This note describes five stages of prostate cancer that can follow its initial detection and the standard drug treatments used in each stage. Understanding of these stages is necessary in order to project the role of Dendreon’s (DNDN) Provenge, Johnson & Johnson’s (JNJ) abiraterone and Medivation’s (MDVN) MDV3100 in prostate cancer therapy used in the succeeding stages.
The treatment of prostate cancer is seeing a surge in new product development that is promising to significantly improve treatment outcomes. This started with the approval of Provenge in April 2010. I have written extensively about Provenge and believe that it has blockbuster potential. Dendreon has just reported 2010 sales of $48 million and has given guidance for 2011 sales of $350 million to $400 million with half of sales occurring in the fourth quarter. My sales estimates are as follows: 2011, $375 million; 2012, $905 million; and 2013, $1.3 billion.
I am also excited about Johnson & Johnson’s new drug abiraterone and I see it as having billion dollar plus potential as well. The results were just reported last year in a phase III trial in prostate cancer patients who were refractory to chemotherapy were stunning. This drug will likely gain approval for treating patients who have failed chemotherapy in the latter half of 2011 and come to market in the U.S. and Europe in 2012 for this indication.
Abiraterone also promises to have significant utility in earlier stages of disease. There will be important interim data from a phase III trial in pre-chemotherapy patients in late 2011 looking at progression free survival. Another interim look in 1H, 2012 will provide insight into overall survival. If the overall survival data is positive, abiraterone could receive approval for use in the pre-chemotherapy setting in 1H, 2013. However, if the results are encouraging but not statistically significant, approval could be delayed until 2H, 2014.
Medivation’s MDV3100 may be a significantly improved androgen blocker, an important class of androgen deprivation drugs. Currently the gold standard drug in this class is Casodex. MDV3100 holds the promise of being markedly superior to Casodex. It is about 18 to 24 months behind abiraterone in clinical development. I am expecting phase III results in the chemo-refractory setting in 2013 and phase III results in the pre chemotherapy setting in 2015. Of the three drugs, MDV3100 might have the most potential. Its mechanism of action is exciting and could hypothetically lead to much better clinical outcomes than Casodex. However, I need to see phase III results before passing judgment. Phase I/II results are encouraging, but there is an axiom in cancer drug development that the phase III results are never as good as phase II.
Beyond Provenge, abiraterone and MDV3100, I am currently tracking eight other drugs in development for prostate cancer. Most of these are drugs that will not come to market in the U.S. until 2015 or later.
Provenge is the first cancer vaccine ever approved and represents a new paradigm for prostate cancer treatment. It is initially indicated for patients whose cancer has metastasized but are asymptomatic or have minimal symptoms. Such patients have likely failed or are responding poorly to androgen deprivation therapy. Now Provenge offers the promise of an improved survival benefit before patients turn to chemotherapy and this is obtained with mild side effects as compared to the gruesome side effects associated with chemotherapy. It is estimated that 35,000 men progress to this stage of the disease in the U.S. each year. Provenge is now the standard of care in this market segment and at Provenge’s price this is a $3.3 billion addressable market opportunity.
Abiraterone can and will be used in the same patient group in which Provenge has approval, (pre-chemotherapy), but not until it gains formal approval in 2013 or 2014. While it should be approved in 2011 in the chemo-refractory setting, strict reimbursement guidelines will limit its use to the labeled indication. I do not expect much off-label use in pre-chemotherapy patients. MDV 3100 may not go head to head with Provenge until 2015. Provenge in the U.S. will have two to three years to establish its role in prostate cancer, before it meets direct competition from abiraterone and MDV3100. In Europe, Provenge will have less of a lead or possibly no lead over abiraterone as its sales in that theater won’t start until 2013 or 2014.
When abiraterone and potentially MDV3100 are approved in the pre-chemotherapy setting, it will not necessarily be the case that they will compete head to head for each patient with Provenge. The benign side effect profile and unique mode of action may encourage doctors to use Provenge first and then turn to abiraterone, which has a more severe side effect profile. MDV3100 is complementary in action with both Provenge and abiraterone and could be used in combination with each. Many of the Wall Street bulls on Provenge see a rapid uptake of the drug until 2013 or 2014 in the US and then a moderation, flattening or slight decline in subsequent years due to competition. This scenario is plausible, but there are also more positive ones. I don’t have enough information to project exactly how this will play out.
Incidence and Death from Prostate Cancer
The American Cancer Society estimates worldwide prostate cancer incidence as follows:
Annual Prostate Cancer Statistics
Other developed Countries
There are over 2.5 million men with a history of prostate cancer in the US and 1 out of six men will be diagnosed with prostate cancer in their lifetime. In this note, I have divided prostate cancer into five stages based on severity and the types of treatment that are employed at each stage.
Stage 1: Local Disease
In the very early stage, prostate cancer is diagnosed by elevated levels of the key biomarker prostate specific antigen (PSA) which is produced by prostate cells and/or an enlarged prostate gland. In about 80% of newly diagnosed patients, the disease is localized to the prostate gland and if properly treated the five year survival rate is nearly 100%. This stage of the disease may treated by: (1) radical prostatectomy in which the prostate gland is surgically removed, (2) radiation targeted at the prostate to kill the cancerous cells, (3) brachytherapy in which radioactive seeds are implanted near cancerous areas in the prostate, (4) cryotherapy that freezes part or all of the prostate gland and (5) watchful waiting in which PSA levels are carefully monitored to gage the growth of the tumor. Of these, radical prostatectomy is the most effective and is generally recommended for younger men who can withstand the rigors of a difficult surgery. Because of the slow progression of the disease, older men may be given less physically demanding treatments or none at all.
Stage 2: Hormone Sensitive (Key Drugs: Lupron. Zoladex, Casodex, ketoconazole)
After therapy for localized disease, PSA levels are carefully monitored to determine if the disease is re-emerging. About one-third of early stage patients who undergo radical prostatectomies and over half of those who undergo other procedures progress to this next stage of the disease in which patients are asymptomatic and the disease has not metastasized but is growing rapidly. In addition, many patients are already at this stage when initially diagnosed.
Standard of care is androgen deprivation therapy which medically castrates the patient by sharply reducing his production of androgens. Surgical castration is also an option. Prostate cancer is an androgen driven disease and activation of the androgen pathway is the key mechanism for prostate cancer growth. The most important androgen is testosterone which is made by Leydig’s cells in the testicles. Additional androgens are produced in the adrenal gland and can also be produced in the tumor cell.
Approximately 150,000 men enter this hormone sensitive stage of the disease each year. Androgen deprivation therapy is usually effective in reducing androgen levels by 95% and about 85% of prostate cancer patients respond. This stabilizes the disease for perhaps two to four years. This stage of the disease is referred to as hormone sensitive.
Currently approved drugs reduce androgen levels in two ways: (1) by blocking their production or (2) interfering with the interaction of androgens with androgen receptors, which are molecular complexes found on prostate cancer tumor cells. The first drug chosen is usually a leutinizing hormone releasing hormone (LHRH) agonist like Lupron or Zoladex. LHRH agonists work by signaling the pituitary gland in the brain to stop producing leutinizing hormone. In men, leutinizing hormone stimulates the testicles to release testosterone. These drugs do not have a direct effect on the cancer, only on the testosterone production in the testicles. If the amount of testosterone is reduced it is possible to slow down or shrink the cancer.
Over time, an anti-androgen which interferes with the binding of androgens to androgen receptors such as Casodex may be added to an LHRH agonist to enhance the androgen deprivation effect. This blocks the ability of testosterone and other androgens to signal the cancer cell to proliferate. Casodex may also be give as monotherapy.
Another drug may be added at the end stages of hormone sensitivity, which blocks the production of androgens through a different mechanism. This is ketoconazole, an anti-fungal agent that lowers both testicular and adrenal produced androgen levels through its non-specific inhibition of CYP 17, an enzyme involved in the biosynthesis pathway of androgens. This is not an approved indication for ketoconazole. Johnson & Johnson’s new drug abiraterone works through this mechanism of action and is sometimes referred to as a super-ketoconazole.
Stage 3: Asymptomatic or Minimally Symptomatic Metastatic Prostate Cancer (Key Drug: Provenge)
Most patients become non-responsive to androgen deprivation therapy and move on to metastatic disease within two to four years. Prostate cancer progresses during androgen deprivation therapy for several reasons. One of the most important is that the testicles are not the sole source of androgen production as low levels are produced in the adrenal gland and within the tumor itself. The androgen receptor can also mutate making it easier for androgens to signal the tumor to grow. Mutations can actually amplify the androgen signal. Because ketoconazole interferes with the biological synthesis of androgens, it can work when other hormone based drugs fail.
At this stage, the cancer has metastasized to the bone or surrounding lymph nodes but is not yet causing much pain. The most horrible part of prostate cancer is that when it metastasizes to bone, it can cause pain which in the final stages of the disease can be excruciating. Each year, about 35,000 patients enter this stage of the disease. Once the disease has metastasized, the five year survival rate is about 30%. This condition may still be treated with the same therapies as in the hormone sensitive stage as some part of the cancer cell population remains sensitive to those therapies.
Provenge is now considered frontline therapy at this stage of the disease. Provenge’s approval in April of 2010 actually created this new treatment stage. Prior to Provenge, the only options were possibly ketoconazole or chemotherapy. However, chemotherapy is reserved for even later stage patients because of its severe side effects and its being the last treatment hope. While waiting for the chemotherapy option, palliative measures and bisphosphanates like Zometa are used to treat adverse events that result from bone metastases.
Stage 4: Moderate to Severe Symptomatic Metastatic Prostate Cancer (Taxoterre, Jevtana)
Chemotherapy is used in the closing and often fatal stage of the disease. There are several approved chemotherapy options with Taxoterre being the most often used drug. Taxoterre, Jevtana, mitoxantrone and estramustine are chemotherapy drugs approved for this indication. Palliative treatment and bisphosphonates continue to be used often in this group of patients. Many of the 32,000 annual deaths from prostate cancer occur in this group.
Stage 5: Chemotherapy Refractory Patients (abiraterone)
There are about 10,000 terminal patients who fail chemotherapy each year. Until recently, these patients had exhausted all therapeutic options. However, Johnson & Johnson’s new drug in development, abiraterone, now offers hope and has created this new stage of chemo-refractory treatment just as Provenge created the new therapeutic option for asymptomatic or minimally symptomatic patients.
Abiraterone is a blocker of androgen synthesis that works through the same mechanism of action as ketoconazole. It is a selective and high affinity inhibitor of CYP17A, a key enzyme in the androgen synthesis pathway in both the testicles and adrenal glands. Remember that the LHRH agonists only affect androgen production in the testicles. Its differentiated mode of action has led to the off-label use of ketoconazole in prostate cancer after androgen deprivation therapy fails. Abiraterone has exhibited 10 fold higher binding activity against this enzyme and has a better safety profile than ketoconazole. It promises to be a much superior drug.
In September 2010, an interim analysis of abiraterone plus steroids in the post-Taxoterre setting in comparison to steroids alone demonstrated statistically significant overall survival of 14.8 months versus 10.9 months and a hazard ratio of 0.65 meaning that it reduced the risk of death by 35%. These results were stunningly positive and the study was stopped and all patients on the control arm were crossed over to abiraterone. Johnson & Johnson has filed for approval of abiraterone on December 20, 2010 in the chemo-refractory setting based on this data. It was assigned a priority review so that Abiraterone could be approved in the U.S. in mid-2011. It was similarly given it an accelerated assessment in Europe so that approval could come in 2H, 2011.