A New Drug Application (NDA) has been submitted by Centocor Ortho Biotech Inc to the U.S. Food and Drug Administration (FDA) for the investigational drug abiraterone acetate administered with prednisone for the treatment of metastatic advanced prostate cancer in patients who have received prior chemotherapy containing a taxane has been submitted At the same time Janssen-Cilag International NV filed a marketing authorization application (MAA) with the European Medicines Agency (EMA) for abiraterone acetate.

Both applications follow completion of a Phase III, randomized, double-blind, placebo-controlled clinical study (COU-AA-301), which evaluated overall survival and tolerability in patients with metastatic advanced prostate cancer treated with abiraterone acetate plus prednisone compared to treatment with placebo plus prednisone.

Prostate Cancer Incidence
Prostate cancer occurs when cancer cells form in the tissues of the prostate, a gland located around the urethra (under the bladder) in men that produces part of the seminal fluid. In some cases, cancer of the prostate can grow slowly compared with other cancers. However, depending on factors including characteristics specific to the patient and the tumor, prostate cancer can also grow very quickly and spread to other places such as the lymph nodes, bones or other parts of the body.

Prostate cancer is considered to be advanced once it metastases beyond the prostate and when resistance emerges to conventional hormonal therapies. Metastatic advanced prostate cancer is also referred to as castration-resistant prostate cancer, or CRPC, when disease progresses despite conventional hormone therapies or appearance of new metastases.
Prostate cancer occurs when cancer cells form in the tissues of the prostate. The prostate is a gland located around the urethra (under the bladder) in men that produces part of the seminal fluid. In some cases, cancer of the prostate can grow slowly compared with other cancers. However, depending on factors including characteristics specific to the patient and the tumor, prostate cancer can also grow very quickly and spread widely.

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Port Worthy

Prostate cancer is the second most common type of cancer in American men. One in six men will be diagnosed with prostate cancer, and in the United States in 2009, nearly 200,000 men were diagnosed with the disease. In 2010, an estimated 217,000 new cases of prostate cancer and 32,000 related deaths are expected to be reported in the United States.

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In the United Kingdom it prostate cancer is the most common male cancer with more than 35,000 new cases diagnosed annually. Around 10,000 men die of the disease every year, almost all of them from its castration-resistant form.

The disease is also the most common cancer among men in Canada (excluding non-melanoma skin cancer) where it is estimated that approximately 24,600 men will be diagnosed with prostate cancer in 2010 and anestimated 4,300 will die of it. One in seven Canadian men will develop prostate cancer during his lifetime.

Globally, the incidence rate of prostate cancer has been increasing since 1980, likely due to an increased rate of early detection and the aging population since the chances of developing prostate cancer increases with age. Globally, prostate cancer is also the second most frequently diagnosed cancer in men and the fifth most common cancer overall. Around the world more than 900,000 new cases of prostate cancer were diagnosed in 2008. While 90% of prostate cancer cases are curable if detected and treated early. more than 258,000 men died from the disease, a 16 per cent increase from 2002. Fortunately, death rates have been declining since the mid-1990s, which is likely due to early detection, better treatment or both.

Abiraterone in castration-resistant prostate cancer
Abiraterone acetate is a novel, targeted, investigational oral androgen biosynthesis inhibitor being developed for the treatment of metastatic advanced prostate cancer that has developed resistance to conventional hormonal therapies. This is also known as castration-resistant prostate cancer (CRPC). These prostate cancers, also known as hormone-resistant or hormone-refractory prostate cancer, do not respond to androgendeprivation or treatment with antiandrogens. It is believed that abiraterone acetate blocks the formation of testosterone by inhibiting CYP17A1 (CYP450c17), an enzyme also known as 17?-hydroxylase/17,20 lyase. This enzyme is involved in the formation of DHEA and androstenedione, which may ultimately be metabolized into testosterone.

This drug was initially discovered at the Institute of Cancer Research in London. Rights for commercialization of the drug were assigned to BTG plc, a UK company that manages commercialization activity in pharmaceuticals. BTG licensed the drug candidate to Cougar Biotechnology, Inc. which began development of the commercial product. In 2009, Cougar was acquired by Johnson & Johnson. Ortho Biotech Oncology Research & Development, Unit of Cougar is currently conducting clinical trials with abiraterone.

The first clinical study with abiraterone acetate was conducted by doctors of the Royal Marsden Hospital in London in patients who had not received previous chemotherapy. These early results showed that abiraterone acetate induced decline in prostate specific antigen (PSA) in up to 70% of patients as well as radiological shrinkage of tumors, symptom improvement, normalization of lactate dehydrogenase.

A Phase III trial in subjects previously treated with docetaxel started in 2008. A placebo-controlled double-blind randomized phase III clinical trial in patients with castration-refractory prostate cancer who are chemotherapy-naive opened to accrual in April 2009 was conducted in 147 centers in 13 countries including 12 centers in Canada. Patients with metastatic advanced prostate cancer previously treated with docetaxel (N=1,195) were randomly assigned 2:1 to receive abiraterone acetate (1000 mg once daily) plus prednisone/prednisolone (5 mg twice daily) (N = 797), or placebo plus prednisone/prednisolone (N = 398). The primary endpoint was overall survival.

Statistically significant improvement ? unblinding recommend
In September 2010, an independent panel of the Data Monitoring Committee found that a pre-specified interim analysis of the trial date demonstrated a statistically significant improvement in median overall survival and an acceptable safety profile. Based on these interim results the committee found it unacceptable to keep half the trial participants on placebo and recommended unblinding to allow all participating patients to begin receiving abiraterone acetate. At the same time of the recommendation and unblinding of the trial, J&J was granted permission make abiraterone available to some prostate cancer patients notparticipating in the trialbefore the FDA approves the drug.

Treatment with abiraterone acetate resulted in a 35% reduction in the risk of death (HR=0.65; 95 per cent CI: 0.54, 0.77; p<0.0001) and a 36% increase in median survival (14.8 months vs. 10.9 months) compared with placebo.

Patients who received abiraterone acetate and low dose prednisone/prednisolone also showed significant improvements in secondary study endpoints when compared to the prednisone/prednisolone plus placebo group: time to PSA progression (TTPP) [median 10.2 months for abiraterone acetate vs. 6.6 months for placebo, HR=0.58 (95% CI: 0.46, 0.73); p<0.0001] and an increase in radiographic progression free survival (rPFS) [median 5.6 months for abiraterone acetate vs. 3.6 months for placebo, HR=0.67 (95% CI: 0.58, 0.78); p<0.0001]. Total PSA response, defined as greater than or equal to a 50 per cent decrease from baseline, was achieved in 38% of patients treated
with abiraterone acetate vs. 10% in the prednisone/prednisolone plus placebo group [p<0.0001].

Patients in the abiraterone acetate group experienced more mineralocorticoid-related adverse events than those in the prednisone/prednisolone plus placebo group. The most frequent adverse events were fluid retention (30.5% vs. 22.3%) and hypokalemia (17.1% vs. 8.4%). Grade 3/4 hypokalemia and hypertension were more frequent in the abiraterone acetate arm than in the placebo arm (3.8% vs. 0.8% and 1.3% vs. 0.3%, respectively). Liver function test abnormalities were observed in 10.4% of abiraterone acetate treated patients compared to 8.1% in the prednisone/prednisolone plus placebo group. Cardiac disorders were observed in 12.5% of abiraterone acetate patients vs. 9.4% of patients who received placebo. Mechanism-based adverse events were amenable to medical management and distinct from adverse events commonly associated with cytotoxic chemotherapy.

?Abiraterone has the potential to meet a significant unmet need so this news will be incredibly important to prostate cancer patients and their families,” said Johann S. de Bono, MD, FRCP, MSc, PhD, The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, one of the lead COU-AA-301 investigators. ?We are very pleased with the definitive results of this rigorous study, which show that abiraterone acetate may extend survival for men with metastatic advanced prostate cancer that progressed after treatment with docetaxel.?

Data from the study was presented at the 35th Annual European Society for Medical Oncology (ESMO) Congress in October 2010. Additional ongoing Phase I/II studies funded by Cancer Research UK, are evaluating abiraterone acetate in women with advanced breats cancer.

Regulatory submissions
“These regulatory file submissions are an important milestone for men with metastatic advanced prostate cancer and for our company,” said William N. Hait, M.D., Ph.D., Global Therapeutic Head, Oncology, Johnson & Johnson Pharmaceutical Research & Development, LLC. “We believe that we can develop important therapies to treat devastating diseases by focusing on the tumor microenvironment. Abiraterone acetate is a key part of this strategy, and we look forward to working with health authorities to provide a new therapeutic option for metastatic advanced prostate cancer patients.”

If approved, abiraterone acetate will be commercialized and distributed by Centocor Ortho Biotech Inc. in the U.S. and by Janssen Pharmaceutical Companies in all other countries around the world.

Photo Johann de Bono: ? The Royal Marsden 2010.

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