Pharma Strategy Blog

Update on Prostate Cancer therapies

It's been a while since I took a look at what's happening in the prostate cancer arena, but it seems a good time after the recent flurry on lung and colorectal cancers, especially as it's Groundhog Day :-).

There are three particular agents that I'm interested in:

1. MDV3100 (Medivation/Astellas)
2. Abiraterone (Cougar Biotech/J&J)
3. Provenge (Dendreon)

I'm going to spend most of this post talking about the first two, as much has been said on Dendreon already.

Dendreon filed their amended BLA on November, and the FDA have given a PDUFA date of 1 May 2010.  The data from 512 patients showed an improvement of 4 months survival for Provenge over placebo, meeting the FDA's threshold. 

We have, however, no idea how the vaccine would have done compared to standard chemotherapy such as docetaxel plus prednisone, and therein lies the rub.  Normally, in oncology trials we compare the standard of care with and without the new agent or compare the standard therapy to a different regimen.  Placebo controlled trials have not done well with ODAC and the FDA, as J&J, Vion and Genzyme all learned with placebo controlled trials in elderly AML patients.

Regular readers of Pharma Strategy Blog will know I'm not a big fan of either placebo trials in cancer or vaccines, so we'll wait and see what the FDA decide.  My expectation is that it will receive approval this time round having jumped through the extra hoops.

Cougar Biotech and J&J are developing abiraterone in advanced prostate cancer.  A phase III trial in asymptomatic or mildly symptomatic patients with metastatic castration-resistant prostate cancer began enrolling this month.

It's estimated to complete in April 2014 and the primary endpoint is overall survival, but initial results should be available in April 2011 for progression free survival at 12 months from what I can see, so perhaps there will be some data around ASCO in 2011.  Based on that data I can't see a filing much before the 2nd half of 2011 at the very earliest, possibly not until 2014. 

Looking at J&J's analyst presentations, I found the following timeline for their pipeline:

Now, many drugs are lumped together in the 2011 timeframe across 3 columns.  It isn't clear whether each column represents 2011, 2012 and 2013 or it's a random list of drugs that will be filed in that period.  Either way, it's hard to see abiraterone getting accelerated approval so my assumption for now is abiraterone will be filed in 2013, with approval in 2014.

It's not going to be a fast development: Cougar is very inexperienced and J&J are relatively weak and slow in oncology.

The asymptomatic nature of the patients will also complicate things because it's a high risk study that may not show much in the end.  If it works, great!  That said, I'm not sure how well the results will fare in what looks like a fluffy trial design comparing abiraterone plus prednisone to placebo plus prednisone.  Patients are specifically excluded if they have received prior chemotherapy.  Well then, why not compare abiraterone to docetaxel, which is the current standard of care in castration-resistant disease, given that this is a front-line trial?

Recently, at the AACR Molecular Targets meeting in Boston, I had the pleasure of listening to a most excellent talk from Dr Charles Sawyers (MSKCC), one of may favourite researchers.  He covered a lot of ground on the lessons learned in targeted agents, principally in CML and prostate cancer.

With regards to prostate cancer, he showed a graphic similar to this one (from Medivation):

Clearly, there are a number of opportunities to explore for the development of new drugs for the disease after hormome therapy ceases to work.  This is where traditional drug development for chemotherapies typically starts.

What was interesting about Sawyers talk is his discussion about the androgen receptor (AR) and whether or not it is important in castration resistant disease.

Previously, AR was thought to be irrelevant in this situation because it is not expressed in 2 common prostate cancer cell lines, but Sawyers argued cogently that this shows a failure to appreciate the potency of inhibition because AR is restored through PSA production.  Several reasons have been evaluated for this, including AR amplification, mutation and alternative pathways among others.  AR is also overexpressed in castration resistant xenograph models, and can confer castration resistance.

What followed was an elegant discourse showing that MDV3100 is distinct from bicalutamide, whereby it has a greater affinity, binds AR selectively, without displaying agonism in AR overexpressing cells and has more potent antagonistic activity. 

In the end, Sawyers argued that what was important was not AR overexpression per se, but AR amplification because prostate cancer cells with natural AR amplification are more sensitive to AR knockdown than AR single copy prostate cancer.  Minor AR knockdown is sufficient to inhibit growth of AR amplified disease.  All of this leads us logically to an important question:

Are AR amplified prostate cancers a different (and important) patient subtype?

Clinical trials with MDV3100 have demonstrated that at least half of prostate cancer patients remain AR dependent, suggesting that this is indeed the case.  Clearly, if you can keep patients hormone sensitive or at least responding to therapies using different approaches, then the opportunity to delay time to metastasis and late stage disease may well exist with these novel approaches.

Time will tell.

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Medivation and Astellas ink deal for MDV3100 in prostate cancer

Wow, that was the Pharma headline news this morning, after the excitement of last night's announcement that Medivation are hosting a conference call at 8.30am to announce a partnership deal.

I was expecting a big Pharma oncology company to have bitten, not a Japanese company known for it's cardiology and immunology franchise.  Granted they have urology products such as Flomax, but this is a cancer drug for late stage prostate cancer.  It will likely compete with Cougar Biotech/J&J's abiraterone, if both make it to the market. Interesting. That shakes up the prostate cancer landscape a little bit.

More details will follow at the 8.30am conference call, so I'll update this post with more information then.

{Update}

The details of the deal can be found on Medivation's website here.

Basically, $MDVN gets $110m in up front payment, followed by $655m in milestones. The two companies  will the share costs and profits in US.  I should add a big caveat here - MDV3100 is currently being evaluated in the Phase 3 AFFIRM clinical trial in men with castration-resistant prostate cancer who were previously treated with docetaxel-based chemotherapy.  The results are as yet unknown.

Medivation announced this morning that they made a competitive decision to choose Astellas as a partner for MDV3100 based on 5 key factors:

1) Global reach in development and commercialisation: Astellas has over $10B in sales globally
2) Expanding use into early stage prostate cancer through urologists: Astellas has a urology franchise (via Flomax)
3) Expand the clinical development program: earlier stage trials after hormone (and possibly before) therapies
4) High priority product: Astellas wants to build an oncology franchise around MDV3100
5) Terms offer compelling value to MDVN and shareholders: ($110M up front, $655M milestone payments, co-development and commercialisation in the US, Astellas exclusivity ex-US with royalty payments to Medivation.

Astellas management declined to provide any details of the proposed clinical development plan, were a little defensive about the market size of the initial indication after failure of docetaxel, which is also treated by medical oncologists not urologists, there were vague mumblings about 'we intend to fast track to the drug market and then develop and expand into earlier opportunities' kind of approach.

Note, it's an oral drug so yes, it would be attractive to urologists but only with data and that will be a long time coming in even the hormone refractory setting.  There are no guarantees that MDV3100 in the chemo refractory trial that started accruing in September will work in that late stage setting (we should all remember the ghost of GPC's satraplatin there), although it might be effective in the hormone sensitive- early refractoriness setting before metastases sets in.  There are some early preclinical data showing it was superior to bicalutamide (Casodex) based on my preliminary search.

All in all - it's a very big leap of faith and a long term strategic play that is very risky indeed.  My suspicion is that Astellas won't want to be outdone by Takeda in the Japanese and Asian markets, so their new strategic focus looks like it will be building an oncology franchise from scratch while possibly leveraging their expertise in urology in the medium term.

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Clinical trial results show Denosumab is superior to Zometa in breast cancer patients with bone metastases

Image via Wikipedia

Amgen's recent announcement of phase III trial data showing that it's monoclonal antibody, denosumab was superior to Novartis' Zometa (zoledronic acid) for the treatment of breast cancer patients with bone mestastases is further news that scientifically driven drug development can yield exciting results. 

Denosumab is in essence a targeted therapy like Gleevec, Avastin or Herceptin.  It's development came about from basic research that discovered the cellular control of bone remodelling and regulation of bone density is reglated by the RANK Ligand pathway.

RANK Ligand is a TNF famly member, a protein that is expressed on the sufrace of marrow, stromal cells and osteoblasts (the cells responsible for bone formation). When RANK-L binds with its receptor RANK it stimulates the activity of osteoclasts (cells responsible for bone resorption).  In the body, RANK-L production is naturally regulated by the protein Osteoprotegerin (OPG), which binds with RANK-L thereby preventing it from binding to its receptor, RANK.  When there is insufficient OPG, or too much RANK-L produced, excess bone loss occurs.   This occurs in post-menopausal women or in cancer related bone loss.

Denosumab acts by attaching itself to RANK-L, thereby inhibiting its action. Deprived of RANK-L, osteoclasts cannot form, function or survive.  The result is less bone destruction and bone loss.  Understanding the RANK Ligand pathway has been a breakthrough step in understanding bone biology.

Many cancer patients end up with bone metastases that not only causes pain, but also bone destruction.  Roodman, in a 2004 New England Journal article, proposed the "vicious cycle" hypothesis to explain this: Tumor cells produce parathyroid hormone-related peptide (PTHrP), which stimulates osteoblasts to produce RANK ligand leading to less production (downregulation) of osteoprotegerin (OPG), thereby stimulating osteoclasts to resorb more bone.  At the same time, production of PTHrP promotes tumor growth directly.  Therefore, it should come as no surprise that denosumab would be effective in cancer patients with bone mets and skeletal related events.

What does the future hold for denosumab?  In the postmenopausal osteoporosis market, a once or twice yearly injection is extremely attractive given its ease of use. Compliance is a real issue with bisphosphates such as alendronate or risedronate where a daily pill must be taken.  Many primary care physicians are not set-up to administer an infusion, which is what Novartis' once a year osteoporosis treatment, Reclast requires. 

However, despite impressive clinical data, Amgen does not yet have a home run.  It lacks a large sales force and infrastructure to sell to primary care physicians. Also with generic fosamax (alendronate) available, the cost/benefit trade off is going to be a key factor in uptake.  The cost of denosumab will need to be carefully considered for Amgen to enter this competitive market.  The FDA advisory board meets on August 13 to discuss Amgen's BLA application and consider whether to recommend approval for the treatment and prevention of osteoporosis, and treatment of bone loss in patients undergoing hormone ablation for prostrate and breast cancer.  Given the positive data from the phase III pivotal studies, a positive recommendation is expected with approval by the FDA expected in October. 

For cancer patients, denosumab could become the gold-standard for treatment of bone metastases given its superiority over Novartis' Zometa.  For oncologists, the fact that denosumab only requires an injection while Zometa requires an infusion is less of an issue.  The key to success for oncology drugs is based solely on the data. If the positive results continue, Amgen are likely to take market share from Zometa once approval for the treatment of bone metastases is obtained in 2010 or 2011.

So, my take on this is that denosumab is a real winner for Amgen.  Whether it will capture the market for postmenopausal osteoporosis remains to be seen, but it is an exciting new drug that will benefit cancer patients.  Further data on denosumab can be expected from the September meeting of the American Society of Bone and Mineral Research (ASBMR) in Denver.

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New cancer treatments - promise or false hope?

The last week or so has seen some rather garish headlines in the news about cancer treatments currently undergoing testing in early clinical trials.

First up was the Mayo Clinic in Minnesota, normally a staid institution renowned for good solid research, but the PR headline screamed pure sensationalism in their press release:

Mayo Researchers: Dramatic Outcomes in Prostate Cancer Study

While we all like to be positive and feel a sense of hope in our lives, what the press releases failed to mention was fair balance, namely that some patients with prostate cancer do actually see occasional stunning results with androgen ablation alone, so highlighting the 'dramatic' results of two patients on androgen therapy plus ipilimumab doesn't really tell us if the results seen were due to the androgen therapy or the ipilimumab.  Making waves about two patients does sadly not a cure make; raising false hopes in patients sick with cancer is a little tawdry at best.

The second headline that caught my eye was an email alert from the FT of all places.  In it, they were reporting about a trial from another venerable institution, the Royal Marsden in London:

New cancer treatment shows ‘great promise’

This time, the article was about AstraZeneca's PARP inhibitor, olaparib, for BRCA1 and 2 breast cancers, although the coverage did not mention that it was the drugs first clinical trial, but the hype really jars a little.  I reported on this data from ASCO in an earlier blog post.

What was interesting that the FT quoted Dr Johann De Bono as saying:

“This drug showed very impressive results in shrinking patients’ tumours. It is giving patients who have already tried many conventional treatments long periods of remission, free from the symptoms of cancer or major side-effects.”

Then I remembered he was the same doctor who constantly talked up the Cougar abiraterone trial results in prostate cancer, although it should be noted that abiraterone is part of the same family as ketoconazole, a generic anti-fungal treatment sometimes used to treat hormone sensitive prostate cancer after standard androgen therapy such as Casodex or Lupron and estrogen.  The goal of treatment is to keep men who are hormone sensitive on such therapies for as long as possible, since this keeps the disease (and PSA levels) in check.  Once they become refractory to treatment, the tumor will start proliferating and metastasize, so having new therapies added to the list to extend and prolong lives with minimal side effects is definitely a positive thing, providing the results pan out that way. 

It should be noted that breast cancer is also a disease where patients often undergo multiple lines of therapy and the data with olaparib has not yet been published in full, although a sample of the initial early results was covered in a poster at the recent ASCO meeting.  The press release was probably one of the poorest I have seen in a long while - short on the trial details and long on wild hype.

Perhaps sometimes we forget that cancer Institutions are a business in their own right.  What these centers are doing is marketing themselves and trying to attract more patients to their clinical trials rather than see community oncologists for standard treatment in the local area.  It's an ongoing battle between the two all over America, and while Europe has mainly Academic cancer centres, they all still compete with each other for patients and the flow of money, either from treatments, trials or for research dollars.  

The prize for the worse headline on this topic must surely go to Sky News, though, which is rapidly becoming the tabloid of British Television:

New Drug Is 'Holy Grail' In Cancer Fight

This headline struck my Mother so forcefully that she made a rare call to me this morning from 5,000 miles away to ask whether venerable cancer hospitals were becoming the Heroin dealers of medicine.  Ouch.

Sensationalism has no place in research and development; patients and their families deserve better than false hope being peddled so brazenly; the Mayo Clinic and Royal Marsden should know better than that.  How could they have done better while mataining their reputations? 

How about something positive, but muted, such as:

"Early but promising results seen in xxxxx cancer - more trials needed to confirm findings"

Including relevant information about the patients, inclusion and exclusion criteria and the trial design would have gone a long way to putting the information in context.  Still, what do I know?  I'm much too old school for inappropriate, tacky and racy tag lines and sound bites in the news media. 

What do you think?

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New data on Abiraterone in prostate cancer

I was away for the Memorial Day weekend last Friday and hence missed the big news in oncology that Johnson and Johnson were purchasing Cougar Biotechnology for $1 billion.  Note the whole company, not just a licensing deal for the promising prostate cancer compound, abiraterone.

Wow.

The data hasn't even been announced at ASCO yet, that's this weekend coming, so one can only speculate that suitors got a sneak peek of the data under an NDA.  A billion dollars certainly gets attention and raises the ante for future small oncology biotech deals.

Just now, Cancer Research UK tweeted about the new data:

Twitter is rapidly becoming my real time alert system for accurate competitive intelligence.  You can read more about CRUK's perspective HERE, but essentially the data tells us the following:

"Researchers at the Institute of Cancer Research and The Royal Marsden Hospital tested the drug on 54 men with aggressive, advanced prostate cancer. In most cases, the cancer had spread around the body, causing many of them discomfort and pain.  The men were given abiraterone daily and, twelve weeks later, were given a PSA test and a CT scan to see if the drug had worked.  The scientists found that abiraterone worked for around two-thirds of the men on the trial, lowering their PSA levels, causing the tumours to shrink and relieving pain. It wasn’t a permanent cure, as the effects only lasted an average of 8 months.  But, interestingly, for men who carried a faulty version of a gene called ERG, the effects lasted much longer – up to 18 months.

This may not sound like long, but it’s certainly a significant improvement on what might be expected for men with such advanced cancer."

Regular readers of Pharma Strategy Blog will know that this is one compound I'm quite excited about.  The abiraterone data has been consistent and appears to have fewer toxic side effects compared to standard of care chemotherapy, Taxotere plus prednisone, which can induce severe myelosuppression in many patients.

What was particularly interesting about the new data is that patients with the mutated ERG gene appeared to do better on abiraterone than those without.  That's a potentially interesting biomarker to look out for because linking a specific biomarker with therapy for patients most likely to benefit from the treatment is increasingly the way to go in oncology.  Now, I'm not sure how many prostate cancer patients might have the mutated ERG gene, so will have to research it unless anyone out there knows?

{UPDATE: Thanks to Twitter and Martin Fenner, it appears that the TMPRSS2:ERG fusion is present in approximately 50% of localized prostate cancers according to this paper}.

Hopefully, there will be more information available at ASCO next week, so watch this space.

Attard, G., Reid, A., A'Hern, R., Parker, C., Oommen, N., Folkerd, E., Messiou, C., Molife, L., Maier, G., Thompson, E., Olmos, D., Sinha, R., Lee, G., Dowsett, M., Kaye, S., Dearnaley, D., Kheoh, T., Molina, A., & de Bono, J. (2009). Selective Inhibition of CYP17 With Abiraterone Acetate Is Highly Active in the Treatment of Castration-Resistant Prostate Cancer Journal of Clinical Oncology DOI: 10.1200/JCO.2008.20.0642

Dendreon's Provenge extends life in prostate cancer by 4 months

After recently writing about Dendreon's Provenge and other prostate cancer drugs, the long awaited survival data has finally been revealed in a late breaking abstract at the American Urological Association. 

Unfortunately, when I tried to access the abstract online, the sign-up form said it would take several days for someone to get back to me.  Huh?  Obviously they have a ways to go in communicating data compared to their efficient brethen at ASH and ASCO, who allow guests, patients and interested parties to sign in and freely read the abstracts from the meetings.

The snapshot of the data is therefore summarised here courtesy of Forbes, Dendreon's press release and the WSJ app on my iPhone (the website will frustratingly only give you the first paragraph or so).

Essentially, Provenge prolonged the lives of men with advanced prostate cancer who had failed hormone therapy and were not responding to treatment with hormonal therapy.  Taxotere was previously approved after failure of hormone therapy with improved survival by 3 months over placebo and a response rate of approx. 18%.  Provenge extended life by 4.1 months in previously pre-treated patients (25.8 vs. 21.7 months), a statistically significant result (P<0.032).

However, the trial design makes it difficult to compare whether Provenge exerted any effect over Taxotere alone.  Therapy was started with either with placebo or Provenge.  As soon as tumours grew, men on placebo got a frozen version of Provenge, followed by Taxotere.  Those who started on Provenge also got Taxotere when they stopped responding to initial treatment. There was no Taxotere only arm to determine the incremental effect of Provenge, as might be expected.  Therein lies the rub for ODAC and the FDA.

In 2007, the FDA declined to approve the vaccine, preferring to wait for survival confirmation from the 512 patient IMPACT study presented today.  Those discussions led to a target of a reduction in risk of death by 22%.  The IMPACT data just squeaked in at 22.5%.  There is no guarentee that approval for Provenge will be a dead cert given the marginal improvement, unconventional trial design and likely exhorbitant price.

The main advantage of Dendreon's Provenge over chemotherapy is better tolerability, since the most common side effect was flu-like symptoms but not heightened stroke or cerebrovascular events, whereas Taxotere can cause severe myelosuppression, fatigue and occasionally, febrile neutropenia.

The next six months will be interesting as a) Dendreon can expect to file with the FDA later this year and b) ODAC can give biotech companies with fuzzy trial designs a run for their money; remember GPC/Spectrum and satraplatin?  I'd sure love to be a fly on the wall for the Dendreon ODAC meeting...

Disclosure: To avoid confusion, I should add that while I don't normally tend to post immediate news about drugs or pharma on this blog, my particular interest stems from having lost a dear father to the disease 9 years ago. It is my hope that one day others will have a better opportunity for an improved quality of life after being diagnosed with advanced cancer.   Most advances are inevitably incremental, rather than being a lengthy improvement in quality of life and survival, as Gleevec was for CML patients. As for Dendreon's Provenge, I'm not sure that flu-like symptoms and a high price tag will be the panacea that many patients and their families were hoping for :(

Dendreon's Provenge and other hot drugs in Prostate Cancer

Recently, ASCO held its annual symposium on GI cancers, which covers a variety of tumour types including pancreatic, colorectal, gastrointestinal, renal and prostate cancers. In this blog review, we will concentrate on an update on prostate cancer.

There is a clear unmet need in hormone-resistant prostate cancer (HRPC) because conventional anti-androgen therapy can stop working after a few years of treatment, leaving a population of men whose cancer no longer responds to treatment and who have a limited life expectancy. Taxotere, a chemotherapeutic agent, is the only FDA-approved drug to treat HRPC and was approved in 1996 on the basis of a 2.5 month survival advantage.  The therapy also has significant adverse events associated with it, including myelosuppression and risk of febrile neutropenia. 

Much of the noise surrounding new treatments for HRPC have centred around Cougar Biotech's abiraterone and Dendreon's Provenge.  

The former announced an update in chemo-naive HRPC. Data on the 31 evaluable patients treated in the trial were reported in a poster by Ryan et al.  77% patients experienced a decline in prostate specific antigen (PSA) levels of greater than 30%, 71% experienced a PSA decline of greater than 50% and 26% experienced PSA declines of greater than 90%.  Median time to PSA progression had not yet been reached, with patients continuing to be treated for 10+ months.  Of the 33 evaluable patients with tumour lesions that were measurable by the RECIST criteria, treatment with abiraterone resulted in partial radiological responses in 24% patients, stable disease in 39% patients and progressive disease in 12% patients; 24% patients were still awaiting radiographic disease assessment.

Cougar has a special protocol assessment for two planned registrational trials of abiraterone - one in a post-chemotherapy population and the other in the pre-chemo/post-androgen deprivation therapy population.   Data from the smaller trial, in the post-chemo population, could be available late this year or early in 2010.  The primary endpoint is overall survival.  

The main reason for all the excitement, I suspect, is because the therapy is a pill and early results from previous announcements suggest that it may be much better tolerated than Taxotere, which will be much better for the elderly population for whom it will be targeted towards.

One therapeutic mentioned at the meeting that I found interesting and novel was Mediavation's MDV3100, an androgen receptor antagonist.  Researchers at Memorial Sloan Kettering in New York presented the initial phase I/II data on PK and anti-tumour activity.  They concluded that MDV3100 was: 

"Generally tolerated with encouraging anti-tumor activity as assessed by PSA declines, CTC changes, imaging findings, and time on treatment. The data suggest a dose-response trend with consistency across endpoints." 

As a result of this trial, a phase III protocol has been approved in HRPC.  Clearly a compound to watch over the next couple of years, although it is too early to say how it may pan out.

Gene therapy is another technology that has seen more misses than hits.  The National Foundation for Cancer Research hopes to change that with an interesting approach being tested by Dr Paul Fisher that is basically:

"A genetically reprogrammed virus, called “Cancer Terminator Virus” (CTV). CTV is designed to specifically infect tumor cells and destroy them by replicating itself within the cells. The secret of restricted tumor targeting lies in a special control system employed in CTV. Dr. Fisher’s therapeutic virus employs a special gene element he discovered earlier which can only turn on virus replication in tumor cells, but not in normal cells. Once turned on, the virus copies itself inside a tumor cell and eventually causes cell death. On the other hand, the normal cells are prevented from being harmed because CTV can not replicate in them. This smart control system ensures that this small biological killing machine only fires on tumor cells."

You can read more about the concept here.

In 3 hours time, Dendreon are hosting an update on the phase III data for their cancer vaccine in prostate cancer, Provenge (sipulucel-T), the results of which are eagerly awaited by many health care physicians and patients alike.  D9902B, also known as IMPACT (Immunotherapy for Prostate Treatment), is an on-going Phase 3 trial and will effectively seal the fate of the drug with the FDA and ODAC. To say the the vaccine has had a chequered history is an understatement.  The previous trials, D9901 and D9902A were not sufficient to gain approval on their own and arguments for and against the drug have raged for a few years now.  The D9901 trial showed a significant increase in survival of 4.5 months over placebo with a hazard ratio of 1.7.   

On March 29, 2007 it was agreed with the FDA that a positive survival result from the IMPACT trial would allow Dendreon to seek approval.  The target indication was for treatment of men with metastatic androgen independent prostatic adenocarcinomas.  Once the webcast has broadcast today, I will update this post for the new trial data.

{UPDATE}

The IMPACT data turned out to be more interesting than many expected.  Dendreon announced this morning on the analyst call that:

"The pivotal Phase 3 IMPACT study of PROVENGE® (sipuleucel-T) in men with advanced prostate cancer met its primary endpoint of improving overall survival compared to a placebo control. The magnitude of the survival difference observed in the intent to treat population resulted in the study successfully achieving the pre-specified level of statistical significance defined by the study's design. The safety profile of PROVENGE appeared to be consistent with prior trials."

The company described the optimal patient for the vaccine as having metastatic, 'androgen-independent' prostate cancer for which Provenge will be a front-line treatment option, putting it head to head with standard chemotherapy treatment, Taxotere (docetaxel). No comparative data between the two treatment options is, however, available at this time so if the FDA approves the product, patients will have a choice of first-line therapies.

No further substantial clinical details were announced other than the trial data wiil not be released until American Urological Association Meeting in Chicago at the end of this month in order to maintain the embargo. Pricing, if the vaccine is approved, was vague. The per-patient price has not been set, but it is expected to be in similar range to other oncology biotech products (I read that as meaning expensive).

Dendreon's BLA submission will be a "type 2", which gives FDA 6 months to respond.  If approved, the drug could be on the market by end of 2009/beginning of 2010.  The company has estimated that 100 sales reps will likely be sufficient to address the North American market, including both oncologists and urologists.

Watch this space on April 28th when the full data will be presented at the AUA meeting.  In the meantime, the stock price surged from $7 to $24 before settling back at $17 today on the back of the positive survival data.

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Potential role for sarcosine in prostate cancer progression

A very interesting paper in Nature this week looked at a metabolite called sarcosine and how it's detection in urine may distinguish slow growing prostate cancers from aggressive ones.  The paper, entitled "Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression", may well be a useful new marker in helping doctors decide when to stop 'watchful waiting' and treat prostate cancer patients more aggressively.

The researchers examined 1,126 metabolites from over 260 samples of blood, urine and tissue in benign prostate tissue, early stage prostate cancer and advanced or metastatic disease to enable them to map alterations in disease state. 

Sarcosine molecule from: jchemed.chem.wisc.edu

They found 10 that were present more often in prostate cancer samples and one, sarcosine, appeared to offer the strongest indicator.

"... by profiling the metabolomic alterations of prostate cancer progression, we reveal sarcosine as a potentially important metabolic intermediary of cancer cell invasion and aggressivity."

Sarcosine is an amino acid and was found to be elevated in 79% of the metastatic prostate cancer samples and 42% of the early prostate cancer samples. None of the cancer-free samples had detectable levels of the metabolite.

So how does this happen?  Is there an explanation for the phenomenon reported?  The researchers went on to say that:

"Androgen receptor and the ERG gene fusion product coordinately regulate components of the sarcosine pathway."

What was also interesting was the finding that:

"Knockdown of glycine-N-methyl transferase, the enzyme that generates sarcosine from glycine, attenuated prostate cancer invasion. Addition of exogenous sarcosine or knockdown of the enzyme that leads to sarcosine degradation, sarcosine dehydrogenase, induced an invasive phenotype in benign prostate epithelial cells."

In other words, they found a clear relationship between the sarcosine and the metastatic invasion.  The study also found that sarcosine was a better indicator of advancing disease than the traditional measure, prostate specific antigen (PSA), which is currently used to monitor prostate cancer.

Sources:

Thanks to Prof Chris Beecher for kindly supplying a copy of the Nature reprint.

Arun Sreekumar, Laila M. Poisson, Thekkelnaycke M. Rajendiran, Amjad P. Khan, Qi Cao, Jindan Yu, Bharathi Laxman, Rohit Mehra, Robert J. Lonigro, Yong Li, Mukesh K. Nyati, Aarif Ahsan, Shanker Kalyana-Sundaram, Bo Han, Xuhong Cao, Jaeman Byun, Gilbert S. Omenn, Debashis Ghosh, Subramaniam Pennathur, Danny C. Alexander, Alvin Berger, Jeffrey R. Shuster, John T. Wei, Sooryanarayana Varambally, Christopher Beecher, Arul M. Chinnaiyan (2009). Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression Nature, 457 (7231), 910-914 DOI: 10.1038/nature07762

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On prostate cancer, genetics and masturbation

This morning I was searching my Google Reader for a missing article on genetics and advanced prostate cancer when I came across this interesting article entitled, "Masturbation and Prostate Cancer Risk", which was a bit of an eye opener on a Monday morning to say the least.  The opening paragraph boldly declared:

"Frequent masturbation in young men is linked to higher risk of early prostate cancer, but it lowers prostate cancer risk for men in their 50s, a study shows."

WebMD reported that the author of the paper, published in the Brit J of Urology, told them that:

"Frequent masturbation during men's 20s and 30s increased their risk of prostate cancer, but men in their 50s who masturbated frequently had decreased risk."

Different results like this always leave me suspicious of meta data manipulation.  Thinking this was a large scale longitudinal study of 800 odd men, I was disappointed to discover they merely used questionnaires and apportioned risk.  Well, that's a poorly controlled study and it's anyone's guess what the real risk actually is.  Random associations and spurious findings are highly likely with this approach, especially given that different studies using different methodologies have elicited different results.

My conclusion?  An amusing, but likely spurious finding, unless a longitudinal epidemiology study can verify what, if anything, is really happening.

As for genetics, well I'm still looking for that particular paper...

Sources:

Sources: Polyxeni Dimitropoulou, Artitaya Lophatananon, Douglas Easton, Richard Pocock, David P. Dearnaley, Michelle Guy, Steven Edwards, Lynne O’Brien, Amanda Hall, Rosemary Wilkinson, Rosalind Eeles, Kenneth R. Muir (2009). Sexual activity and prostate cancer risk in men diagnosed at a younger age BJU International, 103 (2), 178-185 DOI: 10.1111/j.1464-410X.2008.08030.x

Over hyped cancer drugs or sensational journalism?

Today I was thinking about what cancer drugs might be good to watch out for this year, such as abiraterone from Cougar Biotech currently being tested in prostate and breast cancers and Affinitor from Novartis, which is expecting FDA approval this year in renal cancer.  A quick Google search turned up this article from the London Times and made me cringe at the following headline:

"Cancer drug could save the lives of 10,000 a year". 

Oh dear.

The article talks about the potential impact of abiraterone in prostate cancer.  Now, don't get me wrong I like both of these drugs and believe they will make an impact - on survival, but not as a 'cure' which is implicit in the saving lives byline.

Journalists often fail to understand the basics of cancer research.  While the goal is to find a drug that induces remission or cure, in the meantime until our understanding of the science and biology improves greatly, we are stuck with expressing clinical trial results as 'survival', that is how long a patient lives compared to standard therapy.  Otherwise, the only real known cures are surgery and stem cell transplant and even then not all are cured by either procedure.

There is a huge difference implicit in 'saving lives' versus 'living longer'.

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Cyberknife - a new targeted tool for treating cancers more effectively?

Well, I was quite impressed while reading about a new technology for treating cancer on the BBC Health website today:

"A robot radiotherapy machine to treat cancer is to be available in the UK for the first time from February.

Called the Cyberknife, it moves with a patient's breathing so tumours can be targeted with greater accuracy, and damage to healthy tissue is reduced."

Which all sounded fine and dandy until you get to the caveat:

"The machine will be at the private Harley Street Clinic in London."

Oh dear, so you can only get access to the treatment in the UK if you can afford to pay for it?  The situation is equally muddled in the USA, where some Medicare carriers will pay for it and some will not, as reported recently by the WSJ.

By the way, conventional radiotherapy typically involves twenty or more short sessions with low-dose radiation.  The Cyberknife can deliver high dose beams with greater accuracy, which means that patients receive fewer treatments, often as few as 3.

In other words, the new radiotherapy can target the cancer cells and spare many of the surrounding normal cells.  That's very good news indeed for patients.

Although it's still a relatively new technology undergoing research in global clinical trials, it may have applications in treatment of cancers such as brain, prostate and liver cancer; time will tell, as the Washington Post noted last month.  More robust data from the clinical trials may prove to be an interesting area to watch out for.

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Abiraterone in prostate cancer

Dr Johann de Bono, whose group presented the phase I data that generated so much recent interest, has been captured on video at the Prostate Cancer Foundation Scientific Retreat.

In the talk, covers the background behind the drug's development in prostate cancer, as well as explaining the data so far in patients who have failed standard docetaxel chemotherapy.

You can view the videos here and here.

There is more information on a previous post about how abiraterone works in prostate cancer.  The drug is now in phase III development and new trials in breast cancer are expected to start soon.

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Will abiraterone impact survival in advanced prostate cancer?

Prostate cancer, the most common carcinoma in men, is characterised by malignant cells that are both androgen-dependent and androgen-independent.  In the cells that are androgen-dependent, a critical level of androgen is required to activate a sufficient number of androgen receptors (ARs), so that death-signaling genes are repressed.  Ninety percent of androgens are produced by the testes, with 10 percent produced by the adrenal glands or the cancer cells themselves.

Image: Two prostate cancer cells dividing from Cancer Research UK

Prostate cancer treatment is loosely divided into three phases based on the stage of disease; early stage disease, followed by a hormone therapy phase and finally an advanced cancer phase also know as stage IV, which usually leads to metastasis i.e. spread of the cancer cells to others areas of the body.

Early phase disease (stage I and II) can be picked up from an annual physical exam and involves surgical removal of the prostate gland, radiation therapy with or without hormone therapy, and "active surveillance", also known as watchful waiting.

The hormone therapy phase (stage III) is treated with primary androgen deprivation therapy, which may include castration and therapeutic disruption of the normal androgen production regulatory pathways.

Advanced metastatic prostate cancer (stage IV) is where the cancer cells can become androgen ablation insensitive (also called hormone refractory prostate cancer or HRPC).  As the patient becomes insensitive to the hormone therapy, the levels of prostate specific antigen (PSA) increase.  Chemotherapy is considered the standard of care for advanced stage disease. There are only three drugs approved by the FDA to treat HRPC; docetaxel, mitoxantrone, and estramustine, all of which have noticeable side effects, but show an increase in survival over best supportive care by approx. 18 months.

Recent therapies in the clinic have had a difficult time with FDA approval.  Abbott's atrasentan (Xinlay) was found by the FDA advisory panel to be lacking in clear evidence that it prolonged survival despite significant drops in the PSA levels.  Ditto for GPC/Spectrum's satraplatin, although it was approved by the European authorities. 

More recently, Dendreon's Provenge (sipruleucel) was reviewed by the panel and more data was required because the trial just missed significance (0.052).  This vaccine used a technique called Antigen Presenting Cells (APCs) to alert the patient’s T cells to attack the cancer and will likely be available for patients at some point in the next 12 months.

There are several drugs in development for prostate cancer, including AstraZeneca's endothelin receptor antagonist, Zibotentin, Genentech/Roche's Avastin and Merck/Ariad's mTor inhibitor, deforolimus.

In February this year another biotechnology company, Cougar, announced some promising data.  Results of a phase II trial abiraterone in chemotherapy naiive patients demonstrated a 50 percent drop in PSA in 61 percent of patients. A phase II trial in patients having failed first-line chemotherapy with docetaxel showed 48 percent of patients having 50 percent decrease in PSA and 53 percent experiencing on-going stable disease. Additional phase I and II studies show similar promise with patients who have failed other treatment regimens including chemotherapy, leutenizing hormone analogs and other hormonal therapies.  It remains to be seen, however, whether the falls in PSA will lead to a demonstrable improvement in survival (witness the atrasentan and satraplatin experiences).

So how does abiraterone work?  In simple terms, it works by blocking the androgen sex hormones that fuel the cancer.  Ten percent of the normal levels are produced in the adrenal glands, but theories point to cancer cells producing their own testosterone, thereby fueling the tumour's growth.

Abiraterone interferes with the cell's mechanisms for adrenal steroid synthesis through two very specific pathways, P450 enzymes 17-alpha hydroxylase and C17,20-lyase. This approach is thought to result in far fewer side effects and also inhibits androgen synthesis with tumour cells, although the data is still immature.

The latest study, reported in the Journal of Clinical Oncology, is a small one based on 21 patients with advanced, aggressive prostate cancer treated with the drug, but data has been collected on a total of 250 worldwide.  It found significant tumour shrinkage, and a drop in tell-tale levels of a key protein produced by the cancer in the majority of patients.

To date, no patient has taken the drug for longer than two-and-a-half years, and so it has not been possible to determine exactly what the effect of the drug on life expectancy will be.  These findings need to be reproduced in larger scale clinical trials, but the results so far look promising for advanced stage prostate cancer.

News Sources:

BBC News

Reuters

This article is part of the Cancer Research Blog Carnival being hosted by the Sciencebase Science Blog.

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Recurrent fusion genes and prostate cancer

The discovery of recurrent gene fusions in a majority of prostate cancers has important clinical and biological implications in the study of common epithelial tumours.

Gene fusion and chromosomal rearrangements were previously thought to be primarily the oncogenic mechanism of hematological malignancies and sarcomas.  The resulting gene fusions can serve as specific therapeutic targets, as exemplified by the development of imatinib (Gleevec), which specifically inhibits the BCR-ABL gene fusion product that defines chronic myeloid leukemia.

Prostate cancer cells: from www.bu.edu        

The prostate cancer gene fusions that have been identified so far are characterized by 5' genomic regulatory elements, most commonly controlled by androgen, fused to members of the Ets family of transcription factors, leading to the overexpression of oncogenic transcription factors.

The specificity of ETS gene fusions in prostate cancer suggest that they may potentially have causal roles in prostate cancer and suggest utility in prostate cancer detection, stratification and treatment. 

Time will tell.

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Of Mice and Men.....

The latest news from the ASCO prostate cancer symposium is that the disease may be caused by a virus. Essentially the cancer may result from chronic inflammation, perhaps as a response to infection via a virus. To see the press release click here.

The findings are particularly poignant for me because my own father died 5 years ago after a brave fight against the disease. I also have several friends whose own Dads are going through the same thing, which is always very sad. While the current news won’t help any of them, it does give hope for the future that other fathers, brothers, uncles and friends could potentially be screened and diagnosed at a much earlier stage, when the chance of surgical cure is significantly higher. Much in the same way that identification of the HPV has led to the virtual eradication of cervical cancer in the western world, so the latest news may lead to a dramatic impact on prostate cancer over the next 10 years, if the findings hold up.

The virus, called XMRV, was found 30 times more frequently in men with prostate cancer who had a particular genetic mutation than in men without this mutation. What’s interesting is that the XMRV virus is similar to a virus that causes leukemia in mice and could be the first evidence that a virus is linked to prostate cancer. According to the researchers at the Cleveland Clinic, damage to a protein that fights viruses, called RNaseL, may increase susceptibility to prostate cancer. Dysfunction may occur when a gene called HPC1 – the gene that produces the RNaseL protein – is mutated and stops functioning normally. As we saw in a previous post, genetic mutations lead to aberrant cell growth because the apoptotic switch is off. Men with this genetic alteration are thought to be more susceptible to prostate cancer.

Researchers from UCSF used a tool called a DNA ViroChip containing the genetic sequences of nearly 1,000 viruses to screen prostate tumor samples from 86 men who had their prostates surgically removed. They then compared the incidence of viral infection between men who had two mutated copies of the HPC1 gene and men with one or no copies of this altered gene. The XMRV virus was found in 45% of the 20 men with two mutated copies of the HPC1 gene, compared with only 1.5% of the 66 men with one copy or no copies of this mutated gene. Interestingly, the same DNA chip process was used to identify the SARS virus 3 years ago, so the concept has a sound basis. It also validates the use of the virus chip to discover previously unknown viruses, and to learn more about viral causes of disease. The power resides in its ability to simultaneously screen for all viruses, without preconceptions or bias. In the case of these prostate tissues, it is unlikely that anyone would have suspected such a virus to be linked to the disease.

In the past, data from other studies have suggested that some prostate cancers could be caused by infection, but no one has shown a link, until now. An epidemiological study is being planned to look at the association between sexual history, personal and family medical history, viral infection, and prostate cancer.

If the XMRV virus does indeed cause prostate cancer, it could potentially become a therapeutic target for drugs or a vaccine. Wow! Stuff like this often ends up in the ASCO plenary sessions as a major finding in the battle against cancer. Watch this space…