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Prostrate Cancer in BRIC Countries

Promising Pipelines

The prostate cancer market has a high unmet need in terms of safe and effective medicines, but a number of future therapies look set to change the therapeutic landscape, particularly in BRIC countries.

Prostate cancer is the second most common cancer in men by incidence in the population and is the sixth leading cause of cancer-related death in men globally. It is more common in developed countries, with approximately 75 per cent of new cases occurring in developed nations. In Brazil, Russia, India and China (BRIC) this cancer is not very common – accounting for only 12 per cent of the total incidence and 19 per cent of the total number of deaths in a year (1). In BRIC countries, prostate cancer is the 10th most common cancer in terms of incidence.

This cancer generally affects men aged 65 and above; more than 77 per cent of new prostate cancer cases in BRIC countries were in this age range in 2010. Prostate cancer affects the prostate gland cells and can spread to other cells in advanced stages.More than 65 per cent of the cases of prostate cancer progress very slowly and approximately 35 per cent are considered aggressive.

The diagnosis of prostate cancer is made with the help of various procedures and tools such as digital rectal examination (DRE) and the prostate specific antigen (PSA) test.These tests only provide an indication of the disease and are insufficient for making confirmatory diagnosis.The confirmatory diagnosis is made only through biopsy.The treatment of the disease currently involves (2):

  • Close monitoring of patients in the early stages of the disease with no signs of disease progression, following its progression regularly using followup blood tests, DRE and biopsies. If these tests indicate that the cancer is progressing, physicians advise other treatment options such as radiation, surgery and hormone therapy
  • Radiation therapy – generally used to treat localised and locally advanced (stages 1, 2 and 3) cancers, although the benefits accrued are debatable. Some radiation, such as x-rays, cannot be directed effectively and therefore can harm the healthy cells as well as the cancerous ones
  • Surgery – is a key treatment option in the early stages, it involves the removal of cancerous cells. A detailed examination of the patient is necessary before surgery is advised and it is preferred in patients who have good general health. Also, it is very important to ensure that the cancer has not yet spread to the lymph nodes in order to improve the success rates of the surgery. Surgery to remove the prostate gland, referred to as a radical prostatectomy, can be performed using different methods: open radical retropubic prostatectomy; radical perineal prostatectomy; laparoscopic prostatectomy; and robotassisted laparoscopy
  • Hormone therapy – an important option for patients with stage 4 prostate cancer. Also known as medical castration, the therapy primarily works by making a reduction in testosterone level in the body. The level of testosterone in men is associated with the growth in prostate cancer cells and so the reduction in serum testosterone helps in slowing or stopping the progression of the cancer. There are several hormone therapies that primarily serve the prostate cancer therapeutics market, including androgen receptor antagonists such as bicalutamide, and luteinising hormonereleasing hormone (LHRH) agonists such as leuprolide acetate.The therapies are well accepted with adequate safety and efficacy levels.However, the hormone therapeutics market faces the challenge of patients developing resistance to these therapies.Generally, a prostate cancer patient on hormone therapy develops resistance – or becomes refractory within two years – so eventually patients stop responding to hormone therapies. At this stage, chemotherapy drugs can be used for metastatic hormone-refractory or castrate resistant prostate cancer.The market faces a greater unmet need for the treatment of hormone-refractory prostate cancer (HRPC) with Docetaxel-based chemotherapy dominating the therapeutics options available

The prostate cancer market has a relatively high unmet need in terms of efficacy and safety, with efficacy being the major concern. Higher unmet needs imply that the market is currently being underserved and therefore new entrants that can show a better efficacy profile will capture market share in terms of both value and volume. In addition, there is an unmet need for drugs which can treat prostate cancer patients in the earlier stages of development.

The treatment options that are currently available have limited efficacy and safety profiles, and aim to slow the progression of the disease to manage their symptoms.Therefore, there is a need for more effective chemotherapies for late stage HRPC. Recently approved products in the US, such as Provenge, will help in addressing this unmet need to some extent in the coming years. Additionally, the market also faces an unmet need for second-line chemotherapy options if Docetaxel (trade name Taxotere, the current chemotherapy for HRPC) fails. Jevtana (trade name Cabazitaxel) was recently launched in the US and can help address some of the unmet need for a second-line chemotherapy after docetaxel-based therapy.The safety and efficacy profiles of the drug have been evaluated in patients that do not respond to Docetaxel.Despite lower efficacy, the drug is a promising entrant which provides an effective second-line option for prostate cancer patients and has helped to reduce the current unmet need.

The market for both hormone and HRPC therapies in BRIC countries was estimated to be $125m in 2009.The market is expected to grow at a CAGR of 13 per cent between 2009 and 2020 to reach $493m (3).The growth in the market is expected to be driven by the increase in the prevalence of the disease, the increasing awareness of the disease symptoms and treatment options in these countries, and the availability of novel drugs that are able to meet the current unmet demand. However, the low treatment seeking rate (due to the asymptomatic nature of early prostate cancer) and poor affordability in some BRIC countries is expected to inhibit growth.The following factors will affect the patient volume for prostate cancer therapeutics (3):

  • The increased incidence of prostate cancer in BRIC countries, which, according to Globocan 2008, is expected to increase at a CAGR of three per cent to reach 160,779 in 2020.The incidence in BRIC countries is growing at a slightly higher rate compared to the incidence of worldwide growth – globally the incidence of prostate cancer is expected to grow at a CAGR of 2.9 per cent between 2008 and 2020
  • The awareness about prostate cancer in patients at higher risk of the disease in BRIC countries affects the patient volume by driving the treatment seeking rate and the diagnosis rate of the disease.The increased availability of prostate cancer related material on free resources online helps patients in building a better understanding of the symptoms. An overall increase in awareness amongst people in BRIC countries towards their health and wellbeing will continue to drive the treatment seeking rate

Future Therapies for Prostate Cancer

The novel molecules under development will also drive the uptake of drug treatment by patients and physicians. These products are expected to change the prostate cancer therapeutics landscape. A large number of products are being developed for cancers in various stages of development, and the pipeline for prostate cancer products is strong, with many first in class molecules with novel mechanism of action.The recent approval of novel products in some countries has strengthened the marketed products for prostate cancer. See Table 1 for a list of products that are expected to affect the prostate cancer therapeutics market in BRIC in the coming years.

Provenge
An autologous cellular immunotherapeutic, Provenge is an effective therapy for asymptomatic or minimally symptomatic metastatic HRPC (4).

The novelty of the product lies in its ability to use the patients’ immune system to achieve the targeted response to prostate cancer. As part of the therapy, immune cells are collected and combined with proteins associated with prostate cancer.The therapeutic vaccine is manufactured using these cells, and the resultant compound is used as a dose of Provenge.The personalised manufacturing of the vaccine for patients results in a high annual cost.

Jevtana
Jevtana (also known as Cabazitaxel) addresses the unmet need for second-line chemotherapy for patients not responding to docetaxel-based therapy. Cabazitaxel is a derivative of natural taxoid.The drug in combination with prednisone is approved by the US FDA for use in patients that have previously been treated with docetaxel.The drug was approved in June 2010 and is marketed by Sanofi-aventis. It works by stabilising tubulin, by binding to it, which inhibits microtubule depolymerisation and cell division.The drug is important for Sanofi-aventis as it will help in setting off the revenue loss resulting from the loss of exclusivity for Taxotere (5).

MDV3100 and Abiraterone
New types of androgen receptor blockage therapies such as MDV3100 and Abiraterone are expected to provide better efficacy and safety for prostate cancer patients (6).The mechanism of action of these products is different from the existing androgen receptor antagonist and LHRH agonists. MDV3100 is a triple-acting, oral androgen receptor antagonist and works by blocking testosterone from binding to the androgen receptor, impeding movement of the androgen receptor to the nucleus of prostate cancer cells (nuclear translocation), and inhibiting the androgen receptor from binding to DNA.The product currently is in Phase 3 development in patients resistant to bicalutamide therapy.

Abiraterone is also a novel therapy which irreversibly inhibits the CYP17 (17α-hydroxylase/C17, 20 lyase) steroidal enzyme. This enzyme is a cytochrome p450 complex that is involved in testosterone and oestrogen production.Testosterone is not known to cause prostate cancer, but it has been found that cancer cells grow quicker in the presence of testosterone.The treatment aims to block testosterone production in the body.

Monoclonal Antibodies: Ipilimumab
T-cells are an important part of the immune system; the response of T-cells helps in fighting diseases. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is present on T-cells and regulates the natural immune response (7). Its absence enhances the immune system’s T-cell response and its presence suppresses its effects. Ipilimumab is a fully human antibody that binds to CTLA-4 and blocks its activity, thereby sustaining an active immune response in its attack on cancer cells. It is being developed by Bristol-Myers Squibb and Medarex, and is also known as MDX-010 and MDX-101. It is currently in Phase 2 studies for HRPC lung cancer and in Phase 3 for adjuvant melanoma. It has been given a fast track and orphan drug status by the FDA and the European Medicines Agency (EMA) for metastatic melanoma.

Other promising molecules in development for prostate cancer include Aflibercept which is an anti-angiogenic agent. It is a fusion protein specifically designed to bind to and inhibit all forms of vascular endothelial growth factor-A (called VEGF-A). Aflibercept is a VEGF inhibitor. It combines the constant region of a human immunoglobulin G (IgG) antibody with the ligand-binding portion of VEGF.This new mode of action has a greater affinity for the VEGF ligand than anti-VEGF monoclonal antibodies.The drug not only inhibits VEGF-induced signalling and angiogenesis but also blocks placental growth factor, which plays a key role in angiogenesis.This means that vascularisation of the tumour reduces, and therefore tumour growth declines. Aflibercept has a relatively long half-life of approximately two weeks. With its unique mechanism of action compared to monoclonal antibodies, it is a more powerful anti-angiogenesis agent with a broader spectrum of activity (8).

Conclusion

The prostate cancer pipeline looks promising with many novel products in development.These products are expected to have a positive impact on the therapeutics market globally.However, recent failure of many promising products to meet targeted endpoints highlight the uncertainly of pharmaceutical research and development.

Between 2009 and 2010, major molecules in development for prostate cancer drugs such as satraplatin and bevacizumab failed to show promising results. Recent results from Phase 3 satraplatin showed no statistical difference in overall survival rate for patients in the satraplatin arm compared to those in the control group.The molecule is being developed by GPC Biotech. In August 2008, Celgene and GPC Biotech terminated their development agreement for the compound, indicating poor success prospects for the molecule (9). Similarly, bevacizumab trials failed to show any increase in overall survival rate compared to the survival rate in prostate cancer patients using chemotherapy. Bevacizumab is being developed by Roche. In September 2010, Pfizer announced that it has terminated Sutent’s trial for prostate cancer as the drug did not meet its endpoints in interim result analysis. In February 2011, AstraZeneca terminated the Phase 3 trial of Zibotentan in non-metastatic castrate resistant prostate cancer. Earlier in September 2010, the drug failed to meet Phase 3 primary end points in men with metastatic castration resistant prostate cancer.The failure of leading products at late stage highlights the uncertainty of successfully launching promising products.

References

  1. Globocan 2008 and GlobalData analysis
  2. National Cancer Institute: US National Institutes of Health
  3. Prostate Cancer – BRIC drug forecasts and treatment analysis to 2020, November 2010
  4. Provenge Website, www.provenge.com, accessed 7 February 2011
  5. Sebastian de Bono J et al, Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial, The Lancet 376(9,747): pp1,147-1,154, 2010
  6. Hseih AC and Ryan CJ, Novel Concepts in Androgen Receptor Blockade, The Cancer Journal: The Journal of Principles & Practice of Oncology 14(1): pp11-14, 2008
  7. Cancer Research UK, www.cancerresearchuk.org, accessed 7 February 2011
  8. Bradley DA and Hussain M, Promising Novel Cytotoxic Agents and Combinations in Metastatic Prostate Cancer, The Cancer Journal: The Journal of Principles & Practice of Oncology 14(1): pp15-19, 2008
  9. Fierce Biotech, 6 August 2008

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Aditi Singh is a senior analyst in the Pharmaceuticals and Healthcare practice at GlobalData, and has authored several research reports on topics related to the pharmaceutical industry. As one of the lead authors for oncology therapeutics reports, Aditi has examined and presented a variety of topics such as prostate cancer, stomach cancer and breast cancer therapeutics. She has six years of experience in leading research engagements on functional areas like business research, market opportunity analysis, competitive intelligence and providing research-based advisory services to the pharmaceutical industry. Aditi holds an MBA from Symbiosis Institute of Management Studies, India.
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