2005

Prostate cancer is the second most common cancer (after skin cancer) in American men. According to the American Cancer Society, about 232,090 new cases of prostate cancer will be diagnosed in the US during 2005. Although approximately one in every six men will be diagnosed with prostate cancer during his lifetime, only one man in 33 will die from this disease, or about 30,350 deaths in the US during 2005.

More than 99% of prostate cancers are adenocarcinomas originating from the glandular cells secreting seminal fluid. Prostate cancer may develop from prostatic intraepithelial neoplasia (PIN), which may first be evident in men in their 20s, and which may affect almost 50% of men by their fifth decade. High-grade PIN detected on prostate biopsy conveys a 30% to 50% likelihood of cancer also being present.

Growth of most prostate cancers is typically slow, with about 86% of all prostate cancers detected in the local and regional stages, and many are found incidentally at autopsy. Five-year survival is about 99%, 10-year survival 92%, and 15-year survival 61%.

Risk factors for prostate cancer include advancing age, with more than 70% of all prostate cancers diagnosed in men over 65 years of age; African-American race, North American and northwestern European nationality, family history, diet high in red meat or high-fat dairy products, low intake of fruits and vegetables, sedentary lifestyle, obesity, and possibly vasectomy in men younger than age 35. Gene mutations predisposing to prostate cancer may include HPC1, HPC2 (ELAC2), HPCX, and CAPB. High levels of androgens or insulin-like growth factor-1 (IGF-1) may increase prostate cancer risk in some men.

Early prostate cancer is usually asymptomatic, and is typically detected by digital rectal examination and prostate-specific antigen (PSA) blood test, with confirmation by biopsy. Advanced prostate cancers may cause urinary frequency, decreased stream, blood in the urine, or impotence, as well as bony metastases.

Treatment options depend on stage. Early cancers may respond to radiation therapy by external beam or brachytherapy, or radical prostatectomy. For more advanced cancers, treatment options also include hormone therapy, cryosurgery, and chemotherapy. Recent combination therapies including docetaxel have been promising in boosting survival by several months, as well as improving quality of life. Bisphosphonates appear to reduce pain and slow cancer growth of skeletal metastases.

CenterWatch has identified a pipeline of 53 new agents in various stages of development for prostate cancer, including vaccines, monoclonal antibodies, and hormonal therapies.

Abbott Laboratories has submitted a new drug application (NDA) for Xinlay (ABT-627, atrasentan), an oral, once–daily, non–hormonal, non–chemotherapy agent. This selective endothelin A receptor antagonist (SERA) inhibits the activity of endothelin protein thought to be involved in stimulating the spread of cancer cells.

Barr Laboratories is in Phase III development of CyPat (cyproterone acetate), a steroid inhibiting the action of testosterone needed to sustain most prostate cancers. CyPat’s mechanism of action is to bind surface receptors on the prostate cancer cells, preventing the attachment of testosterone. It may be given in combination with injections of other hormonal therapies such as goserelin, buserelin, triptorelin or leuprorelin, which block production of leuteinising hormone that normally stimulates testosterone production.

GVAX prostate cancer vaccine, in Phase III development by Cell Genesys, uses modified tumor cells to secrete granulocyte-macrophage colony stimulating factor (GM-CSF), a hormone which stimulates the body's immune response to vaccines. This non patient-specific vaccine is irradiated for safety, and can be used “off-the-shelf” to stimulate a systemic immune response against prostate cancer, destroying prostate cancer cells still present after surgery, hormone treatment, or radiation. In trials to date for advanced-stage, hormone-refractory prostate cancer, GVAX has had a favorable safety profile.

A different type of vaccine is Gonadimmune (GnRH pharmaccine), in Phase II testing by Aphton for hormone- failed or hormone-resistant prostate cancer. This anti- gonadotropin releasing hormone (GnRH) immunogen neutralizes the GnRH hormone.

Pentrix is Australian Cancer Technology’s version of a novel vaccine for prostate cancer, now in Phase II development. This p53-gene-based vaccine induces an antibody cascade, which triggers an immune response against tumor cells with a mutated p53 gene (present in nearly half of all cancer patients).

Another investigational immunotherapy is Provenge (APC8015), in Phase III testing by Dendreon. This dendritic, ex vivo cell therapy stimulates the immune system to attack cells expressing prostatic acid phosphatase (PAP), a protein expressed on about 95% of prostate cancer cells. Using Antigen Delivery Cassette technology, Provenge delivers small pieces of the PAP protein to a patient's antigen presenting cells (APCs). In turn, the APCs activate other immune cells to find and destroy PAP-containing prostate cancer cells.

Myriad Genetics is in Phase III testing of Flurizan MPC-7869, the R-enantiomer of the nonsteroidal anti- inflammatory drug (NSAID) flurbiprofen. Unlike other NSAIDs, Flurizan does not inhibit cyclooxygenase enzymes (COX-1 and COX-2), and it is therefore devoid of severe gastrointestinal adverse effects. It modulates signal transduction and transcription activation pathways involving nuclear factor kappa B (NFkB), which is a principal transcription factor regulating cell growth and death, as well as inflammation. In animal models, Flurizan is safe and effective.

Satraplatin (JM-216) is a third generation oral platinum drug, in Phase III development by Spectrum Pharmaceuticals for use in hormone refractory prostate cancer. This chemotherapeutic agent binds to DNA, causing disruption of cell division and ultimately cell death. In preclinical models, anti-tumor activity is comparable to that of cisplatin and carboplatin with less cross-resistance. This compound also appears to enhance the antitumor activity of ionizing radiation.

A novel immunological approach is CG-7870, an oncolytic virus designed to target and selectively destroy cancer cells while sparing normal cells. Cell Genesys is in Phase II testing of this virus therapy in early-stage prostate cancer, both by intratumoral and by intravenous routes of administration. Cell Genesys hopes that CG7870 will be a less toxic alternative to radiation seed therapy in newly diagnosed, intermediate to high-risk prostate cancer patients.

Panzem (2-methoxyestradiol), in Phase II testing by EntreMed, is a natural metabolite of estrogen with multiple mechanisms of action targeting prostate cancer. In addition to inhibiting angiogenesis, Panzem disrupts microtubule formation, downregulates hypoxia inducible factor one-alpha (HIF-1a), inhibits bone resorbing osteoclasts, and induces apoptosis, or programmed cell death. This compound has activity in cell lines resistant to various chemotherapeutic agents.

Yet another approach to selective targeting of cancer cells is Genasense (oblimersen G-3139), in Phase II development by Genta and Sanofi-Aventis. In preclinical studies, this antisense oligonucleotide targeting Bcl-2 has been shown to directly kill certain types of cancer cells, and Genta is developing this agent to enhance the effectiveness of standard anticancer therapy.

Another antisense compound is GTI-2501, in Phase II development by Lorus Therapeutics. This drug, which contains antisense sequences directed against R1 and R2 components or ribonucleotide reductase, is being tested in combination with GTI-2501 and docetaxel in patients with Hormone Refractory Prostate Cancer (HRPC).

Gloucester Pharmaceuticals/NCI is in Phase II testing of depsipeptide (FK-228, FR-901228), an inhibitor of histone deacetylase (HDAC) crucial to regulation of gene expression. This compound therefore causes cell cycle arrest, differentiation and apoptotic cell death.

Acapodene (toremifine,GTx-006) is a nonsteroidal selective estrogen receptor modulator (SERM). Based on encouraging results in Phase II testing, GTx began on 1/26/2005 a Phase III, placebo-controlled trial for the prevention of prostate cancer in high risk men with high grade prostatic intraepithelial neoplasia.

MDX-070, in Phase II development by Medarex, is a fully human antibody targeting prostate specific membrane antigen PSMA, a cell surface marker expressed on cancer cells. Based on Phase I clinical data showing a favorable safety and tolerability profile. Medarex has started a multi-dose, dose-escalation Phase II trial of MDX-070 in men with hormone refractory prostate cancer.

Vitaxin (LM-609), an investigational monoclonal antibody blocking the alpha-v/beta-3 integrin receptor (vitronectin), is in Phase II testing by MedImmune. By inhibiting angiogenesis, Vitaxin blocks the growth and spread of solid tumors, at least in animal models. The Phase II trial of Vitaxin in combination with chemotherapy is a randomized, open label, two-arm study enrolling approximately 110 patients with androgen-independent prostate cancer and bone metastases.

Based on the drugs reviewed by CenterWatch, common themes unifying the approaches to prostate cancer involve hormonal manipulation or immunological strategies enhancing the body's natural defense against foreign tumor antigens. The slow course, frequent detection in early stages, and identification of an apparent precursor to prostate cancer offer the opportunity for early intervention in this widespread, sometimes fatal disease.