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This morning Medivation and Astellas announced the interim results of the PREVAIL trial in the pre-chemotherapy castrate resistant prostate cancer (CRPC) setting.

The independent data monitoring committee (IDMC) recommended stopping the trial early due to significant efficacy and unblinding the data.

Accordingly, the press release headline stated that:

“Study Will Be Stopped Early and Enzalutamide Will Be Offered to All Qualified Study Participants; 30% Reduction in the Risk of Death, Hazard Ratio=0.70 (p < 0.0001); 81% Reduction in the Risk of Radiographic Progression or Death, Hazard Ratio=0.19 (p < 0.0001.”

Now, I don’t know about you, but it’s quite a while since I saw a cancer trial with such an impressive hazard ratio (HR) for overall survival (OS) as well as being highly significant. Essentially, there is a 30% reduction in the risk of death compared with placebo even at this early point.

It was interesting though, that initial sentiments on Twitter suggested that some analysts were bothered by the absolute numbers when comparing the PREVAIL and AA-302 trials in the same setting. Enzalutamide achieved a 2.2 month improvement over placebo whereas abiraterone recorded a 5.2 month advantage, although in their case, the curve was only trending towards survival and did not cross the significance line.

Since the drugs were not compared in a head to head study, you can’t really compare apples with oranges even though the placebo arms were similar, at around 30 months each. The important point here is that one trial achieved statistical significance and the other did not. The clue is in the trial design and relative size of the respective studies.

Curious to see what urologist reactions were to the announcement, I checked out sentiments on Twitter, including Dr Benjamin Davies (Univ. of Pittsburgh) and Prof Bertrand Tombal (Leuven):

The other side of the coin, though, is some scepticism and nihilism from the analyst corner:

I’m kind of shocked that anyone would even think that, never mind say it. To be clear, those are not Adam’s words, but rather he’s summarising analyst chatter on the conference call (not verbatims), albeit in his own inimitable fashion. Obviously the point of new therapies is that you want patients to live longer, surely?! Their obvious disappointment, however, can be put into a context of sorts:

Sometimes I despair of people in the industry’s inability to understand basic statistics. What we have is snapshot, not the full data, that will come at a conference presentation when the full analysis is conducted post unblinding. Personally, I think these interim results, based on the HR and P value are encouraging, but what we really need to see are the survival curves because they tell a much more complete picture.

It should be noted that what many of the Wall Street analysts appear to have missed is that what we have is an early slice of the data – median overall survival (MOS) has obviously not yet been reached!  

It is also unfortunate that Medivation only used a small sample of at risk patients (n=59) at 30 months to estimate the survival since the rest were censored or dead as David Miller keenly observed:

 

This is a great way to create confusion unless you are expressly clear in the press release.

That said, if the trial is unblinded and placebo patients still alive are allowed to switch over, then we may only see the MOS for the enzalutamide arm in the future and not the comparator since the data will be confounded by switching.

Professor Bertrand TombalFor a different perspective, I also reached out to Prof Bertrand Tombal (Leuven), one of the lead European investigators in the trial, for his measured and considered thoughts on some of the key issues arising from this news:

1) What are your top line impressions of the PREVAIL data?

“I am a Urologist and every minutes patients are dying from prostate cancer, despite the last-years logarithmic infatuation in drugs. On top of that, recent data from Sweden that the proportion of patients dying from PCa without having received docetaxel is much larger than anticipated. So having more drug in the pre-docetaxel setting is critical, either to delay its use or treat patients that are and will remain unfit for it.”

“As a urologist, I am absolutely impressed by the delay in PFS and the unprecedented HR of 0.19 in radiographic progression-free survival. That speak to me….In addition, it does it without compromise and discussion on the impact on survival 0,70 and a 30% reduction in the risk of death..What more toxicity, especially when you know the limited toxicity of the drug.”

“It is funny to see how people have a different look of the 2 face of the co-primary endpoint coin…I look at PFS because it speaks to my patients.”

2) Many people in the US appear to be concerned that the absolute magnitude of the enzalutamide benefit is lower than that for abiraterone in the pre-chemotherapy setting (2.2 vs 5.2 months), what are your thoughts on this?

“I still have trouble understanding the meaning of a difference in median survival when the median are not reached ??? That’s computed median, arithmetic medicine if you wish. I want to see the curve…There is not mystery that regulators approve drugs based upon hazard ratios and not medians. They are much better representation of the benefit. In addition, due to the availability during the trial of approved drugs known to improve overall survival, placebo patients would be expected to have taken other drugs to increase survival.”

3) Not many countries in Europe have reimbursed abiraterone in the pre-chemo setting, is it likely that enzalutamide will be treated differently based on the fact it shows a significant OS?

“I don’t know, but in Europe most countries values Qualys and ICER, and for qualys you need to extent survival…It is more complex that a simple HR and we will need more results.”

4) Presuming enzalutamide is approved pre-chemo, which drug should urologists give first: abiraterone or enzalutamide?

“That a tricky one…Let’s say that the most popular drug so far is still bicalutamide 50 mg, and in absence of direct comparison between drug, convenience for the patient and the urologist is very often a very discriminating choice…”

5) The cumulative cost of prostate cancer care is increasing as new drugs are approved, is it going to be cost effective to treat for 32 months with an expensive new drug for only a 2 month survival benefit or do we need more effective treatment options?

“That is the real challenge, especially with the European Perspective. In Europe, where the access to treatment is mostly based on solidarity rather than private insurance, it means political choices, ethical choices and a lot of thinking on new model…based on performance, sure.”

Well said, sir!

Ultimately, we need to wait to see the full presentation and look at the survival curves before making a more informed decision. Hopefully, this data will be presented at the ASCO GU meeting in January, making a very interesting start to the 2014 cancer conference calendar.

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Since 2010, we have seen several technological advances in therapies for metastatic castration resistant prostate cancer (CRPC), leading Professor Bertrand Tombal (an Academic urologist in Brussels, Belgium) to describe 2011 as a Grand Cru year for CRPC at the European Society of Medical Oncology. One of the most promising therapies in this category was enzalutamide (Xtandi) from Medivation.

Enzalutamide is an anti-androgen receptor antagonist similar to bicalutamide, but differs in that it is a more potent inhibitor and has no agonist properties. Initially, it was approved by the FDA post chemotherapy but trials are currently ongoing in the pre-chemotherapy setting.

In patients with advanced prostate cancer with hormonally-sensitive disease, the treatment choices can be fairly stark – active surveillance (for low risk patients), surgery (for resectable disease), radiation (risk of long term side effects) and/or androgen deprivation therapy (ADT) for high risk patients with rising PSA.  When ADT fails and PSA rises dramatically again, then men may receive an androgen receptor antagonist such as bicalutamide. An advantage of bicalutamide is that it avoids medical castration and has been shown to have a favourable safety profile compared to ADT.

ADT is useful for controlling PSA levels in high risk patients, but it is not without complications, as Prof Tombal discusses below and explains why there is a need for an alternative approach:

In US, however, ADT is more commonly used in high risk patients than bicalutamide.

Bertrand Tombal ASCO GU 2013The most obvious question though, is how might enzalutamide compare with bicalutamide in the advanced prostate cancer setting? To find out about progress here, I interviewed Prof Tombal about his poster being presented at the ASCO Genitourinary meeting yesterday.

PSB: How would you describe the rationale behind your study?

Prof Tombal: The first thing that is important is what is the philosophy of the clinical trial? There has been a lot of activity in medical treatment for prostate cancer with new drugs like abiraterone, Jevtana, new chemotherapies, a vaccine, but what they all have in common that they are used in patients who are failing hormonal treatment. Today, hormonal treatment worldwide is basically medical castration, meaning that you suppress the testosterone in the whole body to get an effect on the prostate and the metastases.

The idea was to test enzalutamide, not the way it is used and prescribed now in patients who fail androgen therapy, but in patients who have never received androgen deprivation therapy. There was always the hypothesis that it might not work for unknown reasons. So we took patients who needed hormone therapy, some of them were already quite advanced, and we gave enzalutamide alone.

PSB: What kind of results did you see?

We were extremely impressed by the amplitude of response of these men. If we look at the PSA decrease, when we did that hypothesis that if 80% of the men would have a good PSA response, we would potentially have a drug with some future in that setting. But it’s not 80%, it’s much more than that. Almost all the men responded extremely profoundly to the drug with a sharp decrease in PSA, and with a toxicity that apparently is less pronounced than with androgen deprivation therapy.

The hypothesis that we might have a drug that could eventually replace androgen deprivation therapy, we now we know that the idea seems to be working and we are now saying OK, now we might have a compound simply to replace androgen deprivation therapy in all these men who need it and suffer from side effects.

Now it is creating a new paradigm because now we have to think about how we are going to develop this in the next 4 to 5 years. What is striking with the result is that actually enzalutamide is the only drug you can use as an alternative. If you think, for instance, about Zytiga/abiraterone, it needs to be used with hormone therapy, it will never replace hormone therapy. Here it is a short series (of treatment) but you have to understand we went totally blind in that patient population.

What we can say about the results is that it is far beyond any expectations we made when we planned the trial.

PSB: How would these results compare with what you would expect with bicalutamide?

Prof Tombal: In Europe, bicalutamide is registered and we still use it. If I take for instance, my personal patients, I would say 10-15% of the patients are treated with bicalutamide monotherapy.

The problem with bicalutamide is that we know that the PSA drop is never what we see with LHRH agonists; we know it is a good drug, but the trial I have indicated, that it was a chemo-equivalent only for patient with minimal disease.

Although we have no direct comparison, but we have historical comparison in Europe because we use bicalutamide a lot. If we just look at the PSA drop for instance [with enzalutamide], it is apparently much more profound than [we normally see] with bicalutamide. That is clear.

From the patients in the trial, we have observed objective tumor shrinkage, and sometimes very impressive one, something we have not seen very well with bicalutamide. We have no direct comparison, but it is clear from my perspective that it compares well with bicalutamide in terms of side effect profile because there is no castration syndrome, there is a little bit of gynecomastia, little bit of fatigue, things that are extremely well tolerated by the patient in comparison to LHRH agonists.

But the tumor response, seems – and I do insist – much better than with bicalutamide.

PSB: So will you be planning any other head to head trials with bicalutamide or the LHRH agonists?

Prof Tombal: The problem of drug development is that actually the leading dancers are the regulatory authorities. If you go to EMA, European Medicines Agency, because bicalutamide is accepted we could easily plan a trial head to head bicalutamide versus enzalutamide. The problem is that FDA never registered bicalutamide, so we have to see how they are going to behave. There are plans to conduct a trial, but the exact design of the trial, and we can’t do nothing about this, will be decided by FDA. We don’t even know right know whether it is going to be one global trial, or trial made for Europe and the US.

Interestingly also, in contrast to all the agents that have been developed in castration resistant prostate cancer, nobody has ever gone to FDA with a modern plan saying these are the problems, these are the compounds. We don’t know how they will react.

Clearly if I had all the money and all the patients, the ideal trial would be a three arm trial comparing standard hormonal treatment to enzalutamide to bicalutamide. Because, if we do that then we could really have the answer both in term of survival and in term of quality of life.

I am a urologist by training, so most of the patients I see, I would say even 85%, they won’t die from the disease. Those who have aggressive disease are seen mostly by medical oncologists. The medical oncologist concern is primarily to increase overall survival. Where my concern as a urologist is to get a similar overall survival, to keep the good result we have right now, but lower the toxicity. If I want to answer both questions at the same time, the ideal would be a three arm trial to get all the information on the quality of life and overall survival.

PSB: I think the three arm trial would be most optimal and give the definitive answer

Prof Tombal: That would be the more elegant and would be the one that would be the most scientifically satisfying.

PSB: Are there any other combination trials with enzalutamide in that setting that have piqued your interest?

Prof Tombal: If you give me $1 million dollars and ask we what is the best combination, I would say it is enzalutamide and radium-223. Because, we know something in prostate cancer, it is that there is something magical that is happening when you combine radiation therapy and hormonal treatment. That is where androgen deprivation therapy has been shown to increase overall survival. All the trials done by SWOG, EORTC and early work back in the 70’s showing that if you hit the cell with some form of DNA breaking mechanism like radiotherapy plus hormone therapy you have got something magical.

To me, the association of a very effective anti-androgen and radiation therapy is something I want to see. One of the advantage on top of that is that these two drugs do not require corticoids and are extremely well tolerated. So this is really an association i don’t fear. Radium-223 is well tolerated. In all these men we identify now with oligo-metastatic disease, combining these two drugs, give me the drug, give me the money, I would be extremely interested.

PSB: Is that trial planned at all?

Prof Tombal: I think both Bayer and Medivation are speaking to each other, so I am quite sure it is going to be planned sometime.

 

Additional notes…

Although I spoke to Prof Tombal prior to the meeting, I was quite unprepared for the sheer impressiveness of the waterfall plot, which showed a PSA response (i.e. a reduction > 80%) at 25 weeks of 92.5% with a fairly narrow CI (86.2-98.8%).

In a previous interview, Charles Sawyers, the co-inventor of enzalutamide discussed its potential development, including the translational opportunities beyond CRPC in earlier disease.

It looks likely, with these latest results, that enzalutamide has clear activity in advanced (hormonally-sensitive) prostate cancer and a three arm trial, as suggested by Prof Tombal, would actually answer the key question of which therapy would be the optimal solution in this setting. Hopefully, we will see more advances in this area emerge over the next couple of years.  If successful, this would be a large potential market opportunity for enzalutamide, potentially much bigger than the CRPC setting before or after chemotherapy.

This month has brought a flurry of regulatory activity in the prostate cancer landscape with several companies seeing noticeable action in the new product development area:

For this specific post, I want to concentrate on the new trends in advanced prostate cancer, as last weekend I attended the 2012 American Urological Association (AUA) annual meeting, focusing on the basic research sessions hosted by the Society of Basic Urological Research (SBUR) and Society of Urologic Oncology (SUO).  It’s hard to ignore the clinical data though, with so much activity in going on in advanced prostate cancer!

While at the oral and poster sessions, I enjoyed informal chats with urologists and researchers. Many of the urologists I spoke to at AUA were very excited about enzalutamide, certainly much more enthusiastic than in the last two years when we saw the arrival of sipuleucel-T (Provenge) and abiraterone (Zytiga) in the pre- and post- chemo settings respectively. The reasons for this were varied, depending on the respondents, ranging from understanding the mechanism of action (MOA) clearly to ease of logistics to lack of concomitant steroid therapy. The fact that the initial overall survival of 4.8 months for enzalutamide in the post-chemo setting, which hints at a more potent and effective therapy, probably helped as well.

With that in mind, I spoke with Dr Neal Shore, one of the AFFIRM trialists about his perspective of the impact of enzalutamide on his patients.  Firstly, we discussed the expectations for patients who have received chemotherapy:

“Patients who typically have completed a course of docetaxel have historically a 6-12 month life expectancy depending upon… on how symptomatic or asymptomatic they are.”

Secondly, what was the impact of treatment with enzalutamide?

“In the treatment arm, those who received enzalatumide, they lived at the median 4.8 months longer than patients who received the control placebo.

So in fact their survival extended beyond 18 months. I told you that normally this patient population has a 6-12 month survival expectancy range, that to me is dramatic.

It’s a dramatic life prolongation effect.”

Emphasis mine.

One of the things that makes enzalutamide exciting for me is the ability to target splice variants. This may explain why the agent has slightly better efficacy in the post chemo setting than abiraterone, which demonstrated a 3.9 month overall survival advantage over placebo when it was initially approved. This figure has since improved to 4.7 months with more mature data, suggesting that the initial 4.8 months improvement we see with enzalutamide may also potentially improve further with time.

Previously, I discussed the splice variants with Dr David Hung, the Medivation CEO:

Dr David Hung on Splice Variants:

Another area where we may see changes in mCRPC is sequencing, combinations and different trial designs. While it seems logical that good old fashioned sequencing, as with ADTs in earlier disease, will prolong time to disease progression by managing PSA levels, it should be noted that I don’t think any of those agents have actually shown a significant improvement in overall survival in patients. Unlike oncology, urology tends to have looser endpoints and this is something that we may well see changes in going forward as more rigour is applied in the clinical trial setting.

Combination therapy is something that I think we will also see more of in the future if we are to see real shifts in meaningful outcomes. As Charles Sawyers noted in a previous interview, shutting down the AR pathway more comprehensively with dual inhibition and ‘big guns’ makes solid scientific sense. This doesn’t just mean the obvious though, such as determining whether dual upstream and downstream AR inhibition with enzalutamide plus abiraterone versus either alone would work, but also targeting cross-talk and adaptive resistance pathways such as AR inhibition plus a PI3K inhibitor. Some of these trials are already underway, at least in phase II to see what the safety and efficacy signals looks like.

The arrival of multiple new therapies that change the standard of care also means that once the current crop of new drugs have been approved (abiraterone, enzalutamide and alpharadin) it becomes more difficult to conduct placebo controlled trials with OS any more, as Dr Shore astutely observed:

Dr Shore’s point about surrogate markers of survival in advanced cancer is a highly relevant one given the increasing level of competition in this tumour type.

In the pre-chemotherapy setting, both abiraterone (302 trial) and enzalatumide (PREVAIL) appear to have progression-free survival (PFS) and OS as co-primary endpoints. It will be interesting to see how the FDA react if only PFS is significant while OS is not, as many commentators suspect from the rather vague and woolly press release that J&J put out for abiraterone.  I don’t know what was agreed beforehand with the FDA regarding the study design, but I can see an interesting and highly charged ODAC ahead here as well as much speculation prior to the ASCO presentation of the data in the prostate cancer oral session next month.

OS is a clear, but challenging measure because ultimately, as Dr Shore noted, the endpoint is death.  Remember, recent breast cancer trials discussed here on PSB achieved a significant OS of 6 months or more, precisely because crossover wasn’t allowed. These trials had an active arm as a comparator, not placebo, though. We don’t yet know if patients in the placebo arm who relapsed were allowed to crossover to abiraterone early (ie before the IDMC recommendation). If they did, then OS was doomed from the start and the trial design itself was flawed, but we will have to wait for the presentation to see before jumping to conclusions.

I really hope that’s not the case here, because once crossover does occur, it is very hard statistically, to sort out a true survival signal. If the placebo patients didn’t crossover before the IDMC recommended study stoppage, then it’s hard to see why OS wasn’t met (if truly the case) unless the patients had long term compliance and adherence problems as a result of the concomitant steroid therapy. I do find it hard to believe, however, that an IDMC would stop a trial early if a primary registration endpoint was not met, for that would be akin to regulatory hari-kiri!

Overall survival has long been the standard of care in advanced prostate cancer and several drugs have either received approval or will receive approval as a result of meeting that high hurdle. Future entrants will find it very hard to ethically justify using placebo in the comparator arm and will likely need to be compared to sipuleucel-T, docetaxel, cabazitaxel or abiraterone as the currently approved new standards of care and potentially other options will be considered that are seeking approval such alpharadin and enzalutamide in the near future.

This improvement in care raises the bar for companies considering advanced prostate cancer in several ways:

  • Increased costs (active comparator arm, prolongation of treatment)
  • Increased time to market (OS takes longer than PFS)

In the end, though, for men with prostate cancer it’s largely all good news as new therapies that clearly prolong life become available and make a difference to their lives, not just in terms of more time with their families, but also in terms of improved quality of life and symptom management.

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It’s that time of the year again where we cogitate and contemplate on what might be hot at the annual meeting of the American Society of Clinical Oncology (ASCO) before the abstracts are available (they’re released online tomorrow at 6pm ET).

This year, while interesting early data from up and coming small biotechs is likely to be eagerly presented in poster sessions, the focus is more likely going to be on big Pharma with various phase III and also late phase II trials that are due to report data.  Unfortunately, not all of these will produce overwhelmingly positive results though!

What I’m most interested is things that shift the needle meaningfully  in terms of survival by six months or more, as we saw from the recent BOLERO2 and CLEOPATRA trials in ER+ and HER2+ breast cancer.  There are plenty of agents that offer minor or incremental improvements (colon cancer has long suffered from that syndrome, sadly), but let’s be honest – most of us get excited by the possibility of major shifts in survival.

Please note that I’ve mostly selected some promising agents in development that might achieve that effect, explained why they are different and focused on new data/drugs rather than rehash what I call the ‘middlings’ i.e. minor upgrades to the standard of care.

Without much further ado, here are my ASCO preview highlights for 2012:

Please do check back during the convention both here on PSB, and also on Biotech Strategy, for reports and analysis as the interesting data emerges at ASCO.

If you have any comments or thoughts, please do share them below…

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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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Amazingly, it’s been a year since I started doing conference highlight videos, with the first one rolling out at EAU meeting in Vienna last March. They’ve proven to be much more popular than expected! The good news is that the video recording, production and presentation skills have improved along the way.

Unlike last year, the 2012 EAU Congress wasn’t lit up with excitement about new data (abiraterone and MDV3100 dominated last year).  Instead, there were more reflective discussions about how to consider sequencing and combinations in a more crowded castrate resistant prostate cancer market going forward as well as some mention of new up and coming targets outside the androgen receptor (AR) such as ERG and Src.

Here’s the short (under 5 mins) video update:

If you can’t see the video, click here.

Meanwhile, the next conference update will be from the annual American Association for Cancer Research (AACR) meeting from March 31st-April 4th.

EAU-2012-Congress-Paris-View-of-Eiffel-Tower-By-NIght

Sights of 2012 EAU Congress

Greetings from the European Association of Urology (EAU) congress in Paris. Despite the grey drizzle typical of Europe in winter, this is actually quite an interesting meeting with lots of poster presentations.

One poster that caught my eye yesterday was from Martin Gleave’s group on clusterin knockdown synergising MDV3100 activity. Previously, we discussed on this blog how inhibiting clusterin with custirsen (OGX-011) potentiated docetaxel. At the AUA meeting last year, the issue of whether the same would happen with MDV3100 was suggested, as you can see in the short video blog.

Clusterin is also known as testosterone-repressed prostate message-2 or TRMP-2, and has been shown by Miyake et al., (2000) to be important in advanced prostate cancer. This is because the treatment of choice in hormone-sensitive disease, androgen deprivation therapy (ADT), can lead to clusterin upregulation, thereby causing castrate resistance.

The group’s latest study at EAU looked at whether clusterin knockdown sensitised MDV3100 activity and evaluated potential mechanisms for how this might work.

The results showed that:

  1. Neither MDV3100 or custirsen alone affected AR levels, but in combination, the AR protein levels were reduced.
  2. The combination synergistically suppressed LNCaP (human prostate cancer cell lines) in vitro and in vivo compared to monotherapy with either alone.
  3. Inhibition of the AR has been shown to activate the PI3K-Akt pathway, but the combination prevented this from occurring.
  4. Dual treatment also increased AR instability via decreased levels of the AR chaperone, FKBP52.
  5. AR degradation occurred with combination therapy via the proteasome, leading to synergistic repression of AR transcription.

While these data offer a very nice and logical preclinical rationale for considering a combination of MDV3100 and custirsen to overcome castrate resistance in advanced disease, we also need to see clinical evidence in advanced prostate cancer before getting too excited. I like the idea scientifically but Oncogenex, the manufacturers of custirsen, have not exactly been swift at moving their previous trials along, as Luke Timmerman noted his Xconomy article last year.

Ultimately, the proof is always in the (clinical) pudding.

References:

ResearchBlogging.orgMiyake H, Nelson C, Rennie PS, & Gleave ME (2000). Testosterone-repressed prostate message-2 is an antiapoptotic gene involved in progression to androgen independence in prostate cancer. Cancer research, 60 (1), 170-6 PMID: 10646870

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Many readers will have noticed that the advanced prostate cancer market is rapidly becoming crowded with three new therapies (cabazitaxel, sipuleucel-T and abiraterone) already approved and several more in late stage development, including Alpharadin (radium-223) and MDV3100, both likely to file this year. In addition, others are focused on bone complications, such as denosumab, which is expected to have a tough ODAC meeting this month, and cabozantinib, a multikinase inhibitor currently in phase III trials.

Unlike breast cancer, where progression-free survival (PFS) is a used as a surrogate measure of survival, in advanced prostate cancer, overall survival (OS) has pretty much become the gold standard by which prostate cancer trials are reviewed. This makes it much easier to judge whether the drugs are having a positive effect on true efficacy, i.e. do patients live longer as a result of treatment.  PFS is particularly difficult to measure in prostate cancer, so it’s not surprising this approach has evolved as the standard measurement.

Interestingly though, Health Authority approval does not always mean reimbursement coverage, as NICE showed yesterday in declining to approve abiraterone in the UK on the grounds that it is too expensive. The BBC quoted a patient who had been on abiraterone for only three months, with a positive impact:

“I have my life back. I have a lot more energy and no pain. My quality of life is excellent. I wouldn’t even know I have cancer now, it’s that good.”

The BBC also quoted his wife, who had an excellent point:

“We know NICE has to take a lot of things into consideration, but when you have a terminal illness an extra four months is very precious.”

Source: BBC

Of course, it’s very much a case of balancing available resources with potential benefits and unfortunately, advanced stage patients will inevitably take the lion’s share in terms of budget for disease management. Post EMA approval, some local UK health providers permitted the drug to be used on an individual basis, raising the old contentious issue of the rather unfair post code lottery (zip code for Americans).

Going forward, no doubt there will be much political posturing and pressure, as you can see from Cancer Research UK, who helped fund the research, but hopefully a deal can still be struck between NICE and Janssen, the manufacturer, on price to enable British men broader access to the drug.

One of the things that has struck me lately, though, is how prostate cancer is attracting serious research focus, such that a heterogeneous disease is slowly being more segmented based on the underlying biology of the tumour. Examples include Arul Chinnaiyan’s superb work on the TMPRSS2-ERG fusion gene and Charles Sawyers’ work on the Androgen Receptor.

Thanks to Sawyers work we now know that the old terminolgy ‘androgen independent’ prostate cancer is an incorrect way of descibing advanced disease because as Clegg et al., (2012) described Scher et al’s original research findings in 2005:

“Despite administration of androgen-depleting therapies, continued androgen receptor (AR) signaling is a common feature of CRPC, attributed to AR gene-amplification, AR gene mutation, increased AR expression or increased androgen biosynthesis in prostate tumors.”

In other words, the AR is very much an oncogenic driver of the tumour’s survival.

This week, we saw promising data for MDV3100, an AR antagonist in the post chemotherapy setting but what of the pipeline beyond abiraterone and MDV3100?

Previously, we came across Aragon’s ARN-509 AR antagonist, which is much further behind in phase I/II clinical trials. Sawyers and Michael Jung, the co-inventors of MDV3100 while at UCLA also developed (along with several other scientists) additional AR compounds, the most promising of which became ARN-509. Aragon is a privately held company formed out of the UCLA discovery with the intent of developing and commercialising this compound.

The obvious question arises – is it a ‘me-too’ or potentially better than MDV3100?

Preclinical data has just been published in Cancer Research by Clegg et al., (2012) addressing this issue. They argued that, based on their findings:

“In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100.”

Of course, preclinical data doesn’t always translate to the clinical setting, but my first reaction was ‘Whoa!’

Let’s take a look at the agent in more detail.  ARN-509, like MDV3100, is a pure antagonist of the androgen receptor, unlike bicalutamide (Casodex), which has both agonist and antagonist properties.  The idea behind this is that there will be less resistance and greater therapeutic potential for more comprehensive binding with the receptor.

We know from work in Sawyers lab that MDV3100 targets splice variants, which have been shown to cause resistance in CRPC, but we don’t yet know how ARN-509 will fare on that front.

So why did Clegg et al., (2012) suggest that ARN-509 might be superior to MDV3100?

“Maximal therapeutic response in this model was achieved at 30 mg/kg/day of ARN-509, whereas the same response required 100 mg/kg/day of MDV3100 and higher steady-state plasma concentrations.

Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists.”

In other words, it’s much more potent and has a greater therapeutic index; these things are important clinically. It also has a longer half-life:

“ARN-509 exhibits low systemic clearance, high oral bioavailability and long plasma half-life in both mouse and dog, supporting once-daily oral dosing.”

Androgen deprivation therapies are more commonly used in castrate-sensitive disease, so this begs the question of whether there is anti-androgenic activity in the non-castrate setting:

“At higher doses of 30 mg/kg/day, robust tumor-regression (>50% reduction in starting tumor volume) was observed in 6/8 ARN-509-treated animals, similar to regressions observed in mice castrated on the day treatment initiated.”

The promising results led the researchers to conclude that:

“ARN-509 is a next generation anti-androgen selected for pre-clinical and clinical development based on its efficacy and pharmacodynamic profile in mouse xenograft models of CRPC.”

They also stated that:

“Unexpectedly, given a similar in vitro profile, ARN-509 is more efficacious per unit dose- and per unit steady-state plasma-level in mouse models of CRPC than MDV3100.”

In other words, ARN-509 is a next generation AR antagonist with a good efficacy and PK profile in mouse xenograft models of CRPC.  It’s clinical development, although further behind abiraterone and MDV3100, will be well worth watching over the next few years.

In summary…

While there has been a lot of activity in the advanced prostate cancer market lately with new approvals making a difference to the lives of men with prostate cancer, there are also several other promising near term agents in development, as well as some potentially more potent and effective treatments in early clinical development.  What we have seen to date is merely the beginning of new advances in R&D.

The early and advanced prostate cancer markets are likely to see some significant changes over the next 24 months, as new products based on rational drug design and an improved understanding of the biology of the disease make it to market.

More on prostate cancer coming soon!

All this new data is very timely, considering on Monday I’m off to the AACR Special Conference on Prostate Cancer, jointly chaired by Drs Chinnaiyan and Sawyers.  I’ll be interested to learn what new events are emerging as biological targets and what factors can help us predict response to treatment.  If you’re going to this meeting do stop and say hello, it’s always good to meet new people in the field.

References:

ResearchBlogging.orgClegg, N., Wongvipat, J., Tran, C., Ouk, S., Dilhas, A., Joseph, J., Chen, Y., Grillot, K., Bischoff, E., Cai, L., Aparicio, A., Dorow, S., Arora, V., Shao, G., Qian, J., Zhao, H., Yang, G., Cao, C., Sensintaffar, J., Wasielewska, T., Herbert, M., Bonnefous, C., Darimont, B., Scher, H., Smith-Jones, P., Klang, M., Smith, N., de Stanchina, E., Wu, N., Ouerfelli, O., Rix, P., Heyman, R., Jung, M., Sawyers, C., & Hager, J. (2012). ARN-509: a novel anti-androgen for prostate cancer treatment. Cancer Research DOI: 10.1158/0008-5472.CAN-11-3948

Scher, H. (2005). Biology of Progressive, Castration-Resistant Prostate Cancer: Directed Therapies Targeting the Androgen-Receptor Signaling Axis Journal of Clinical Oncology, 23 (32), 8253-8261 DOI: 10.1200/JCO.2005.03.4777

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This weekend heralds the annual American Society of Clinical Oncology (ASCO) Genitourinary (GU) meeting in San Francisco, although ASCO held their press briefing today to provide an update on some of the key topics.

For those of you interested in Alpharadin (radium-225) in castrate-resistant prostate cancer (CRPC), check out the update of Dr Oliver Sartor’s presentation, which is covered on Biotech Strategy Blog.

The key topic that most interested me though, was Dr Howard Scher’s update on Medivation’s Androgen Receptor antagonist, MDV3100, in CRPC.  Previously, Medivation announced that the data showed an improvement in median overall survival (OS) of 4.8 months and this is still solid (Note: J&J’s abiraterone was approved by the FDA based on an OS of 3.9 months in the same population and must be taken with prednisone).

Three new things were important in this presentation though:

  1. There has been some previous concern about the risk of seizures, after they were reported in an earlier trial, but that was at much higher doses.  In this study, the now standard (and much lower) 160 mg dose of MDV3100, demonstrated low levels of seizures (0.6%), which is very reassuring and not something I think many will worry too much about.
  2. MDV3100 has a nice effect not only on OS, but also median time to confirmed PSA Progression, i.e. 8.3 months vs. 3.0 months for placebo (HR 0.248, P<0.0001). Yes, I had to do a double take at that HR – it’s quite phenomenal!
  3. Aside from PSA drops, patients often like to know if their tumour is shrinking or not as evidence of activity and progress. Dr Scher showed the soft tissue response by CT/MRI imaging. There was a 28.9% response rate with MDV3100 compared with 3.8% for placebo (P<0.0001).

From this data we can definitely say that patients lived longer, saw a positive impact on their PSA levels, and felt better compared to placebo. In terms of serious adverse events, there were fewer in the MDV3100 arm (28.4%) versus the placebo arm (33.6%). There were also slightly more discontinuations in the placebo (7.0%) than MDV3100 (3.8%) cohort.

Overall, I wasn’t at all surprised when the host, Dr Nicholas Vogelzang (Medical Director of the Developmental Therapeutics Committee of US Oncology) exuberantly said he had only one comment to Dr Scher’s presentation of the MDV3100 data,

“Wow, that’s very impressive! It’s unprecedented.”

For once, I thought that ‘impressive’ was actually an understatement to apply to a cancer drug.

I also talked to Dr David Hung, CEO of Medivation afterwards. Many readers will remember my interview with Dr Charles Sawyers, the co-inventor of MDV3100, last year about the science behind the development. It was nice to see Medivation’s side of the R&D story, which has gone pretty rapidly so far.

PSB: Are you going to be filing soon based on this data?

David Hung: We are having a pre-NDA meeting with the FDA. Once we have that meeting we will be able to give much more concrete guidance on when we will be filing.

PSB: Some of the pre-chemo trials have started, would they be due to report some data soon?

David Hung: We haven’t given any timelines on any of our other trials.

PSB: When I interviewed with Charles Sawyers previously, he said that many pharma companies were not interested in what is now MDV3100. What did you see in it when many others said “no”?

David Hung: Charles didn’t approach me. I found him! I had read, with great interest, his work on the AR. I was very familiar with his Nature Medicine publication in 2004 showing that overexpression of the AR is a significant molecular change in patients with castration resistant disease. While I think a lot of people thought that targeting the AR would create just another AR antagonist, like casodex, the data suggested to me there was more here.

Because, in Charles’ lab by being able to over-express the AR, we were able to much more carefully assay and screen compounds for their ability to block androgen receptor signaling very thoroughly. And we found in the process that a number of compounds in the series that we were testing had ability to not only block just AR binding by testosterone, which is something that Casodex does, but unlike Casodex these compounds were able to inhibit nuclear translocation as well as DNA binding and activation by the AR.

I am an oncologist by training and was pretty familiar with this area, so when I saw the compounds and saw the data in more detail, I didn’t agree that it would just be another casodex like molecule. I thought the mechanisms suggested that this drug could be special, so when I went ahead and licensed the drug back in 2005. We then took the program forward rapidly through development. We had to do all the standard pharmacokinetics, metabolism, tox, formulation work, then take it into a clinical trial as quickly as we could, led by Howard Scher. So, we were able to develop the molecule very quickly.

One of the differences with MDV3100 over weaker AR antagonists such as bicalutamide, is it’s ability to target splice variants. This was a surprising but important finding. I asked Dr Hung about them:

PSB: Does that potentially mean that the patients in the current trial data presented by Dr Scher, may actually do better over time or is the 4.8 months OS probably going to be the final number?

David Hung: Well, I won’t know the answer to that until I unblind the PREVAIL trial. What is very interesting from our phase 1 / 2 data is that the time to PSA progression in post-chemo patients in that data set is about 203 days. Yet, the time to PSA progression in the pre-chemo patients was 4x longer than that, 812 days, suggesting that the drug may have even more robust activity upstream than it does downstream. Downstream it already has robust activity. We will be greatly looking forward to seeing the PREVAIL data, because that is the pre-chemo population. If we can recapitulate our phase 1 / 2 results, that would be great news for patients.

PSB: At AUA last year, I heard from Charles Sawyers that if you inhibit the androgen receptor, you often activate the PI3-Kinase pathway. His colleague Neil Rosen had also noticed that if you inhibit PI3K, you activate androgen receptor in prostate models. So Charles was saying in their joint paper that the logical thing to do would be to combine an androgen receptor inhibitor and a PI3K-inhibitor to potentially reduce the resistance and hopefully improve outcomes. Is that the kind of combination you might consider in the future?

David Hung: We actually are. You point out exactly the kind of things that we think about. We look to see how our drug works and we look to see what mechanisms might possibly complement our drug. That is the way we think about potential combination studies that we might do.

All this is very exciting news for both Medivation (and commercial partner Astellas), as well as patients with advanced prostate cancer. I hope that the discussions with the FDA go well and we will see a filing, perhaps even with Accelerated or Priority Review in the near future. Based on the data so far, the data clearly shows that MD3100 can make a difference to the lives of men with advanced prostate cancer.

Next week, I’ll be at the American Association for Cancer Research (AACR) Special Conference on Prostate Cancer, jointly chaired by Charles Sawyers (MSKCC) and Arul Chinnaiyan (Michigan) to learn more about the biology of prostate cancer. It promises to be both a timely and exciting meeting!

References:

ResearchBlogging.orgChen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, & Sawyers CL (2004). Molecular determinants of resistance to antiandrogen therapy. Nature medicine, 10 (1), 33-9 PMID: 14702632

Carver, B., Chapinski, C., Wongvipat, J., Hieronymus, H., Chen, Y., Chandarlapaty, S., Arora, V., Le, C., Koutcher, J., Scher, H., Scardino, P., Rosen, N., & Sawyers, C. (2011). Reciprocal Feedback Regulation of PI3K and Androgen Receptor Signaling in PTEN-Deficient Prostate Cancer Cancer Cell, 19 (5), 575-586 DOI: 10.1016/j.ccr.2011.04.008

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Last week a very interesting article appeared in Cancer Discovery that reported a new target in neuroendocrine tumours (NET) of the prostate, a particularly aggressive subtype. Now, these tumours are “rare” and “uncommon” based on a spot check with a couple of oncology specialists I asked this morning.  In fact, according to this latest research, fewer than 2% of men with prostate cancer actually present with neuroendocrine disease and adenocarcinoma of prostate can also (rarely) evolve into neuroendocrine disease, but overall, the prognosis for NET of the prostate is generally poor.

What did they find?

Rubin and et al., (2011) used next-generation RNA sequencing to profile samples of neuroendocrine prostate cancers or NEPC (n=7), prostate adenocarcinomas or PCA (n=30) and benign (BEN) samples of prostate tissue (n=5) to try and characterise the molecular imprint. Previously, it has been shown by Tomlins et al., (2005) that TMPRSS2-ERG occurs in 50% of prostate NET, which is approximately the same rate as adenocarcinoma of the prostate. The big question is whether other molecular subtypes can be identified?

In this research, it was discovered that the genes AURKA and MYCN were overexpressed and amplified in neuroendocrine prostate cancers (40%) and in prostate adenocarcinomas (5%). The findings were then validated in tumours from a larger cohort of patients (n=37 with NEPC, n=169 with PCA, and n=22 with BEN) using immunohistochemistry and FISH:

“We discovered significant overexpression and gene amplification of AURKA and MYCN in 40% of NEPC and 5% of PCA tumors, respectively, and evidence that they cooperate to induce a neuroendocrine phenotype in prostate cells.”

For those of you interested in the Aurora kinase, here’s what AurA looks like from a broad perspective as part of the cell cycle pathway:

Source: Cell Signal

In order to determine if AURKA was a valid (driver rather than passenger) target, treatment with an aurora kinase (AURKA) inhibitor (PHA-739358, Nerviano Medical Sciences) was evaluated in cell lines and xenografts to determine if the agent inhibited the growth of the neuroendocrine tumours:

“There was dramatic and enhanced sensitivity of NEPC (and MYCN overexpressing PCA) to Aurora kinase inhibitor therapy both in vitro and in vivo, with complete suppression of neuroendocrine marker expression following treatment.”

What do these results mean?

This study has identified new potential targets in neuroendocrine tumours of the prostate in AURKA and N-myc that are well worth evaluating in clinical trials with patients who have this condition:

“We propose that alterations in Aurora kinase A and N-myc are involved in the development of NEPC and that future clinical trials will help determine the efficacy of Aurora kinase inhibitor therapy.”

Interestingly, PHA-739358 (danusertib) has been studied in prostate cancer before without success, but this may be due to the fact that the trial was in patients with adenocarcinomas and not neuroendocrine tumours.

What we learn from this is that the oft heralded argument about targeted therapy – ie first find a valid driver target still holds true – some subsets may respond to therapy while others will not, so identifying the right subset for therapeutic intervention is critical if we wish to increase the chances of success in clinical testing.  While a number of aurora kinase inhibitors have gone by the wayside due to lack of efficacy or excessive toxicities, the good news is that there are still several other aurora kinase A inhibitors in active R&D in addition to PHA-739358, including:

  • MLN8237 (Millennium)
  • AT9283 (Astex)
  • AZD1152 (AstraZeneca)
  • AMG 900, a pan aurora kinase inhibitor (Amgen)

There are probably a few others, but these are the ones I can remember off the top of my head.

Overall, I think these results are very promising indeed, albeit for a small subset of patients with prostate cancer.  That said, it does suggest that another ‘slice of the pie’ has potentially been identified and I look forward to seeing a more precise and well defined clinical trial emerge in the near future in NET prostate cancer to validate the new research findings.

References:

ResearchBlogging.orgBeltran, H., Rickman, D., Park, K., Chae, S., Sboner, A., MacDonald, T., Wang, Y., Sheikh, K., Terry, S., Tagawa, S., Dhir, R., Nelson, J., de la Taille, A., Allory, Y., Gerstein, M., Perner, S., Pienta, K., Chinnaiyan, A., Wang, Y., Collins, C., Gleave, M., Demichelis, F., Nanus, D., & Rubin, M. (2011). Molecular Characterization of Neuroendocrine Prostate Cancer and Identification of New Drug Targets Cancer Discovery, 1 (6), 487-495 DOI: 10.1158/2159-8290.CD-11-0130

Tomlins, S. (2005). Recurrent Fusion of TMPRSS2 and ETS Transcription Factor Genes in Prostate Cancer Science, 310 (5748), 644-648 DOI: 10.1126/science.1117679

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