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Posts tagged ‘provenge’

J&J unblind Zytiga phase 3 trial in pre-chemotherapy castrate-resistant prostate cancer

By on March 8, 2012

The big cancer news that hit the news wires this morning was not entirely surprising:

“Janssen Research & Development, LLC today announced that it has unblinded the Phase 3 study of ZYTIGA (abiraterone acetate) plus prednisone for the treatment of asymptomatic or mildly symptomatic patients with metastatic castration-resistant prostate cancer (CRPC) who have not received chemotherapy.”

Source: Press Release

Given the accelerated approval of abiraterone in the post-chemotherapy setting last year, the results in the pre-chemotherapy setting were widely expected to:

  1. Be even better in earlier stage than the 3.9 months OS advantage already seen
  2. Likely to have an early study halt

Zytiga already has Compendia listing through mention in the NCCN Guidelines with level 2a evidence in the pre-chemotherapy setting, essentially listed with ketoconazole.  Several industry friends with access to market data have mentioned that the pre-chemotherapy share for abiraterone is already around 20-25%, not bad at all given it doesn’t have full approval prior to docetaxel use and has been on the US market less than a year.

No clinical details were provided by the Data Science Monitoring Committee (DSMC), but the data are expected to be presented at a clinical meeting later this year (Adam Feuerstein of The Street speculated that ASCO was a likely target).  I do hope so, but that would suppose an abstract was sent in with no data by the late breaking deadline of Feb 1st.

The company did state that:

“The company plans to submit for regulatory approval in the United States and around the world beginning in the second half of 2012.”

At this rate, J&J should receive the new indication in the first half of 2013, based on the 302 trial data, depending on whether the filing is accepted as an accelerated, priority or regular review.  No doubt this information will be apparent after filing has taken place.

One challenge with early stoppage of trials based on progression-free survival (PFS) is that determining whether patients truly live longer, as judge by overall survival (OS), becomes much more difficult, if not impossible.  Once patients on placebo are offered the active drug, there is a crossover effect confounding any subsequent data analysis.

The news today will impact several other companies in the advanced prostate cancer landscape

Medivation and Astellas are expected to file MDV3100 in the post chemotherapy setting soon based on the phase 3 AFFIRM study.  This agent has several attractive advantages over abiraterone in that:

  • no concomitant prednisone or steroid administration is required (hence less puffiness and related side effects) and
  • it targets splice variants as well as the AR, which may lead to less drug resistance.

Based on the post-chemotherapy data we’ve seen so far (MDV3100 saw a slightly longer improvement in OS, which may be related to the above), we can expect that the phase III PREVAIL trial prior to docetaxel to also show a similar trend to the Zytiga study.  It won’t surprise me at all if the interim analysis also leads to the DSMC recommending early unblinding.  Based on the Zytiga data, it wouldn’t surprise me if the interim analysis for MDV3100 came up as early as mid next year, which would be earlier than expected.

Two drugs that will be impacted by these developments with hormonal agents are Dendreon’s Provenge, which is approved prior to docetaxel and Sanofi’s Jevtana (cabazitaxel), which is approved after docetaxel.

The immunotherapy sipuleucel-T (Provenge) is an unlikely partner for combination with abiraterone given that steroids suppress the immune system, while many older men with metastatic would much rather take a pill than undergo the debilitating side effects of myelosuppressive cytotoxics such as the taxanes.  Certainly my Dad was in that category, as are many men in their 70’s.  Once approved, Alpharadin (radium-223) may well offer a useful option for that subset of patients, especially of they have already tried ADT and seen biochemical relapse with rapidly rising PSA levels.  Provenge is likely to be negatively impacted by Zytiga approval pre-chemotherapy.

Approval of Zytiga in the pre-chemotherapy setting will likely increase its share there, since many oncologists are somewhat sceptical about Provenge in terms of how it works, how effective it is, how to monitor patient progress on it (it doesn’t seem to affect pain, PSA or any of the usual markers of disease) and the hefty price tag ($93K for 3 infusions) doesn’t help either.  MDV3100 would likely have an even stronger impact, since urologists dislike using steroids and managing the complications, plus Astellas have a solid franchise in urology already.

At this rate, Jevtana will be pushed further out down the treatment paradigm and reserved for salvage therapy in the younger, fitter patients.  Its biggest challenge is competing with it’s fellow taxane, docetaxel, since many oncologists will re-challenge with the generic if the patient previously did well on it.  Any delay (through improved survival with newer, earlier treatments) will delay time to cabazitaxel uptake.  This will likely get worse once MDV3100 is approved, and oncologists can sequence them.

At what point will we see placebo trials go away?

I’m not a big fan of placebo-controlled trials, except where there are no standard of care or alternative clinical options for patients.  Until recently, the advanced prostate cancer market was relatively immature with few approved therapies, so placebo trials were de rigeur.  Going forward though, new entrants to the market will face the ethical dilemma of how can placebo-controlled trials be justified in a market where drugs such as abiraterone (or MDV3100 and Alpharadin, if approved) have a proven survival advantage?  It will push the bar for new market entries higher (and more costly).  Millennium’s TAK-700 (orteronel), which is similar to abiraterone but may or may not need steroids, may well have just made it into clinical trials in time before that window shuts off.

And finally…

The good thing is that after a decade of not much happening in the advanced prostate cancer market, we are seeing a lot if new therapies, often with different mechanisms of action, being developed for this disease.  There are others I haven’t mentioned here, including custirsen (Oncogenex) and cabozantinib (Exelixis) which are also undergoing clinical trials and we await those results too.

As more drugs for castrate-resistant prostate cancer (CRPC) are approved, sequencing and combinations will also come to the fore to determine optimal strategies for improving outcomes for men with prostate cancer.  It’s an exciting market to be following given the rapid progress over the last year or so, but hopefully, this is just the beginning and there will be much more yet to come.

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The challenge of prostate cancer drug approval versus reimbursement

By on February 27, 2012

Arc de Triomphe, Paris

Scenes from EAU - Arc de Triomphe

Here at the European Association of Urology (EAU) congress in Paris, there are some interesting debates amongst delegates attending the meeting regarding new therapies either recently – or about to be approved – for castrate-resistant prostate cancer (CRPC).

For example:

  1. How should abiraterone and MDV3100 be sequenced pre or post chemotherapy?
  2. Would combining the two drugs post chemo be a better strategy that leads to superior outcomes?
  3. Where does chemotherapy fit into this emerging paradigm?  Do we need chemotherapy in an new era of oral therapies?  If yes, which patients should be considered eligible?
  4. How will immunotherapies such as Provenge be used once approved – before or after abiraterone in the pre-chemo setting, but likely not together given the steroid component?

Reimbursement remains a challenge in Europe

Now, these are all valid clinical questions, but there is an elephant in the room that isn’t being discussed so far (Dendreon got a lot of stick over the US price last year, which was publicly considered ‘very expensive’ or ‘too expensive’ by many thought leaders for Europe), namely, reimbursement.

Consider that the US wholesale price for Provenge is $93K and abiraterone is ~$48K, depending on how many months are needed (likely more in the pre-chemotherapy setting), you can already see that both sequencing and combinations are going to take the economic costs much higher for European health care systems.  That’s without figuring in the price for MDV3100 and Alpharadin, which have not been filed yet or cabazitaxel, which costs around $42K in the US depending on the number of cycles taken (from memory).

However, with Taxotere now generically available, it’s not hard to imagine many centres repeating docetaxel in second-line if the patient had a good response rather than administer the more expensive cabazitaxel.  In general, though, there is little doubt that the impact of either sequencing therapies, or using in combination, will add to the cumulative cost of treatment in an upwards manner.

The bigger questions for Europe in this scenario then become:

  • How to best manage available resources from the allocated healthcare pot?
  • The majority of money in cancer care is spent on the last 6 months of people’s lives – how should that be addressed ethically, economically and medically?

By the way, for American readers of this blog, please don’t call European provision ‘socialist healthcare’ – this is a silly misnomer, because:

  • It isn’t free – people pay for it – it’s deducted at source from wages in most countries
  • Several EU members such as the UK have a conservative, not socialist, Government in power
  • In Germany, a model of private providers similar to the US exists, and even in the UK additional private care can be bought through an employers offering, proving that not all European countries provide healthcare in the same way.

Abiraterone will likely be reimbursed at a discount in the UK

Meanwhile, J&J’s abiraterone is an interesting case study in point.  While approved by the EMA/CHMP, it isn’t available in all EU countries yet, as it wenders its way through the reimbursement approval process.  As I understand from delegates here, it is available in Ireland, for example, but was rejected by NICE in the UK as ‘too expensive’.

What was interesting here at EAU was learning from some EU thought leaders and competitor manufacturers that Janssen have apparently negotiated a discount of 40% of the list price in order for it to be available in the UK, although nothing official has been announced yet.

Will UK pricing have a broader impact on continental Europe?

Given the severe pan Europe economic hardship at present, one wonders how low this pricing strategy might go given that Greece is usually the lowest priced country.  If the 40% discount being bandied about here at EAU is correct, will other other EU countries look at the UK price and demand a similar discount?  It’s one thing the UK and say, Spain and Greece being 10-20% lower than Germany, but nearly half the price might upset the natural basket negotiations and wheeler dealing that usually occur.

You can almost imagine a satirical cartoon in Private Eye or The Economist, whereby jaundiced eye balls loom eerily out of a map of Europe, as each country warily looks at its usual reference baskets.

It will be interesting to watch what happens in the near future, because what happens in the advanced prostate cancer arena may have broader implications, not only for all EU countries, but also other manufacturers in the cancer marketplace.  Everyone involved is going to be following this evolution carefully.

 

The spiralling costs of cancer research and treatment

By on August 23, 2011

“The problem at the moment is that it takes $1bn [£600m] to get a drug to market and 15 years or more. That is the justification for the pharmaceutical industry charging high prices.

If on the other hand by the time you get to phase 2 you know exactly which patients it is going to work on, you only put those patients through and instead of 10% you get an 80% response rate.

You get a licence on the basis of the data and don’t have to go to phase 3 (a trial involving thousands of people). That saves vast sums of money and years of development. What that does to the business model is it means you can justify charging lower prices because it cost a lot less in the first place.

If we get this right, it changes the entire dynamics of the business model of the pharmaceutical industry.”

Source Harpal Kumar, the chief executive of Cancer Research UK (CRUK) via The Guardian

A UK friend kindly sent me this article today and provocatively asked me what I thought. Hmmm, a very interesting, meaty and relevant topic indeed.  Here goes…

Will this change the way we do business in cancer research?

The theory behind this statement by CRUK is that if we develop more targeted drugs to fewer patients and generate higher response rates e.g. 70-80% in a specific biologic subset, instead of say, 10% in a broader population, then the costs of development will come down and thus the treatment cost of the disease will ultimately lower.

Not so fast!

The reality might actually be different, and here’s why:

  1. For this to happen you need more translational research, biomarkers and companion diagnostics.
  2. The cost of researching and developing the targets is quite high.
  3. While clinical development costs might be lower with fewer large scale trials, the costs of iterative phase II trials will go up and the available pool of patients for commercialization is now much lower e.g. 5% of patients with the ALK translocation in lung cancer not 100% of all available relapsed patients.
  4. In order to maintain revenues, it is basic economics 101 that smaller patient niches will equal higher costs.

If you are not convinced of the last point, take a look at the costs of treating rare diseases or small subsets of patients.

Some good examples exist in the hematology space include:

  1. Alexion’s Soliris (eculizumab),which is approved for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH). This is a rare hematologic disorder that affects approx. 8,000 to 10,000 people in North America and Europe. The cost is something like $400K per annum.
  2. Genzyme’s Fabrazyme (agalsidase beta) for the treatment of Fabry Disease, another rare hematologic condition, this time an inherited metabolic defect that affects 1 in every 40-50,000 people in the US. Fabrazyme lowers the amount of a substance called globotriaosylceramide (GL-3), which builds up in cells lining the blood vessels of the kidney and certain other cells. It’s very effective, but certainly not inexpensive at around $160K per annum.

What is the likely impact of the changing research paradigm?

Both of the above patient pool sizes are not out of the realm of reality for a comparison with oncology.

In the old model, clinical trials tended to involve more allcomer trials, i.e. patients with a particular tumor type (e.g. non-small cell lung cancer), stage of disease (metastatic) and line of therapy (frontline, relapsed or refractory).

In the new world order, things are changing in clinical trials already:

  1. Roche’s Zelboraf (vemurafenib) was recently approved in metastatic melanoma in patients with the BRAF V600E mutation, reducing the available pool who might respond by 50%. It was launched last week with a price tag of around $56.4K for an average of 6 months treatment.
  2. Crizotinib (Xalkori) is being evaluated in patients with NSCLC who have the ALK translocation and have failed prior therapy. That’s a tiny subset of patients. Patients with this aberration make up maybe 4-7% of the total NSCLC pool. Imagine how small the target population will be for other ALK inhibitors in crizotinib refractory disease?!
  3. The cost of funding and finding biomarkers that predict response is a huge undertaking.  Genentech have no doubt spent many millions looking for a predictive biomarker for Avastin, so far to little avail.

Of course, there are plenty of other exciting targets with small subsets being evaluated in the clinic, but there are several factors to consider:

  1. Small subsets = fewer patients = higher cost.
  2. Will combination strategies be affected by the cumulative costs that will inevitably result? e.g. Yervoy + Zelboraf in metastatic melanoma potential treatment cost = $170-180K if the studies are successful in showing that survival is improved.
  3. Since Dendreon’s Provenge ($93K) was recently given the green light by the CMS, the costs of new targeted entrants is creeping up over the $100K watershed marknot down, viz Yervoy ($120K) and Adcetris (~108K), for example.

In conclusion…

I admire the chutzpah of CRUK, but disagree with some of their conclusions, which I think are rather naive.

Today, I will go on record here and declare that I believe specialised treatment based on the underlying biology will ultimately cost more, not less, in the long run in terms of research and development, diagnostics/biomarkers and treatment costs of ever smaller subsets.

However, I have no doubt we will ultimately see better results clinically with this more scientific approach but this will come at a cost.  While that’s great news for patients and caregivers, it is not so great for the payers, Government or investors, because higher risks and R&D costs will inevitably equate to more failures and this drives higher costs in a spiral fashion.  Ultimately, those costs will trickle down to all of us in the form of higher co-pays and more expensive medical plans to cover the payers margins.  Success has to be paid for somewhere down the line.

And the constant refrain from everyone in Pharma of “let’s do more with less” will increase.

It’s a vicious cycle of unsustainability, with no end in sight.

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How picking up prostate cancer earlier may improve outcomes

By on August 4, 2011

Prostate cancer is very much in the news this morning, not all for good reasons though.

Dendreon’s Provenge launch to community oncologists did not go well

Dendreon’s stock is in free fall after the company missed it’s earnings and revenue expectations rather badly yesterday.  Adam Feuerstein of The Street has a nice overview of the 2Q earnings call for those of you interested.

There are a couple of things that come to mind though:

  1. The reimbursement may well have a broader impact on the landscape than many realise – CMS may pay for a drug or vaccine, but it doesn’t always pay for the surrounding expenses associated with it*
  2. The “cost dense” issue is offset by ipilimumab (Yervoy) doing better than expected in their metastatic melanoma launch despite a higher overall price (execution matters!)
  3. The root of Dendreon’s problem may well be lack of demand and healthy scepticism from medical oncologists over the value of Provenge relative to the cost:benefit (no impact on tumour shrinkage, bone pain, etc; patients just live a little longer)
  4. Strategy and execution are key in cancer launches to community oncologists

* There are some excellent reimbursement experts out there such as my good friend Bobbi Buell at Covad who steer companies through this kind of minefield.  In fair disclosure, I know I appreciated and valued her solid advice when I was at Novartis and we launched Gleevec in CML.  Having such expertise is a necessity, not a luxury, these days.

Medivation’s MDV3100 may have new opportunities

There was good news from Medivation that caught my interest.  Medivation are developing their androgen receptor (AR) antagonist, MDV3100, in castrate resistant prostate cancer pre and post chemotherapy, with interim results from the latter possibly expected by the year end.  Today, the company announced some positive preclinical data in breast cancer:

“Researchers at the University of Colorado Denver… provide evidence that MDV3100 inhibits proliferation of breast cancer cells.

In different cell-based assays, MDV3100 was able to inhibit both androgen- and estrogen-mediated breast cancer cell proliferation.”

What are the significance of these findings?  Well, the company quoted one of the study authors, Dr Jennifer Richter:

“Our findings are exciting because they challenge the existing idea that androgens are protective in breast cancer by demonstrating that androgens can stimulate proliferation of breast cancer.

These preclinical data show that MDV3100 suppresses androgen-driven breast cancer cell growth and, surprisingly, also suppresses estrogen-driven breast cancer cell growth.”

I think it would be reasonable to expect a phase I clinical trial to evolve soon to test the hypothesis in women with hormone-sensitive breast cancer.

TMPRSS2:ERG may be a more useful marker than PSA in prostate cancer

The big news that really cheered me most this morning, though, was new  data from Science Translational Medicine showing the feasibility of a simple urine test to pick up signs of prostate cancer potentially earlier than we do now. Having had a father who was suddenly diagnosed with stage IV disease, hearing about a test that may help diagnose it earlier than currently feasible with biopsies or PSA is a most welcome advance.

Back in 2005, Arul Chinnaiyan’s lab reported a fusion between two genes present in around half of all prostate cancers called TMPRSS2:ERG.  When the two genes, TMPRSS2 and ERG, combine, they cause aberrant activity and drive prostate cells to grow out of control, leading to cancer.  This is in much in the same way BCR-ABL drives aberrant activity in chronic myeloid leukemia (CML).  The next step after the discovery was to evaluate the reliability and faithfulness of the gene in indicating whether men had prostate cancer.

In the latest report, the researchers measured the level of the fused gene in the urine of men (n=1312) with high PSA levels in their blood, then looked at TMPRSS2:ERG levels, tumour volume and clinically significant prostate cancer, and PCA levels.  They analysed the data to see if the two markers were a good indication of prostate cancer or not.

Half of the men sampled were found to have the TMPRSS2:ERG gene, confirming previous research by the group.

The results also demonstrated:

 “TMPRSS2:ERG, in combination with urine prostate cancer antigen 3 (PCA3), improved the performance of the multivariate Prostate Cancer Prevention Trial risk calculator in predicting cancer on biopsy.”

Essentially, this means that by combining the TMPRSS2:ERG results with PCA data, the group have found a way to stratify men with prostate cancer in terms of risk – in other words, they have a larger and more invasive tumour that requires aggressive treatment.

The diagnostic technology was developed by Gen-Probe, so I think it would be reasonable to assume the company will submit the data to the FDA for approval once further tests have been completed to evaluate accuracy and specificity of the test.  If those are successful, we may well have a new diagnostic test for prostate cancer in the not too distant future.

It goes without saying that picking up aggressive disease earlier and treating it effectively will likely lead to better outcomes for men with prostate cancer.

 

References:

ResearchBlogging.orgTomlins, S., Aubin, S., Siddiqui, J., Lonigro, R., Sefton-Miller, L., Miick, S., Williamsen, S., Hodge, P., Meinke, J., Blase, A., Penabella, Y., Day, J., Varambally, R., Han, B., Wood, D., Wang, L., Sanda, M., Rubin, M., Rhodes, D., Hollenbeck, B., Sakamoto, K., Silberstein, J., Fradet, Y., Amberson, J., Meyers, S., Palanisamy, N., Rittenhouse, H., Wei, J., Groskopf, J., & Chinnaiyan, A. (2011). Urine TMPRSS2:ERG Fusion Transcript Stratifies Prostate Cancer Risk in Men with Elevated Serum PSA Science Translational Medicine, 3 (94), 94-94 DOI: 10.1126/scitranslmed.3001970

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Wnt/β-Catenin Signaling in T-Cell Immunity and Cancer Immunotherapy

By on December 1, 2010

Recently, at the NY Chemotherapy Foundation symposium, Dr Phil Kantoff from Dana Farber gave a lecture on new therapeutic strategies in prostate cancer. Despite the unsociably early hour (7.30am), the room was almost packed.

While waiting for the session to start, over coffee I had some cheerful banter with some of the oncologists around me.  They expressed a keen desire for more tolerable and effective therapies for their mostly elderly patients with prostate cancer, many of whom were too frail or disinterested to really consider chemotherapy once hormone therapies ceased to work.

Several of them were really interested in, but somewhat puzzled about, the recent spate of new data on hormone therapies (abiraterone) and immunotherapy (sipuleucel-T) and how they work, after all, as one pointed out – after a lifetime of treating thousands of patients with chemo and more recently, targeted therapy – getting their heads around new technologies such as vaccines was difficult and challenging to explain to patients in simple language:

“We know that it works, but how does it work?  That’s what I’m stuck on.”

Another oncologist wondered why does abiraterone appear to work after failure of docetaxel chemotherapy?  He wanted to know if the break from hormone therapy with chemotherapy meant that the androgen receptor (AR) was still driving tumour growth and whether re-treatment with any hormone therapy would actually be beneficial?

Fast forward to Kantoff’s lecture.  He covered the basic ground well and also went through the recent trials, including the recent data from ESMO on abiraterone, the NEJM data on MDV3100 and several trials for sipuleucel-T, including the Small et al., (2006) data and the more recent IMPACT trial in asymptomatic and mild symptomatic metastatic castration resistant disease (CRPC) that showed a 4.1 month advantage over placebo, leading to approval by the FDA earlier this year.

There was some discussion of the survival data, since disease progression, measured as progression-free survival (PFS), may often not be significant, but overall survival (OS) is. Why is this?  Kantoff postulated that the time to the biological effect of sipuleucel-T may take longer than the time of measurement of progression (yes, but why?)  PFS is also a difficult thing to measure in prostate cancer

The question for me, though, is what is the mechanism behind the delayed biological effect?  How can this be explained?

In simple terms, vaccines such as sipuleucel-T rely on stimulating the bodies T-cells to fight the cancer.  It doesn’t mean that there will necessarily be any effect on the tumour size, as measured classically by RECIST, but rather the overall impact is inevitably more on immunity effects, which are probably less well understood.  Looking through the recent literature, though, I came across a most interesting article in Clinical Cancer Research:

“Wnt ligands are lipid-modified secreted glycoproteins that regulate embryonic development, cell fate specification, and the homeostasis of self-renewing adult tissues.  In addition to its well-established role in thymocyte development, recent studies have indicated that Wnt/β-catenin signaling is critical for the differentiation, polarization, and survival of mature T lymphocytes.  Here, we describe our current understanding of Wnt signaling in the biology of post-thymic T cells, and discuss how harnessing the Wnt/β-catenin pathway might improve the efficacy of vaccines, T-cell–based therapies, and allogeneic stem cell transplantation for the treatment of patients with cancer.”

We’ve covered Wnt on this blog before, so I’m not going to cover canonical signalling and the delights of Frizzled and Dishevelled in this post, but see here for more background if you’re interested in the biology.  Of relevance to this discussion, though, is a quote from the article:

“… the discovery that Wnt/β-catenin signaling is a key regulator of T-cell immunity now raises the possibility that potentiating Wnt signaling could be used to improve cancer therapies through immune-based mechanisms.”

It will be interesting to see if prostate cancer vaccines such as sipuleucel-T actually have an effect on Wnt signalling, thereby explaining the enhanced T-cell effect.

Wnt signalling has also been shown to have a pivotal role in promoting stem cell self-renewal while limiting proliferation and differentiation (see Staal et al., and Fleming et al., 2008 in the references below).  Inevitably, the biological effects on immunity can take time to take effect compared to the direct effects of say, DNA methylation or angiogenesis, and this may well explain the delay in efficacy with vaccines.  The important thing for men with asymptomatic metastatic prostate cancer is that once it happens, the effect is both prolonged and durable, thereby offering them a new therapy option prior to chemotherapy.

As for the question about re-challenge with existing hormone therapies on the market, I don’t know the answer to that, but it’s a very good question, and perhaps best covered in another blog post unless some of the oncologists reading this have any practical experience to relate?

References:

ResearchBlogging.org Gattinoni, L., Ji, Y., & Restifo, N. (2010). Wnt/β-Catenin Signaling in T-Cell Immunity and Cancer Immunotherapy Clinical Cancer Research, 16 (19), 4695-4701 DOI: 10.1158/1078-0432.CCR-10-0356

Staal, F., Luis, T., & Tiemessen, M. (2008). WNT signalling in the immune system: WNT is spreading its wings Nature Reviews Immunology, 8 (8), 581-593 DOI: 10.1038/nri2360

Fleming HE, Janzen V, Lo Celso C, Guo J, Leahy KM, Kronenberg HM, & Scadden DT (2008). Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo. Cell stem cell, 2 (3), 274-83 PMID: 18371452


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#ESMO 2010 round-up #2

By on October 12, 2010

"Do or do not. There is no try."

  Master Yoda

 

2010 looks to be a good year for prostate cancer after a six year wait since the last therapy (docetaxel) was approved for what was then known as hormone refractory (now called castrate resistant) prostate cancer, or CRPC, for short.

This year has already seen two new approvals for the disease, namely:

  • Sipuleucel-T (Provenge) from Dendreon in asymptomatic or mildly symptomatic CRPC prior to chemotherapy.
  • Cabazitaxel (Jevtana) from sanofi-aventis in docetaxel failure CRPC.

In addition to these, we have also seen new data for two other novel hormonal therapies, namely abiraterone (Cougar/J&J) and MDV3100 (Medivation/Astellas) in the CRPC setting.

MDV3100 is now entering phase III trials in the 2nd line and asymptomatic setting, while the phase III data was presented on abiraterone here at ESMO yesterday in the Presidential Symposium.

Abiraterone was originally developed by the Institute of Cancer Research (ICR) in the UK and is a CYP17 steroid inhibitor that prevents the biochemical conversion of cholesterol to testosterone. Testosterone is secreted by the testes, adrenal gland and prostate tumour to ensure it's growth and survival via androgen receptor (AR) signalling. The simple idea here is that biochemically inhibiting the key pathways with both abiraterone and a steroid such as prednisone or dexamethasone, will lead to improve outcomes for men with prostate cancer.

The proof of the pudding lies in a randomised phase III trial to determine whether the combination is both safe and effective.

The results were interesting, to say the least.

The overall survival (OS) was as follows:

  • Abiraterone + prednisone: 14.8 months
  • Placebo + prednisone:       10.8 months

The PSA response also favoured the treatment arm:

  • Abiraterone + prednisone: 38.0%
  • Placebo + prednisone:      10.1%

Adverse events with abiraterone treatment were obviously higher than for placebo, but in general it appeared well tolerated and an important common side effect was fluid retention (30.5% of patients, with 2.4% of them being severe ie grade 3/4 in severity).

No data on the circulating tumour cells was given at this meeting, but the analysis is underway and will be published in 2011.

The big questions that spring to my mind are how do these results stack up against what we have and is the control arm ideal?

Cabazitaxel was approved earlier this year in combination with prednisone versus mitoxantrone plus prednisone, with an OS benefit of 2.8 months. Previously, mitoxantrone was approved in 1996 with a survival benefit over prednisone. Other therapies were not so lucky – GPC's satraplatin showed no benefit at all over prednisone.

If we look in the absolutes, the 3.9 month benefit for abiraterone sounds great until we look at the relative vales and comparators in more detail:

2nd line metastatic setting:

  • Satraplatin vs prednisone:               14.3 vs 14.3 months
  • Cabazitaxel + pred vs mitox + pred: 15.1 vs 12.3
  • Abiraterone + pred vs prednisone:   14.8 vs 10.9

Mitoxantrone generally offers some benefit over prednisone, based on the original head to head trial, leading it to become the first chemotherapy to be approved for advanced prostate cancer by the FDA. I've no idea why mitoxantrone plus prednisone was not used as the control group instead of prednisone alone, but we can only evaluate what we have.

You have to say, based on this top line overview, GPC were really unlucky to have a placebo group do uncommonly well! An OS of 10-12 months for prednisone might well be a most logical expectation, but that's how clinical research goes sometimes.

It's odd, but had the abiraterone control group done as well as satraplatin's control, the outcome difference would likely be minimal and not significant. Such is the crapshoot we call R&D! Overall, my sense is that mitoxantrone plus prednisone does better in terms of OS than prednisone alone, so we would expect abiraterone's control group to be lower than cabazitaxel's, making the relative difference higher, and that is indeed the case based on the data so far.

Still, we also have to think about this from the patient perspective. Many men are like my own Father was – they would much rather pop a pill or have an injection than go through chemotherapy and risk feeling sick and have their hair fall out. Indeed, I suspect he was typically of many 70 year olds who declined chemotherapy, but might have considered abiraterone or sipuleucel had they had been available ten years ago.

If you're wondering what will happen next, well according to the press releases, J&J will be submitting the filing to the regulatory authorities by the end of the year, which means we should know some time in 2011 whether we will have a 3rd active drug approved for this cancer.

 

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Dendreon's sipuleucel-T data from the IMPACT trial shows no surprises

By on July 29, 2010

Yesterday was a travel day but thanks to gippy wifi and a packed day, I didn't have the opportunity to post about some interesting articles on prostate cancer published in the NEJM, which I read and digested on the train up to Boston. Now that the embargo has lifted, we can all talk and write about the data publicly.

Kantoff et al., have reported the full results of the IMPACT trial data for sipuelucel-T (Provenge) from Dendreon (a client), which led to the vaccine being approved by the FDA for the treatment of asymptomatic prostate cancer recently.   The results are not new and contain no surprises as they are already well represented in the prescribing information (PI), which are available online for anyone to read and have been presented ad nauseum at recent meetings at the American Urology Association (AUA) and American Society of Clinical Oncology (ASCO).

For those who missed the meetings, the data can be summarised by the following quotes from the article:

"This reduction represented a 4.1-month improvement in median survival (25.8 months in the sipuleucel-T group vs. 21.7 months in the placebo group." 

"The 36-month survival probability was 31.7% in the sipuleucel-T group versus 23.0% in the placebo group." 

"Adverse events that were more frequently reported in the sipuleucel-T group than in the placebo group included chills, fever, and headache."

What can conclude from this is that the vaccine helped men with asymptomatic prostate cancer live longer without the known significant toxicities seen with chemotherapy such as alopecia (hair loss), severe myelosuppression, neutropenias, anemias, febrile netropenias and infectious complications. That would be a win in most people's books because people want to know whether their relative with cancer will live longer, feel better than they do and have a reasonable quality of life with their families. The price might be a bit of a sticker shock, but insurers seem to be covering it to date without any major hiccups.

The accompanying editorial, however, from Dan Longo, a cancer researcher and Scientific Director, National Institute on Aging, National Institutes of Health in Maryland, was probably well meaning, but rather surprising and a little harsh at times.

Science is about the pursuit of truth and in this case, finding out whether men with an advanced cancer would live longer, which they clearly did, so to grumble about the lack of tumour shrinkage is a little odd. Oncologists have for years focused on this as an indication of response rate through a measurement system known as RECIST although whether the patient lived any longer was somewhat moot.  In Longo's editorial, he noted:

"It is hard to understand how the natural history of a cancer can be affected without some apparent measurable change in the tumor, either evidence of tumor shrinkage or at least disease stabilization reflected in a delay in tumor progression."

This is rather old school thinking and as we develop new therapeutic approaches, the end points and surrogate biomarkers may well change.

There have been far too many studies in cancer that showed that traditional chemotherapy could shrink a cancer (great) while toxically poisoning everything in its wake as well (not so great), making many of us wonder whether this was actually a useful approach if survival wasn't impacted. By this, I mean are we measuring the right thing in the first place? 

In full disclosure, my own Father passed away from this disease 10 years ago this month, so it possible that I'm biased in my thinking have gone through his experience with him.  It was a very stressful time for all of us, him especially, although he held up well and maintained his dignity until the end.  Still, I think I would rather know that a new therapy would help a male relative of mine lived longer (improved overall survival) and felt better (less sickness and pain). Then we could all enjoy their last few years together in dignity with quality time than go through the hell that is chemotherapy, which he chose not to do because after many discussions, because if it wasn't going to cure him he saw no point in putting my Mother through that agony.

Sometimes, we need a more humanistic approach to oncology and to remember that these are people's lives we are talking about, not a number on a stat sheet. Tumour shrinkage?  "Pshaw, what does that mean?!" was my Dad's cynical reaction.  Looking back, he was instinctively right.

Another question that was raised in the editorial was the study design, ie was the control group an ideal one? Well, to be fair the time for input into those issues is during the protocol design stage when many people's input is sought before a trial even begins enrolling. Grouching about it after the event seems a little churlish at best. 

Could the control group have experienced some stimulatory effect?  Possibly, but then when you look at the data, the survival time is not out of kilter with those from other control groups previously reported versus chemotherapy who mostly received best supportive care, ie usually pain medications and growth factor support. Perhaps had that approach been taken the difference between the control group and the sipuleucel-T group would have been even greater.

"As the authors point out, differences in subsequent treatments (e.g., docetaxel) do not appear to account for the survival differences, but methods for assessing such effects are imperfect. New prognostic variables such as statin use, the duration of the first off-treatment interval, circulating tumor cells (as assessed as EpCAM+CK+CD45− objects), and new prognostic algorithms may need to be accounted for in assessing therapeutic effects."

Well quite, but I'm sure we'll hear more about further meta analyses of the data at some point. There are a number of other vaccines in phase II/III trials and as we learn more about how this therapeutic approach works, which markers to measure and what impact they have on both the immune system and the natural course of the disease, so our scientific and clinical knowledge will improve and hopefully, patient outcomes as well.

Promising phase II data doesn't always translate into significant phase III data, as we have seen more compounds and vaccines than I remember over the years. For now, we have two new therapy options for men with prostate cancer at different stages of the disease, more choice can only be a good thing, as is having a active pipeline for treatment of prostate cancer, offering hope for many that progress is being made after years of stagnation.

{UPDATE: I spotted Adam Feuerstein's (The Street) and Matthew Herper's (Forbes) excellent articles on this topic after writing this blog post, so they are linked for further information and background reading for those interested.

ResearchBlogging.org

Kantoff, P., Higano, C., Shore, N., Berger, E., Small, E., Penson, D., Redfern, C., Ferrari, A., Dreicer, R., Sims, R., Xu, Y., Frohlich, M., & Schellhammer, P. (2010). Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer New England Journal of Medicine, 363 (5), 411-422 DOI: 10.1056/NEJMoa1001294 

Longo, D. (2010). New Therapies for Castration-Resistant Prostate Cancer New England Journal of Medicine, 363 (5), 479-481 DOI: 10.1056/NEJMe1006300

Two new cancer drugs approved – cabazitaxel and nilotinib

By on June 18, 2010

Yesterday brought two new approvals in a day from the FDA in completely different cancer types.

In the morning, sanofi-aventis' cabazitaxel (Jevtana) was approved in castrate-resistant prostate cancer after failure of docetaxel (Taxotere) several months ahead of schedule.  This approval comes hot on the heels of Dendreon's sipuleucel-T (Provenge) in asymtomatic metastatic prostate cancer last month.

What this means is that once androgen ablation therapies stop working, there are three new treatment options for men with prostate cancer, none of which compete with each other, with the possible exception of the chemotherapies, since docetaxel is often given in second-line in men who previously responded well and have had a treatment break.  It will be interesting to see if this approach continues or if oncologists will prefer cabazitaxel in those with a good performance status.

The real impact of cabazitaxel though, is on other agents in development. Currently, abiraterone (Cougar Biotech/J&J) and MDV3100 (Medivation/Astellas) were being tested in docetaxel refractory prostate cancer, but now there is a new standard of care, whereas previously there was none.  Clearly, common sense suggests that their role might be more impactful earlier in the disease, either after hormonal therapies fail, instead of or in combination with them, especially given that they are oral therapies, making them attractive to urologists. 

Classic drug development usually means starting in the relapsed or refractory metastatic setting. The next few years will be thus be interesting to watch, especially if the agents in clinical trials prove successful. For now, Dendreon have a couple of years breathing space until the market potentially starts to get more crowded.

The other Priority approval yesterday was for Novartis' nilotinib (Tasigna) in newly diagnosed chronic myeloid leukemia (CML) on the basis of higher and earlier response rates versus the current standard of care, imatinib (Gleeevc). Full approval follows later once the survival data is more mature, but the early 12 month data looks interesting with a significant advantage to nilotinib over imatinib. It's still early though, survival curves can do strange things over time and can cross over. 

Still, it's a promising start and a good result, especially since the bar was raised very high by imatinib. Prior to imatinib, ten year survival in CML was 10 to 20% at best with high dose interferon, but imatinib raised that dramatically to 90%. The second generation TKIs such as nilotinib and dasatinib (BMS) will thus potentially represent incremental survival improvements to 93 or 94%, to put them in context.

Of course, nilotinib's approval will possibly impact dasatinib (Sprycel) since they have just filed for the same indication, making Priority review more unlikely. The last time that happened to two drugs in the same cancer type was for Erbitux (ImClone) and Avastin (Genentech), who filed a few weeks apart, but in two different indications (newly diagnosed and 3rd line).  

If dasatinib does get a Priority review after nilotinib it will set a new precedent, but if it doesn't get Priority review, I wonder if an ODAC will occur given that's usually what happens with standard 12 month review?  

What's fascinating about the dasatinib data is that it also demonstrated earlier and deeper responses than imatinib, but the front-line data presented by Drs Kantarjian and Baccarani at ASCO and EHA respectively, did not appear to show any earlier survival benefit at 12 months for dasatinib vs imatinib, unlike nilotinib. I say 'appear' because the curves were very close together and no P value was given, so my assumption is that they weren't significantly different at this stage. That may change over time, but for now, the DASISION data presented by Dr Kantarjian showed a 12 month OS of 97.2% to dasatinib and 98.8% to imatinib, presumably not a significant difference. Deaths in the two arms were 10 and 6 respectively, again favouring imatinib, but not significantly. 

Obviously, comparing these curves at 5 years would be a much fairer comparison for overall survival, but for now, the 12 month data is all we have to go on and there are early differences between nilotinib and dasatinib.  

It was also interesting to watch the often hyped and inelegant reporting of the data by the media at the Congresses proclaiming superiority. We know that in solid tumours, shrinkage or tumour response does not always lead to an improved survival benefit for the patient. Similarly, in leukemia, we also measure response rates – in this case – complete cytogenetic response (CCyR), major molecular response (MMR) and complete molecular response (CMR), as initial surrogate markers for initial approval, but survival is also critically important for full approval in the US. Interestingly, the early log 4 reduction (CMR) rates seemed to slightly favour nilotinib over imatinib (but not significantly), however none were presented at ASCO or EHA for dasatinib over nilotinib (unless I missed the slides).

Ultimately, ASH will herald the 2-year and 18-month data for nilotinib and dasatinib respectively, which will hopefully be an important milestone on the way to seeing how the mature five year surviv
al data will evolve.< /p>


Disclosure:  I'm a former Novartis employee and marketing director for Gleevec, so naturally I'm slightly biased towards imatinib :).  Many thanks to @erohealth for proofreading suggestions.


#AUA2010: new perspectives and learnings in prostate cancer

By on June 2, 2010

It's been an interesting time here in San Francisco at the American Urology Association (AUA) meeting. Mostly, I've attended prostate cancer sessions to get both a breadth and depth perception of what's going on this cancer type.  

My focus is very much therapeutic development, so here are three key trends that I've noticed at the 2010 AUA meeting:

  1. PSA is not a brilliant biomarker, but it's all we have for now.
  2. Androgen ablation is not permanent.
  3. Immunotherapy is a hot new topic.

What alternatives are there to PSA?

An abstract today from the Colorado Cancer Center suggested that PCA3 may offer a urine based genetic assay for detection of prostate cancer in men with elevated levels of PSA. PSA can offer false positive results and up to 75% men with prostate cancer have a negative biopsy. This new approach sounds promising. PCA3 is overexpressed in more than 90 percent of prostate cancers and the gene overexpression is specific to prostate cancer.  It has been linked to more accurate prediction of positive biopsies compared to PSA, and it is easy to test in urine samples following a digital rectal exam of the prostate.

Presumably it may turn out to be more accurate than PSA and perhaps offer a better way to detect either the actual disease earlier or more aggressive disease earlier.  The test was developed by GenProbe and is not yet approved by the FDA, but a new test to watch out for.

Androgen ablation therapies are not particular effective

Often times, testosterone levels rise above the minimum castrate level after about a year.  Ultimately, more effective androgen receptor antagonists are needed, hence the significant interest in this meeting in abiraterone and MDV3100, two new antagonists in phase III development.  Long term use of androgen deprivation is also inevitably associated with side effects, which have not been well appreciated until recently.

The approval of Provenge gives hope that survival can be extended without drastic side effects

Pharma companies in the oncology space would do well to realise that sick people with cancer don't want to be reminded of such and most certainly do not want a 'relationship' with a brand.  This is not Nike or a FMCG brand offering coupons and offers.  What most people do want is less side effects and better efficacy without having to trade them off.  

Now that we have a proof of concept poster child in Provenge in a solid tumour, we can also see that it may ultimately offer a way to combine newer hormonal therapies with a vaccine to offer men a more effective tool against their disease, delaying the time not only to progression, but also to metastases and chemotherapy.

Other immunotherapies are also being evaluated in prostate cancer, including ipilimumab (BMS), an anti-CTLA4 inhibitor and ProstVac, a cancer vaccine.  More on ipilimumab in another blog post but having had a few queries as to what ProstVac is, here's my basic take on it.

ProstVac differs from Provenge in that it requires 7 infusions over a 6 month period as opposed to 3 within the first month.  My understanding is that it is a sequentially dosed combination of two different Poxviruses which each encode prostate specific antigen (PSA) plus three immune enhancing co-stimulatory molecules, B7.1, ICAM-1, and Lfa-3 (TRICOM). The first Poxvirus is Vaccinia-PSA-TRICOM, which is replication competent and is good for immune priming. The second Poxvirus is Fowlpox-PSA-TRICOM, a non-replicating virus, which is good for repetitive immune boosting.  In some ways, it seeks to achieve the same end as Provenge (T-cell stimulation) but via a slightly different approach.

What's next?

More on prostate cancer at the American Society of Clinical Oncology (ASCO) meeting next week!

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#AUA2010: The beginning of a new era for prostate cancer?

By on May 30, 2010

Past American Urological Association (AUA) meetings have seen a lot of same old, same old with very little that is new in the way of truly innovative and exciting new developments.  In many ways, prostate cancer is the male equivalent of ovarian cancer, with pharma companies considering it after the breast, lung and colorectal cancers, despite prostate cancer being fairly large in terms in epidemiology, from a pure numbers perspective.

Why is this?

Firstly, we need to consider the natural course of the disease, which unlike breast and lung cancers, is fairly indolent.  Men diagnosed early with prostate cancer can live for 10-15 years, often with long periods of watchful waiting, making adjuvant trials necessarily long ones.

Secondly, once hormonal therapy begins to enable castration and reduction in the levels of testosterone that drives the cancer's growth, patients are seen and managed by urologists, who prefer to treat with oral therapies.  Until recently, Pharma focused very much on intravenous infusions designed for oncologists and never the twain really met in the middle.

Thirdly, traditional drug development for chemotherapy begins in the latest stage of treatment after failure of existing therapies (typically 2nd or 3rd+ line) and moves earlier up the disease stage in a classic niche by niche development strategy.

These factors combine to essentially create 3 distinct, albeit crude, phases of treatment for prostate cancer:

  1. Watchful waiting
  2. Androgen deprivation therapy (ADT)
  3. Chemotherapy for stage IV metastatic disease

How are things changing?

Dendreon recently received approval for their autologous cell vaccine, sipuleucel-T (Provenge) in asymptomatic metastatic castration resistant disease, meaning that in men where hormonal therapies cease to work but have some early evidence of metastatic disease, now have a completely new and relatively non-toxic therapeutic option prior to chemotherapy with Taxotere, mitoxantrone or even prednisone.

Much has been written about the potential for vaccines earlier in the disease when the tumour burden is much lower, so hopefully we will see some future exploration in this area now that the proof of concept for the first commercial cancer vaccine exists and Dendreon will have more funds to reinvest in R&D as revenues are generated.  They have a real opportunity here.

Past studies with docetaxel (Taxotere) have shown an improved survival benefit of 2.4 months over prednisone alone in androgen independent (hormone refractory) population that was essentially symptomatic.  Two phase III Provenge studies reported a median survival benefit of 4.1 and 4.5 months respectively, meaning that 50% of the men did better and 50% did worse than 4-4.5 months. 

There are now at least 8 other compounds in phase III development for the treatment of advanced prostate cancer.  One of these, sanofi-aventis' cabazitaxel (Jevtana) has already been filed and DDMAC review is expected in the summer, meaning the drug could possibly get approval in the 2nd-line setting after Taxotere by September in an area of high unmet need since there are few options available in this setting.  The data is expected to be presented at ASCO next week, so more on that then.

So now we have two potential therapeutic options before and after Taxotere in 2010 alone, which is progress indeed.

What other compounds are there?

There are a number of agents that I like. Cougar and J&J's abiraterone is probably the most advanced. It is an inhibitor of 17,20 lyase that essentially throttle testesterone production in the testes and adrenal glands.  Millennium-Takeda also have a similar compound in earlier development called TAK700.  The two appear to differ in that one is steroidal and the other is non-steroidal, but whether this will make any meaningful difference isn't yet clear.  Time will tell.  

The abiraterone trials are not scheduled to complete until mid 2011 at the earliest, so assuming the data is positive, approval likely won't happen until the 2nd half of 2012, giving Dendreon a two year commercial advantage over the competition, who are mostly testing their compounds in the post Taxotere setting, at least initially.

Perhaps the most exciting agent from a biology perspective is MDV3100 from Medivation/Astellas, which I have written extensively about in past blog posts.  Essentially, the current androgen blockers are fairly ineffective at controlling aggressive disease so a more complete inhibitor of the Androgen Receptor (AR) may offer a better chance of making an impact.  Medivation have quickly realised that their real opportunity may well be either after hormonal therapies, in combination with them, or perhaps even in place of them earlier in the disease and have announced several new phase II and III trials will commence later this year.  Astellas have significant advantage over J&J as a partner since they already have a strong urology franchise, which is vitally important going forward.

Several other therapies interest me too, but they will be the subject of another blog post later during this meeting as the mutations and critically expressed pathways as the disease progresses may well drive future therapeutic interventions.

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