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Posts tagged ‘medivation’

Medivation announce interim results of PREVAIL in pre-chemotherapy CRPC

By on October 22, 2013

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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Video Report from 2012 European Association of Urology Congress in Paris

By on March 2, 2012

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.

Will combining custirsen and MDV3100 reduce resistance in advanced prostate cancer?

By on February 26, 2012

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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The role of the Androgen Receptor in breast cancer

By on February 10, 2012

This week I have been in Orlando for the American Association for Cancer Research (AACR) Special Conference on prostate cancer chaired by Drs Arul Chinnaiyan (U. of Michigan) and Charles Sawyers (MSKCC).  It was a superb meeting, probably one of the best I’ve attended since the PI3K meeting that AACR hosted in February last year.  I wrote nearly half a Moleskine of notes that vaguely resemble chicken scratch – there were so many good talks that stimulated new ideas and explained a few scientific things I also didn’t know too well.  Learning is a continuous lifetime experience, after all.

During the meeting, I had a nice correspondence with one of our regular blog readers, the thoughtful Biomaven.  Peter mentioned some data on the androgen receptor (AR) as a potential target in breast cancer following Medivation’s recent conference call.  It’s an interesting topic and one well worth discussing.  Here’s a map of the AR pathway for reference:

Source: wikipedia

The AR is not something one naturally and immediately thinks of in women, since testosterone is usually considered a manly thing.  That said, it is present in women in both normal breast epithelial cells and ~70% to 90% of invasive breast cancers.

Until recently, the link, however between AR status and breast cancer survival is uncertain and perhaps a little controversial, but Hu et al., (2011) looked at the association between the AR status and breast cancer survival in the Nurses’ Health Study (NHS) – see references at the end for the link to the article.

What was the study about?

According to the authors:

“The NHS is a prospective cohort study established in 1976 when 121,700 female registered nurses from across the United States, aged 30 to 55 years, completed a mailed questionnaire on factors that influence women’s health.

Follow-up questionnaires have since been sent out every 2 years to the NHS participants to update exposure information and ascertain nonfatal incident diseases. Follow- up rate from 1976 to December 2007 is 98.9% in our study.”

Not to be confused with an population/epidemiology study from the NHS (National Health Service) in the UK!  The main goal of this study was to:

“… determine the association of AR status with survival outcomes adjusting for covariates.”

What did the research find?

Out of all the breast cancers followed (n=1467), 78.7% were AR+. Additionally, amongst the ER+ patients (n=1,164), 88% were AR+:

“AR positivity was associated with a significant reduction in breast cancer mortality (HR, 0.68; 95% CI, 0.47–0.99) and overall mortality (HR, 0.70; 95% CI, 0.53–0.91) after adjustment for covariates.”

The situation was very different in women who were ER- (n=303) though:

“42.9% were AR-. There was a nonsignificant association between AR status and breast cancer death (HR, 1.59; 95% CI, 0.94–2.68).”

In other words, AR+ confers a better prognosis in ER+ breast cancer.

Now, the relevance of all this research is potentially important when considering possible mechanisms of resistance to aromatase inhibitor (AI) therapy in ER+ breast cancer.  Recall that one mechanism of resistance to AI treatment is mTOR, which is why the BOLERO2 trial with an AI (exemestane) plus an mTOR (everolimus) in the relapsed setting did so well in ER+ women.  Not all of the women in the trial responded to the treatment though, suggesting that other factors may play a role in acquired or adaptive resistance.

What is the importance of AR to therapies for breast cancer?

Normally, knowing whether a particular situation has a better or worse outcome isn’t particularly helpful for patients, since it doesn’t predict which therapy might be more appropriate. However, there is some other AR and breast cancer research from Cochrane et al., (2011) which was presented to the Endocrine Society Peter referred to that tells us a bit more of the AR story:

“We postulate that ER+ breast cancers that fail to respond or become resistant to current endocrine therapies (tamoxifen or AI) may do so because they have switched from growth controlled by estradiol (E2) and ER to growth controlled by liganded AR.

We therefore sought to determine if blocking AR activity could serve as a therapeutic intervention for such tumors.”

What did they do?

Cochrane et al, (2011) stated that:

“We used breast cancer cells that express ER and AR such as MCF7 cells and a cell line that we recently isolated that contains more AR than ER.

Our data indicate that although DHT does slightly inhibit E2-mediated proliferation, DHT alone is proliferative in cells such as MCF7 with both ER and AR, and is even more proliferative than E2 when AR is more abundant than ER.”

What did the results show?

The results were a) interesting and b) a little surprising:

“We found that while both the anti-androgen bicalutamide and the triple acting, non-steroidal, AR antagonist MDV3100 block DHT and R1881-mediated proliferation of breast cancer cells, we made the novel observation that MDV3100, but not bicalutamide, inhibits E2-mediated proliferation of breast cancer cells.”

These results led the authors to conclude that:

“Anti-androgens, such as MDV3100, may be particularly useful to treat patients whose tumors fail to respond to traditional endocrine therapy despite being ER+, or who have ER-/AR+ tumors.”

Not surprisingly, Medivation announced on their recent conference call this month that they will be seeking to explore this phenomenon in clinical trials.  I think this is a logical and exciting development that is well worth a shot on goal.  We know that not all the women in the BOLERO2 trial responded to exemestane and everolimus, so other mechanisms must be at play here.  This is certainly worth exploring.

The question with the study design of me for me though, is patient selection.  How do we determine which women whose initial AI therapy leads to relapse should go onto an mTORor an AR antagonist?  I’m guessing that maybe biopsies will be part of the answer.

In conclusion…

On the positive side, it would be pretty cool if we could uncover two mechanisms of resistance to AI therapy in ER+ breast cancer and have some viable therapies to offer women once relapse or acquired resistance sets in.  It would start to offer a) hope and b) potentially prolong outcomes further as we determine ways to shut down the various escape routes and signaling pathways.  If the concept works, given that up to 30% of women with ER+ breast cancer may have AR+ signaling, then it would also be good news for Medivation and Astellas with MDV3100’s potential upside.

References:

ResearchBlogging.orgHu, R., Dawood, S., Holmes, M., Collins, L., Schnitt, S., Cole, K., Marotti, J., Hankinson, S., Colditz, G., & Tamimi, R. (2011). Androgen Receptor Expression and Breast Cancer Survival in Postmenopausal Women Clinical Cancer Research, 17 (7), 1867-1874 DOI: 10.1158/1078-0432.CCR-10-2021

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Is ARN-509 (Aragon) potentially better than MDV-3100 (Medivation) in advanced prostate cancer?

By on February 2, 2012

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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Update on Medivation’s MDV3100 in advanced prostate cancer

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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Excellent news in Advanced Prostate Cancer – Medivation's MDV3100 meets primary endpoint

By on November 3, 2011

It’s not often that you wake up to really exciting news in the cancer field, but that’s what happened this morning with Medivation’s announcement on the interim analysis of their androgen receptor (AR) antagonist, MDV3100:

“As reported by the IDMC, MDV3100 produced a 4.8-month advantage in median overall survival compared to placebo.

The estimated median survival for men treated with MDV3100 was 18.4 months compared with 13.6 months for men treated with placebo. MDV3100 provided a 37 percent reduction in risk of death compared to placebo (Hazard Ratio=0.631).

The IDMC further determined, considering the observed safety profile, that MDV3100 demonstrated a favorable risk-to-benefit ratio sufficient to stop the study.”

The 4.8 month improvement in OS in post-chemo setting is superior to that previously reported for abiraterone (Zytiga), which had a 3.9 month advantage over placebo and received regulatory approval in the US and EU earlier this year.

This is great news for patients, for Medivation and also for Charles Sawyers at MSKCC who originally invented the MDV3100 compound. If you are interested in the MDV3100 story, you can read my interview with Dr Sawyers posted earlier this year.

There are several points to note about these results:

  • MDV3100 does not require concomittant steroid therapy as abiraterone does, this is huge for urologists who as surgeons do not generally want to manage side effects.
  • Given the excellent results in the post chemotherapy setting, I would expect the survival advantage in the pre-chemotherapy session for both therapies to be more than 6 months.
  • Ultimately, as hormone therapy, I can see the real advantage for MDV3100 being as a more potent and complete inhibitor of the AR than bicalutamide, so there is a huge potential for MDV3100 as ADT therapy in the earlier stages of disease.

With regards to filing, Medivation announced that:

“Medivation and Astellas plan to hold a pre-NDA meeting with the U.S. Food and Drug Administration (FDA) in early 2012 and will provide an update on regulatory timelines for MDV3100 subsequent to that meeting.”

At this rate, I would expect to see MDV3100 approved sometime in 2012.

The future is looking very bright indeed for patients with advanced prostate cancer – these new therapies offer the potential with sequencing to extend lives significantly.

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Custirsen – a new treatment for castrate resistant prostate cancer?

By on August 8, 2011

I’ve been following the development of Oncogenex’s custirsen for a while based on various posters presented at meetings such as ASCO and AUA, but with the publication of phase II data in prostate cancer, it seems a good time to discuss the compound in more detail.

According to Oncogenex:

“OGX-011, also known as custirsen sodium, inhibits the production of clusterin, a protein that is associated with treatment resistance in a number of solid tumors, including prostate, breast, non-small cell lung, ovarian, and bladder cancers.”

Essentially, I think of it a chemo-enhancer, although more technically, it seems to help delay the onset of resistance developing by targeting clusterin (CLU).  CLU is a stress-activated cytoprotective chaperone.  It is upregulated by a several cancer drugs and confers resistance when overexpressed.

Low levels of CLU are therefore more desirable and may be useful as a predictive biomarker of response.

Previous data on custirsen from the phase II front-line trial showed an encouraging shift to the right in the survival curves, validating the hypothesis that resistance is delayed:

The current phase II clinical trial received support from both Sanofi and Oncogenex. Results were reported by Saad et al., (2011), who assessed the weekly administration of custirsen in combination with either docetaxel or mitoxantrone in second-line metastatic castrate resistant prostate cancer (CRPC).  Patients had previously been treated with a minimum of 2 cycles of a docetaxel-based chemotherapy regimen and progressed during or within 6 months of discontinuation of docetaxel treatment.

Overall, patients (n=42) were randomized to receive either docetaxel + prednisone + custirsen (DPC) or mitoxantrone + prednisone + custirsen (MPC).

What did the data show?

Given that the preclinical in vitro and in vivo models have demonstrated the potential of custirsen to enhance chemotherapy and reduce docetaxel resistance, I was keen to see how the concept would pan out in humans.  We all know that preclinical evidence is no guarantee of success in clinical trials!  Although the primary goals of the trial were to measure safety and tolerability, the effects on tumour response and disease progression were interesting.

DPC (n=20):

  • Received: median of eight cycles
  • Overall survival:15.8 months
  • TTPP: 10.0 months
  • 10 of 13 (77%) evaluable patients had pain responses
  • Three of 13 (23%) evaluable patients had objective partial responses
  • PSA declines of ≥90%, ≥50%, and ≥30% occurred in 4 (20%), 8 (40%) and 11 (55%) patients, respectively.

MPC (n=22):

  • Received a median of six cycles
  • Overall survival was 11.5 months
  • TTPP was 5.2 months
  • 6 of 13 (46%) evaluable patients had pain responses
  • No objective responses were observed
  • PSA declines of ≥50% and ≥30% occurred in 6 (27%) and 7 (32%) patients, respectively.

Based on experience, we would expect the results with docetaxel chemotherapy to be better than mitoxantrone, since the latter is only palliative at best.

Additionally, custirsen treatment was shown to significantly decrease levels of the target protein, CLU, and low serum CLU levels during treatment demonstrated superior survival.

Two phase III trials in combination with docetaxel are now ongoing in both the first and second line setting in CRPC.  The trials are currently enrolling patients, so results will not be available for a while, ie 2013 at the earliest.

Many of you will remember the video discussion from the American Urological Association meeting earlier this year, where we highlighted the potential for custirsen in combination with an AR antagonist such as MDV3100 from Medivation/Astellas.  For those interested, the initial data from the custirsen/MDV3100 combination is shown in the short vlog.

In the meantime, the results look most encouraging, although there is a-ways to go yet, since phase II data is no guarantee of phase III performance.

{Update: Luke Timmerman from Xconomy posted about the slow recruitment to the phase III trials and the protocol amendment to include Sanofi’s cabazitaxel (Jevtana).

References:

ResearchBlogging.orgSaad, F., Hotte, S., North, S., Eigl, B., Chi, K., Czaykowski, P., Wood, L., Pollack, M., Berry, S., Lattouf, J., Mukherjee, S., Gleave, M., & Winquist, E. (2011). Randomized Phase 2 Trial of Custirsen (OGX-011) with Docetaxel or Mitoxantrone in Patients with Metastatic Castrate-Resistant Prostate Cancer: CUOG Trial P06c Clinical Cancer Research. DOI: 10.1158/1078-0432.CCR-11-0859

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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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Update on new data in prostate cancer

By on May 9, 2011

The interview with Dr Charles Sawyers from Memorial-Sloan Kettering recently, talking about his role in Medivation’s MDV3100, turned out to be rather good timing.  On Friday, Medivation announced their 1Q earnings and clinical progress.

The big news is that aside from the ongoing phase III trials in castrate-resistant prostrate cancer (CRPC) before (PREVAIL) and after failure of docetaxel (AFFIRM), the company are seeking to explore the use of MDV3100 earlier in the disease.  This makes a lot of sense, both clinically and strategically.  A phase II trial is already open in the pre-chemotherapy setting, comparing MDV3100 to bicalutamide (TERRAIN).

Highlights

  1. The first phase II trial evaluates the combination of MDV3100 with bicalutamide in the treatment of advanced prostate cancer patients who have progressed while on LHRH analogue therapy or following surgical castration. TERRAIN is expected to enroll approximately 370 patients in North America and Europe. The primary endpoint of the trial is progression-free survival.  This trial is ongoing and patients are enrolling.
  2. A second phase II trial has now opened and is the first trial to examine the effects of MDV3100 without medical or surgical castration.  Patients will be given MD3100 monotherapy and “enrolled patients would not have had any previous hormonal therapies for the treatment of prostate cancer.” In other words, both hormone and chemotherapy naive, so very early in the prostate cancer treatment cycle where LHRH analogues are traditionally given.  On Friday, Medivation announced that the first patient has now begun treatment with MDV3100 in this setting.  Approx. 60 patients will be enrolled in Europe, with PSA as the primary endpoint and will take MDV3100 orally for 24 weeks (160 mg dose).
  3. The main phase III registration trial,  AFFIRM, is a randomized, double-blind, placebo-controlled study in 1,199 patients with advanced prostate cancer who were previously treated with docetaxel-based chemotherapy.   MDV3100 was compared to MDV3100 versus placebo.  The primary endpoint is overall survival.  The study completed enrollment last November, so Medivation plan an interim analysis  by the end of the year.

Interestingly, MDV3100 is now being positioned as “a triple-acting oral androgen receptor antagonist.” As Dr Sawyers noted in the interview, MDV3100 and abiraterone (Zytiga) have very different mechanisms of action in throttling either the androgren receptor signaling directly, or by inhibiting testosterone production that drives tumour growth through CYP17 inhibition.

What does all this data mean?

On Friday this week, I’ll be heading off to the annual meeting of the American Urology Association (AUA) and will be live tweeting, blogging and vlogging the event to see what urologists and oncologists think of these new developments.

Essentially, abiraterone’s recent FDA approval means that they will compete head to head with Sanofi’s cabazitaxel (Jevtana) in the post Taxotere setting, and Medivation look to be about 18 months behind with MDV3100, although the latter are aggressively expanding their trial program earlier in the disease, where I think it will have a more lasting impact.  The proof of concept for androgen receptor antagonists has already been proven with bicalutamide, so the question there is whether MDV3100 will be a more complete and effective inhibitor.  In the long run, a phase II trial combining abiraterone and MDV3100 to take advantage of their different mechanisms of action in early prostate cancer makes a lot of sense.

The last few weeks have provided some amusement with naysayers insisting that the PDUFA date for abiraterone wasn’t until October instead of realising it was getting Priority approval early (oops) and that the MDV3100 phase III trial couldn’t possibly be mature for an interim analysis by year end (another oops).  I’m glad I called both of those correctly 🙂

This leads me to ponder the next controversy – will urologists use these new hormonal agents in the pre-chemo setting once approved in the post chemo setting?  My hunch is yes based on the overwhelming feedback I heard this year at both ASCO GU and the European Association of Urology meeting in Vienna.

I say this with hindsight, knowing that many people insisted when imatinib (Gleevec) was approved for CML in refractory and advanced disease, that it wouldn’t be used front-line without FDA approval.  When we looked at the data at the end of 7 seven months from approval, guess what?  There was a fair bit of front-line use even without compendia listing, so it can happen when there is pent up demand and high desire to use a product.

My sense is that will happen here too, especially as bicalutamide and ketoconazole are already well established in the prostate cancer treatment paradigm as patients cycle through multiple therapies, but we will see.  Urologists, we all know, much prefer pills over the complexity of infusional therapies.

What’s next?

In the meantime, with another round of urology and cancer conferences coming up, we can expect to see the final OS survival data from the FDA submission for abiraterone presented at AUA by Fred Saad and an update on the much awaited circulating tumour cells (CTC’s) data from Prof De Bono at ASCO.  All in all, it’s going to be a very interesting two months!

 

 

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