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Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts from the ‘Urology’ category

It’s now time to turn our attention to genitourinary oncology and, in particular, prostate, renal and urothelial bladder cancers. This week brings this ASCO GU meeting (#GU15), which is being held in Orlando this year and began this morning.

There are quite a few interesting topics being covered here, particularly in the poster sessions over the next three days. Hopefully, 2015 will also bring more good news in this space as 2014 was a rather dismal one on several fronts!

We decided to highlight some of the most interesting abstracts on castrate resistant prostate cancer and urothelial bladder cancer in our latest conference preview.

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TBMS Sprycel Logohe results of the phase 3 clinical trial of dasatinib (Sprycel) plus docetaxel/prednisone versus placebo and docetaxel/prednisone in men with castration-resistant metastatic prostate cancer (CRPC) are expected soon.

BMS recently updated the clinicaltrials.gov website to show that the dasatinib phase 3 randomized prostate cancer “READY” trial (NCT00744497) of 1500 men completed data collection in August.

Data is expected before year end and, If positive, could be a late breaker at the ASCO Genitourinary Cancers Symposiusm (ASCO GU) in Orlando from Feb 14-16, 2013.

Dasatinib inhibits Src-family kinases (SFK)

Dasatinib is approved for Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia (ALL). It is a BCR/ABL, LYN and Src family tyrosine kinase inhibitor.

Src-family kinases (SFK) are involved with tumor proliferation and bone metabolism.

In the phase 1 & 2 clinical trials of dasatinib with docetaxel, many of the men with prostate cancer saw a decrease in PSA from baseline, reduction in tumor size and bone scan improvement and stabilization. Encouraging early results led to the start of a phase 3 randomized trial of dasatinib in combination with the chemotherapy, docetaxel.

However, the results for Src inhibitors in prostate cancer have been mixed to date, with not all agents generating positive data. Astra-Zeneca’s saracatinib (AZD0530), for example, showed little clinical effect on its own in a phase 2 prostate clinical trial.

It has been suggested by KOLs at numerous conferences that Src inhibitors may potentially be more effective in combination with other cancer agents. Data suggests that Src might be a resistance mechanism to enzalutamide (MDV3100), so it would be interesting to see whether a dasatinib/enzalutamide combination may be more effective than enzalutamide on its own.

Meanwhile, we await the data to see whether the combination of dasatinib with docetaxel generates a significant increase in overall survival over docetaxel alone. While some are “hopeful”, Dr Oliver Sartor, Professor of Cancer Research at Tulane Medical School noted in a prostate cancer session at ESMO 2012 that, “the docetaxel-combination graveyard is big!

Update Jan 26 2013: Dasatinib Phase 3 Data at ASCO GU

Results from the dasatinib phase 3 prostate cancer trial are a late breaking abstract at the 2013 ASCO Genitourinary Cancer Symposium (ASCO GU) in Orlando. The data will be presented on February 14 by John Araujo MD PhD, Assistant Professor in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston.

LBA #8: Overall survival (OS) and safety of dasatinib/docetaxel versus docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC): Results from the phase III READY trial.

One of the late-breaking abstracts (not yet published) that I am looking forward to at the forthcoming annual Congress of the European Society for Medical Oncology (ESMO 2012) in Vienna is on ODM-201 (Orion Pharma):

LBA25-PR:  ARADES trial: A first-in-man, open-label, phase I/II safety, pharmacokinetic, and proof-of-concept study of ODM-201 in patients (pts) with progressive metastatic castration-resistant prostate cancer (mCRPC)

ODM-201 is a new antiandrogen from Finnish company, Orion Pharma, and is being developed in partnership with Endo Pharmaceuticals (NASDAQ: ENDP).

Orion Pharma LogoIn a corporate presentation, Orion Pharma describe ODM-201 as:

  • Potentially best-in-class antiandrogen
  • Does not enter brain in preclinical models
  • No testosterone increase in animal models
  • Well tolerated

“We are studying and developing an anti-androgen with qualities that currently cannot be found in any of our or our competitors’ drugs”

says Mika Mustonen (@MikaMustonen), Head of Oncology, Research and Development at Orion in an article, “Pursuing a targeted drug for prostate cancer” published by the company. Mustonen says:

“The research on our new drug candidate, ODM-201, suggests that we may be able to provide patients with a new alternative for the treatment of prostate cancer.”

Of note, is Orion’s focus on biomarkers, which may help predict which patients are more likely to respond to the therapy. According to Mustonen:

“Biomarkers increase the chance of success.  By following them we can study topics that have not been considered before in this type of research.  We can predict different phases of the disease, survey any safety risks associated with the drug and find out what kind of patients benefit most from the drug.”

At ESMO 2012 (Twitter hashtag #ESMO12) I expect we will hear preliminary data from the ARADES 3104001 phase 1 dose escalation study (NCT01317641) with ODM-201.

According to clinicaltrials.gov this multicenter, non-randomized clinical trial is being undertaken at sites in Finland, Czech Republic, France, United Kingdom and the United States.

After 12 weeks in the phase 1 dose escalation study, patients with stable disease can continue treatment in a phase 2 extension study on the safety and tolerability of ODM-201 (NCT01429064).

As of May 2012, Orion Pharma reported that the ARADES 3104001 phase II expansion component had 105 patients enrolled, with 3 dose levels to be expanded.

Company senior management have told me they “are very excited about the ODM-201 data,” to be presented at ESMO. I have not seen the data, but presume the results will be positive. After all, company executives don’t get excited about negative data!

Is there a market for a new antiandrogen?

Although Medivation are first to market with their androgen receptor (AR) inhibitor, enzalutamide/MDV3100 (Xtandi) that does not mean that other companies will not be able to make in-roads into the market with cheaper or more effective AR antagonists.

In a Pharma Strategy Blog interview with Sally Church, Dr Charles Sawyers noted that Aragon’s ARN-509 (another AR inhibitor in development) is “more potent” than enzalutamide and “might produce a higher percentage of responders or longer duration of response.”

Medivation recently announced that enzalatumide is available in the United States for patients with metastatic castration resistant prostate cancer previously treated with docetaxel.

At a price of $7,450 a month, however, Xtandi is considerably higher than Johnson & Johnson’s Zytiga.  This aggressive premium pricing strategy opens the door to competitors who may offer equally effective, but less expensive drugs.

The prostate cancer market remains a dynamic one and very much one to watch over the next few years.

I look forward to learning more about ODM-201 at ESMO 2012.

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Dr Benjamin J. Davies, an academic urologist at the University of Pittsburgh today castrated the media over their coverage of the Prostate Cancer Intervention versus Observation Trial (PIVOT).

Pivot Prostate Cancer Trial Conclusion

In an article titled “Prostate Cancer: Lessons from PIVOT lost in media hype” published in the News and Views section of Nature Reviews Urology, Dr Davies states, “we must be careful to ensure the less-newsworthy facts and limitations of high-profile trials, such as PIVOT, are not lost in the media hype.

Davies goes on to say,

“an odious meme is circulating in the medical media, suggesting that prostate cancer is universally diagnosed, that PSA screening causes more harm than help, and that urologists should disregard basic epidemiologic data.”

Strong words perhaps, but those who follow Davies on twitter (@daviesbj) will know that he does not mince words and is not lost for an opinion.

However, in writing for a publication such as Nature Reviews Urology, which is probably not on the reading list of the private practice urologist or member of the mass media, he is preaching to the converted, namely academic-orientated physicians like Davies himself.

All clinical trials have their limitations, and Davies makes valid points that the PIVOT trial has a number of noticeable weaknesses.  Attention was also drawn to this in the accompanying editorial when the data was recently published in the New England Journal of Medicine.  I encourage you to read his review.

I reported the presentations of the PIVOT data from the plenary sessions at the 2011 annual meeting of the American Urological Association (AUA) and the 2012 congress of the European Association of Urology (EAU) on this blog and do take exception to Davies’ implied assertion that ALL the media coverage of the PIVOT trial was “hype.”

Experienced Healthcare journalists such as Scott Hensley (@scotthensley) provided fair and evenly balanced coverage on NPR Shots, for example.

If the media coverage of the PIVOT trial data was not as balanced or did not contain the message that Davies wanted to hear, then rather than shoot the media messenger the urology community should ask themselves why they did not obtain it?

Interestingly, at AUA 2011 and EAU 2012 there were no press conferences on the PIVOT trial data, yet it was an important topic and a plenary presentation.  Press conferences allow the media to ask questions of a panel of speakers and the opportunity to gain a variety of perspectives.  Why did the leading urologists who organize these major medical congresses not provide this access?

It is the responsibility of the urology community to reach out and educate the media if you think we don’t understand the nuances of the data.

Davies singles out the PIVOT trial for critical review, but in so doing he touches upon the wider issue of the lack of quality clinical trial data to support treatment and practice in urology.  It is for this reason that those clinical trials that are published, whatever their limitations, have disproportionate impact.

As I wrote from EAU 2012, why is there no level 1 evidence-based medicine that shows the benefits of robot assisted radical prostatectomy?  Are academic physicians unable to do high quality and robust clinical trials that justify their practice?

In his article, Davies goes beyond criticizing the PIVOT trial to castigating the media over their coverage of PSA screening, for which he is an ardent proponent.

Unfortunately, he ignores the reality that mass media don’t generate the data, they only report what organizations such as the United States Preventative Services Task Force (USPSTF) recommend.  If academic urologists believe the USPSTF got it wrong, then the failure is theirs in their inability to generate compelling data or influence the recommendations.

Finally, when Davies says, “no doubt urologists have not helped themselves by overscreening and overtreating” he touches on what I believe is the underlying cause of much of the problem associated with PSA screening.

Academic urologists need to educate their community colleagues.  Influencing everyday practice and treatment decisions will do more to help patients in the long run than being critical of the media, however justified that may be in some cases.

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American Urological Association 2012 Annual MeetingAlthough there is a lot of buzz around ASCO 2012 in a few weeks time, this weekend sees the start of the annual meeting of the American Urological Association (AUA) in Atlanta.  AUA 2012 runs from May 19-23 at the Georgia World Congress Center.

A few of the sessions that caught my attention include:

  • Basic Science Symposium on Nanomedicine and its application to urology. Several speakers will discuss how nanoparticles can be used for drug delivery, imaging and as therapeutic tools.
  • Society for Basic Urologic Research (SBUR) and Society of Urologic Oncology (SUO) joint meeting on personalized medicine and novel targets for cancer therapy.

For those of you who missed AUA 2011, you can obtain a flavor of the meeting from Sally Church’s video that was published on Pharma Strategy Blog.

If you can’t be in Atlanta, you can follow updates from the conference on Twitter (hashtag #UR012). A few people to follow at the meeting include @cooperberg_ucsf, @daviesbj, @MaverickNY@NeuroUroGastro.

We are aggregating the #URO12 tweets so you can easily catch up on the conversation and news below:

2012 Annual meeting of American Association for Cancer Research in Chicago. Photo Credit: Pieter DroppertAs Sally Church, PhD noted on Pharma Strategy Blog, the 2012 annual meeting of the American Association for Cancer Research (AACR), recently held in Chicago, showcased many new cancer products in early development.

Cancer new products have a high attrition rate as they move through the development pipeline, so any promising results seen in early stages of development must be viewed with caution.

Results from laboratory studies using cell lines or trials in animals do not always translate into new drugs that work in man, e.g. they may have an unacceptable toxicity, not target the driver mutation, or adaptive resistance may just lead to the cancer bypassing the blocked pathway.

However, scientific meetings such as AACR do provide a window into the possible new drugs of the future. One prostate cancer new product that caught my attention at AACR 2012 as one to watch is AZD3514.

Sarah Loddick from AstraZeneca gave one of the few oral presentations at AACR on this exciting new compound.  This was the only AACR session I attended where I was able to access wifi. Some of my live-tweets are captured in the Storify below (click here to access this on Storify):

http://storify.com/3nt/aacr-2012-azd3514-in-prostate-cancer

Unfortunately, Sarah Loddick has not (as of time of writing) shared a copy of the AZD3514 prostate cancer poster that she presented later in the meeting, so I’m unable to write more about the preclinical prostate cancer data.

AZD3514 is a novel selective androgen receptor down-regulator (SARD) and has a different mechanism of action to drugs such as enzalutamide (MDV3100) that functionally inhibit AR signaling by binding to the AR & AR splice variants.

Sarah Loddick concluded at the end of her oral presentation that AZD3514:

  • inhibits prostate cancer growth in vitro & in vivo
  • has activity against wild-type and mutated AR
  • has activity in pre-clinical models that represent castration resistant prostate cancer (CRPC)
  • inhibits seminal vesicle growth in rats in the presence of physiological levels of circulating tumor cells.

AZD3514 is in a multi-center phase 1 clinical trial in patients with metastatic CRPC in Europe (NCT01162395) and Japan (NCT01351688). I look forward to seeing the presentation of the results from these trials.

From what I saw at AACR, AZD3514 is a new prostate cancer drug to watch.

Update April 20, 2012

I was delighted to receive an email this morning from Sarah Loddick of AstraZeneca with a copy of the AZD3514 poster that I requested (AACR abstract #3848): “Pre-clinical profile of AZD3514: a small molecule targeting androgen receptor function with a novel mechanism of action and the potential to treat castration resistant prostate cancer.

I am sensitive to the unpublished status of much of the research presented at AACR, but without giving too much away, some of the key messages from this poster are that AZD3514:

  • Binds to the androgen receptor (AR) ligand binding domain & reduces viability of prostate cancer cells in vitro. 
  • Inhibits AR transcriptional activity within 2h of exposure in LNCaP cells, and reduced both PSA & TMPRSS2 mRNA
  • Inhibits AR induced translocation to the nucleus
  • Causes AR down-regulation in prostate cells in vitro
  • Causes AR down-regulation in rat R3327H prostate tumors
  • Has activity in pre-clinical models of CRPC

A drug such as AZD3514 in prostate cancer could potentially be used to overcome resistance to enzalutamide (MDV3100), or alternatively it could be used ahead of enzalutamide if it has the potential to avoid resistance and offer better outcomes. We obviously will have to wait for clinical data to see what it’s true potential is and the data from AACR, while promising, is still only preclinical.

The prostate cancer market is a busy one and companies with AR targeted new products in development will have to offer drugs that are superior to enzalutamide if they wish to have lasting commercial success.

Update June 6, 2013: AstraZeneca terminates development of AZD3514 in Advanced Prostate Cancer

At ASCO 2013 it was announced that the development of AZD3514 in advanced prostate cancer has been terminated. You can read more about what happened in the first-in-human clinical trial in my AZD3514 blog post from ASCO 2013.

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Maha Hussain MB ChB is Professor of Medical Oncology at the University of Michigan. I was privileged to interview her about cabozantinib (XL184), a novel drug in development for multiple indications, including prostate cancer.

You can read part 1 of the interview on cabozantinib and pain here, and part 2 about the bone effect seen with cabozantinib, here.

In this final post, Dr Hussain discusses the scientific rationale behind the mechanism of action for cabozantinib, a multi-kinase inhibitor of C-MET, VEGF and others.  She also shares her thoughts on where the scientific data suggests it should have most impact on prostate cancer.  I have emphasized in bold a few sections that stood out to me.

BSB:  We saw that the VEGF inhibitor bevacizumab (Avastin) failed in prostate cancer, so what is the scientific rationale behind targeting c-MET & VEGF? 

Dr Hussain: Let me just begin with a little background. The c-MET pathway and VEGF pathway from a generic perspective in cancer are specifically of interest.  The trial [with cabozantinib] was originally designed, not that there was any specific preclinical data with the drug in prostate cancer, but rather because of the fact that the MET signalling pathway appears to be relevant in a variety of tumors where there is an overexpression.  This potentially causes us, or at least the sponsor I should say, to believe this is worth targeting.

In retrospect, the sponsor targeted diseases where there seems to be overexpression of MET and that’s how it started.  Now, there is data though in terms of overexpression, if you looked at tissues from primary versus lymph node versus metastatic disease there appears to be a stepwise increase in the rate of overexpression of MET in specifically prostate cancer.  

In the short audio clip below Dr Hussain next discusses the key finding that if you block Androgen Receptor (AR) signaling, MET expression goes up. Click here if you can’t see the SoundCloud audio player.


Dr Hussain continuesWhat happened is serendipity occurred, and that is the drug appeared to be very active.  In essence, we are now going back to the lab to try to figure out exactly why does it work?  Is it just a bone only issue, and when I say bone I mean microenvironment issue, or is it actually more than that, is it a totality of both microenvironment and an anti-tumor effect?

What’s interesting is in the literature, there is data that would indicate that when you activate MET, one protects the cancer cells from potential damaging effects of DNA damaging agents. There is also some data, not in prostate cancer specifically, that MET actually mediates resistance to other growth factors like EGFR and Src and so on.  When you try to inhibit them, MET actually appears to potentially mediate resistance to those inhibitors.  There is also data that potentially MET pathway stimulates angiogenesis in the context of sunitinib resistant tumors.

Now in prostate cancer, what we we know is that VEGF is critical for the osteoblast, osteoclast action, and both MET and VEGF seem to crosstalk to regulate the interaction between the tumor cells, the bone cells, the endothelial cells and so on. There are several trials that have targeted the microenvironment. 

You mentioned Avastin, but the reality of it is that sunitinib was a negative trial also, and  the bone targeted drugs have been generally negative trials. 

The question is, why does this thing work when everything else has failed?  My guess is that it may very well may be that pure targeting of one pathway is not enough and that you need a multi-targeted approach. 

The drug, while it is targeting VEGF and MET, it is not a pure target of VEGF and MET, it has multiple other effects, and truthfully no one can say the reason it is working in prostate cancer is because it is inhibiting MET.  I honestly don’t think that we have demonstrated that. 

We do have a clinical trial actually that has just started to specifically look at what happens in the tumors in the bone in patients who are going to be treated with this drug.

BSB:  Did you see the recent paper in Cancer Discovery that talked about suppression of tumor invasion and metastasis by concurrent inhibition of C-MET and VEGF signaling in pancreatic neuroendocrine tumors? 

[As an aside for those interested, Sally Church, PhD has an excellent post on Pharma Strategy Blog, Combined VEGF and MET inhibition in some cancers may be better than either alone,” which discusses the Cancer Discovery paper by Sennino et al.)

Dr Hussain:  In my [AACR] presentation, I do put the data from the pancreas neuroendocrine [research]. It is not from that paper, but I think it is data from previous papers that were published that looked at how the drug works. This was data that I was able to get through the sponsor from Drs Sennino and McDonald.

BSB: Would we we better off combining separate c-MET and VEGF inhibitors rather than have one drug like cabozantinib that has multiple targets?

Dr Hussain: I think you want to go with what works and thus far, this is the first drug that has again what we think is a MET and VEGF targeting based on the preclinical data, that seems to work.  But I would also point that it is not a pure VEGF & MET it also has RET, KIT, FLT and AXL.  My point here is, we assume that this is the reason.

But I would point out is, that I think the notion that you are going to declare victory on cancer by targeting one pathway in a disease that has multiple redundant pathways, in my view is a naive assumption.  We have known for example, with even diseases that are chemosensitive that you couldn’t cure them with one drug and Testes cancer is a perfect example.  Probably, the model of a curable cancer is Testes cancer. Because there is no other cancer, a solid tumor that you actually target, treat in metastatic disease and can cure at a high rate.  There is just nothing else, with all these new discoveries with targeted drugs, none of them have thus far cured a metastatic patient.  And I would stand corrected if I am not right.

BSB: So your suggestion is that we will need to combine these drugs?

Dr Hussain:  Absolutely! The problem is if you are a scientist and you put in for a grant and you put in a drug that is quote unquote a “dirty drug” because it is has multi-targeting, that is not scientifically good enough. Yet from a clinical perspective, I think that what is clear is we are not curing people by having one target targeted. I would argue that all of the “progress” that has occurred if you look at the drugs, they are targeting pathways that are isolated pathways that are not necessarily highly prevalent in all diseases. In some diseases it is a small percentage of patients that have those pathways.

If you look at the outcomes, these are clearly not what I would call huge victory, because you are basically either causing a response or a short lived remission and not significantly impacting survival, as in curing cancer, prolonging life by years.  So I go back to the model of Testes cancer, which is again one of the most curable cancers that we have in the metastatic disease setting.  And even then, we do not cure it with one drug.

BSB:  Can I take you back briefly to something you said earlier that caught my attention. You said earlier that expression of c-met was increased after attenuation of the androgen receptor signaling, so one strategy would be to inhibit activation of both the c-MET and AR signaling pathways.

Dr Hussain:  Correct, correct.

BSB:  I saw that there is a phase 1 trial just starting looking at abiraterone in combination with cabozantinib, so is the theory there that we could potentially delay time to castration resistance if we inhibit both AR signaling and the c-met/VEGF pathway?

Dr Hussain:  Correct, but I would say that the place to start is not with abiraterone, but with primary hormonal treatment when the tumor is still sensitive to hormones.

BSB: So when we are doing androgen deprivation therapy?

Dr Hussain: Correct. I personally think that is where we need to start.  And in fact because of that, in partnership with one of my colleagues here who is also my co-leader for the prostate cancer program at Michigan, we have some preclinical data that is in progress looking at hormone sensitive tumor model.

The question comes up where is the right time to put these drugs, and the truth of it is you brought up the issue of expense, and while I am not the person who says how much life is worth, clearly if it is my life or my family’s life or my patients life, it is worth a lot. But society has to decide how much money to spend on what and for what magnitude of benefit. That is something that I think we are all struggling with, as you point out, because healthcare dollars are going down and a lot of these drugs are very expensive. And when they work we talking about prolongation of life anywhere from 2 months to 5 months, and that’s average. The reality of what that means is that you are treating thousands of patients to get benefits in a smaller number of patients, and is this something sustainable and is this the way we should go?

I would argue that, life is very precious and very valuable, the more that we can do to impact it, the better we will be as doctors, patients and society.  But that in order to get a bigger bang for the bucks, so to speak, for the drug itself is we need to begin to think about moving these drugs in settings whereby you have cancers that are not as resistant where the impact might be higher.  Imagine then, we would then prolong life by maybe years, as opposed to months.  I think that would be much more worth it.

Yes, it will be more costly to test these drugs earlier, and certainly there is the financial aspect of it for Pharma. They would want to go in a setting where they can get the results sooner rather than later, and not treat ten times more patients to find the results. I would say from the big picture perspective as a doctor, that’s not my focus, my focus is to move these drugs to settings where we can have more impact for more patients, and more meaningful impact on their outcomes.

BSB: In essence, you do think that is where cabozantinib could have most effect at that time?

Dr Hussain:  Maybe. I think this is a question that should be asked. We have proposed to look at in the preclinical setting, to try to justify a clinical trial potentially.  Recognizing that it is one of those things, clearly we are limited by access to drugs and $ to support these type of questions. And if it is not cabozantinib, it’s the next in line targeting that pathway. I do think someone needs to ask that question and we could envision trial designs that can give you short-term answers that will give you a sort of Go/No-Go type strategy.  It is a complex process, obviously. I would say if the world was perfect, and if it was my money and my drug, I would go that way to see how it behaves.

BSB: Thank you!

This brings to an end the series of posts covering my interview with Dr Maha Hussain, a thought leader in prostate cancer clinical research. I would like to sincerely thank her for the time she took out of her busy schedule to talk to Biotech Strategy Blog.

To effectively treat prostate cancer will require drugs to be given in combination. A VEGF/MET inhibitor may have a role to play in the treatment of prostate cancer, but whether Exelixis have the appropriate clinical trial strategy in place with cabozantinib to achieve this, remains to be seen.

Other pathways that we didn’t have time to discuss may also need to be targeted e.g. Src and PI3-Kinase.  It will be interesting to see what new data is presented at the annual meeting of the American Association for Cancer Research (AACR) in Chicago later this month.

This is part 2 of my interview with Dr Maha Hussain, Professor of Medical Oncology at the University of Michigan.  You can read part 1 about cabozantinib and pain here.

Cabozantinib-Prostate-Cancer-Bone-Effect

At the 2011 ASCO annual meeting, Dr Hussain presented data from a non-randomized phase 2 trial with cabozantinib that showed dramatic improvements in bone scans before and after treatment.

Bones are living tissues that are constantly being remade, a dynamic process that involves formation of new bone and taking up of old bone, a process known as bone resorption.  Cancer cells can interfere with bone remodeling, resulting in increased new bone formation (osteoblastic response) or excessive bone resorption (osteoclastic response).

Bone scans involve the injection of radioactive tracers such as technetium-99m-MDP. In simple terms, the radioactive material detects bone turnover and areas of high bone metabolism.  These show up as darker “hot spots” where the tracers accumulate.

Bone scans have poor specificity because tumors, fractures and infection all lead to hot spots. Also, not all tumors or lesions are detected by a bone scan.  Bone scans have a sensitivity of around 62-89%.

At the 2011 Society for Translational Oncology Prostate Cancer Symposium, Professor Johann de Bono (The Institute for Cancer Research) noted that bone scans do not accurately reflect the activity of the disease in men with prostate cancer.

This raises the question as to what we should conclude from the bone scans seen with cabozantinib.  I put this question to Professor Hussain.

BSB: What is the significance of the bone scans that we see and what should we interpret from them given that bone scans don’t accurately reflect the disease?

Dr Hussain: I will refer you back to my presentation at ASCO originally and my recent AACR presentation.

I have specifically put a slide (together) to address, is what we are seeing a fluke, a function of a technique issue because you are targeting the osteoblasts?  Consequently if you inhibit osteoblastic function, you are not going to see much changes on the scan, or is there more too it?

Dr-Maha-Hussain-ASCO-2011-Cabozantinib-Presentation

The specific slide actually puts in columns the (percentage of) patients who had a partial or a complete resolution on the bone scan, versus those who had stable or progressive disease, and then matches it with other evidence of an anti-tumor effect as in target lesion regressions, progression free survival at I think the 6 month mark if I recall correctly, as in the pain improvement, narcotic use.

Recognizing that by the way the pain and narcotic use, both of these were post-hoc assessments that were done.  Once we saw the observation, the sponsor went back and began asking all the investigators to record these things.  Clearly, the ALK phosph going down, the bone turnover markers going down.

The short audio clip below expands on Dr Hussain’s viewpoint about cabozantinib and bone. Click here if you can’t see the SoundCloud audio player.

Dr Hussain’s conclusion is interesting from a marketing strategy perspective.  She does not position cabozantinib as a bone targeted drug such as Xgeva or a bone targeted radiopharmaceutical such as Alpharadin.  Instead, her view is that cabozantinib should be developed as a “prostate cancer specific drug that does have the added advantage of significant anti-tumor effect in the bone” ie an anti-cancer tyrosine kinase inhibitor (TKI).

This is at odds with how Exelixis appear to be positioning it.  The corporate presentation at the Cowen Annual Healthcare Conference on March 6, 2012 had a strong focus on bone metastases: “Cabozantinib demonstrates unique ability to resolve bone metastases and decrease bone pain in CRPC,” one slide said.

If Dr Hussain is correct and we should consider cabozantinib as a prostate cancer specific drug, then it will need to compete on endpoints with other drugs that have shown an impact on overall survival.

Cabozantinib will likely not obtain regulatory approval on the basis of the bone scans, whatever they may show.

Without demonstrating a significant effect on overall survival, it’s hard to believe that cabozantinib will be able to compete effectively in what is fast becoming a very competitive prostate cancer market.

The final installment of the Biotech Strategy Blog interview with Dr Hussain will cover her perspective on the mechanism of action of cabozantinb, and where the drug, theoretically, might be expected to have most impact in prostate cancer.

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Maha Hussain MB ChB is Professor of Medical Oncology at the University of Michigan.  She is an international expert into genitourinary malignancies with a focus on clinical research into prostate and bladder cancer.

Cabozantinib is a new drug in development by Exelixis for multiple indications.  It captured a lot of attention at the ASCO 2011 annual meeting last year, when Dr Hussain presented data from a phase 2 prostate cancer trial that showed a dramatic improvement in bone scans and pain reduction in those men receiving it.

Unlike other new prostate cancer drugs such as abiraterone (Zytiga) or MDV3100 that target the androgen receptor, cabozantinib is a multi-kinase inhibitor of MET and VEGFR.  It has both an anti-tumor effect and an effect on bone metabolism.

At the AACR Advances in Prostate Cancer Research conference last month, chaired by Charles Sawyers (MSKCC) and Arul Chinnayan (Michigan), Dr Hussain gave a presentation on “Cabozantinib (XL-184) and prostate cancer: preclinical and clinical profile of a novel agent.”

I was privileged to have the opportunity to interview Dr Hussain by phone recently and obtain her insight into cabozantinib as a potential new treatment for prostate cancer.

We covered a lot of ground, too much for one blog post, so I’ve broken down the interview into segments that I will be posting separately.

Cabozantinib & Pain

As many readers will be aware, one of the dramatic results presented at ASCO last year, was the impact that cabozantinib had on pain.

AACR-Molecular-Targets-2011-Cabozantinib-Pain-DataAt the AACR Molecular Targets meeting in San Francisco last November, further pain data was presented by Howard Scher’s group at Memorial Sloan-Kettering Cancer Center. They showed in a non-randomized phase 2 trial that:

Cabozantinib treatment resulted in high rates of pain improvement and analgesic reduction or discontinuation in patients with moderate to severe pain at baseline

–  Rapid and durable pain relief

–  Pain relief observed regardless of prior lines of therapy

–  Improvement in pain accompanied by reduced interference with sleep and daily activity

Exelixis has since moved forward with clinical trials focusing on prostate cancer pain.

Pain response is the primary outcome in the phase III trial (COMET-2) of cabozantinib (XL184) Versus Mitoxantrone Plus Prednisone in Men With Previously Treated Symptomatic Castration-resistant Prostate Cancer (COMET-2 trial formerly known as XL184-306). Overall survival is a secondary endpoint.

The challenge with using pain as a primary endpoint is that all the advanced prostate cancer drugs that have recently been approved by the FDA such as cabazitaxel (Jevtana), abiraterone (Zytiga), and those for whom approval is expected, such as MDV3100 and radium-223 (Alpharadin), have all shown an improvement in overall survival.

I was, therefore, interested to hear Dr Hussain’s perspective on cabozantinib and its effect on pain in prostate cancer.

BSB: Can pain be a surrogate for survival that regulatory agencies might accept?

Dr Hussain: Honestly, I am not the expert on what the regulatory agencies will do. I know what they have done and I would say that pain has been an indication for regulatory approval of prostate cancer. That’s a long story, it’s an old story. Mitoxantrone was approved based on pain, so I don’t think that is going to be an issue.

Whether it is a surrogate for survival remains to be seen, and to be honest with you, I think that it may not be if you are really using it in far advanced cancer. As we have seen with mitoxantrone, it didn’t seem to make an impact on survival and it is really more about disease progression and pain and quality of life type issues. 

I am not aware of a trial that has been done with a primary endpoint being pain, and another key primary endpoint or a secondary endpoint being survival, that has been positive.  Having said that, I think in my view, it is a mistake to just focus on the pain. 

Pain, as far as I can tell from our experience and others, it’s very late in the setting of the disease by a nowadays standard. I would argue that using this drug as a pain only type drug, you could do it cheaper and less toxic with other agents, with morphine for example. 

My point here is, I go back and say to focus it on pain only, my average patient is interested in living longer, not just in controlling their pain. 

You can hear more about this in the SoundCloud audio clip below.  Prostate cancer patients are not just interested in “how will this drug make me feel,” but also “will I live longer?”  Click here if you can’t see the audio file.

Dr Hussain: My point is in a perfect world if the drug delivers, the importance is going to be a totality of effect, that is prolonging life and improving quality of life overall.

BSB: Thank you

The next installment of the Biotech Strategy Blog interview with Dr Hussain will focus on the clinical significance of the dramatic bone scans seen with cabozantinib.

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EAU-2012-Congress-Media-Briefing-Professor-Jelle-Barentsz“The Mannogram – Yes we scan” Jelle Barentsz, Professor of Radiology at Radbound University, Nijmegen, The Netherlands told the assembled media at the recent European Association of Urology (EAU) annual Congress in Paris.

Professor Barentsz described how advances in magnetic resonance imaging (MRI), and in particular multi-parametric MRI (Mp-MRI) offer the potential for the improved detection and characterization of prostate cancer.

In the same way there is a mammogram that women use for breast cancer screening, Professor Barentsz raised the possibility that using magnetic resonance imaging, men could have a mannogram to screen and diagnose prostate cancer.

Some of the advantages of multi parametric MRI he highlighted include:

  • Prediction of tumor aggression
  • Prediction of low vs intermediate or high grade prostate cancer correctly in 95% of men in a trial as compared to 54% with TRUS (trans-rectal ultrasound guided) biopsy
  • In cases where there was a negative TRUS biopsy initially, mp-MRI and MR guided biopsy detected prostate cancer in 41% (108/265 of trial participants), with 87% of the prostate cancer detected being significant.

It is beyond the scope of this post to go into the physics of multi-parametric MRI or discuss in more detail the imaging trial data on which the above conclusions are based.  However, for those interested in this area, I have included details of some of the references Professor Barentsz kindly provided at the end of the post.

Why do we need new techniques for prostate cancer diagnosis? 

During their lifetime 1 in 6 men will be clinically diagnosed with prostate cancer.  There are 899,000 new cases and 258,000 deaths per year in Europe.

The current diagnostic tools of digital rectal examination (DRE), serum prostate specific antigen (PSA) and trans-rectal ultrasound guided (TRUS) biopsy have a number of limitations for prostate cancer detection.

This includes a lack of specificity (PSA = 36%), insensitivity (DRE = 37%) or failure to detect cancer due to sampling error with TRUS biopsy (more than 20% of cancers are not detected on first biopsy).

The result is that we end up with large numbers of men with elevated men or rising PSA, who have repeat biopsies. This comes at a high cost to health care providers, the uncertainty of diagnosis and the discomfort that comes with a TRUS biopsy (TRUS-Bx).

Many men undergo diagnostic procedures only to find they don’t have prostate cancer. One of the key issues in the prostate cancer screening debate is this unacceptable harm/benefit ratio.

Prostate biopsy to confirm cancer diagnosis is an invasive procedure as Professor Jenny Donovan, Head of the School of Social  and Community Medicine, at the University of Bristol told the EAU Congress.

In a plenary session, Prof Donovan described some of the initial findings from the PROBE (Prostate Biopsy Effects study), which looked at 1,147 men who received a TRUS-Bx.

“The majority of men tolerated biopsy reasonably well – over 60% experience minor symptoms. However, around one third experience symptoms that bothered them,” she said.

Professor Donovan went on to give examples of some of the feedback on the biopsy experience that researchers obtained:

“I found it incredibly painful and distressing – biopsy with a nail gun,” one man in the PROBE study said.

Data presented by Professor Donovan showed that after the procedure, 11% of men would not want another biopsy (this rose to 20%) seven days later.

Magnetic Resonance Imaging Guided Biopsy may offer benefits

Given the discomfort that many men experience with TRUS biopsy, and the fact a negative biopsy does not automatically mean no cancer (there’s a risk of sampling error), the use of MR guided biopsy may offer significant benefits.

One is that instead of 12 cores being sampled by the TRUS-Bx, only 2 cores are obtained using the MR guided biopsy technique that Professor Barentsz described.

Personally, I would prefer to have two precise cores samples taken from me through imaged based guidance, than have a TRUS biopsy that is like a nail gun that shoots in 12 sampling rods into the target area of the prostate.  This would be like the difference between a sniper rifle and a blunderbuss, metaphorically.

One of the practice implications of this is that radiologists may end up performing MR guided biopsies instead of urologists performing TRUS biopsies.

Urologists in private practice or those who are paid per procedure may not be happy about the practice changing implications that may result.

The MR imaging research that Professor Barentsz described at EAU is not without its limitations and one concern is the reproducibility of advanced imaging techniques outside of an expert university or academic setting.  I put this question to Professor Barentsz in the media briefing and have included an excerpt of his reply that you can listen to:

According to Professor Barentsz, the imaging techniques for MR guided prostate biopsy are readily reproducible outside the academic environment with guidelines already in place for standardized acquisition protocols and structured interpretation of results.

We are now at the point that the standardization of prostate MRI as well as the standardization of reporting with all kind of computer assistance is a fact and not fiction anymore,” said Barentsz.

The European Society of Urogenital Radiology (ESUR) recently published MR guidelines, that include a structured reporting system, called PI-RADS (prostate imaging, reporting, and data system).  This has been adopted in the United States by the American College of Radiology (ACR).

Before men with prostate cancer can expect to see these advanced imaging techniques used outside of expert centers, however, urologists and radiologists will need to agree on the benefits they offer and adapt their practice accordingly. Urologists may be reluctant to move away from TRUS biopsy, so it is likely widespread implementation will take some time and require education, and explanation of the evidence based medicine that supports the proposed change in practice.

The conclusion from Professor Barentsz’s EAU presentation is that imaging looks likely to play an increasing role in the diagnosis of prostate cancer.

It will be an exciting area to watch. The idea of a Mannogram has the potential to become a reality that would benefit the 1 in 6 men who will be diagnosed with Prostate Cancer during their lifetime.

References

ResearchBlogging.orgHambrock, T., Somford, D., Huisman, H., van Oort, I., Witjes, J., Hulsbergen-van de Kaa, C., Scheenen, T., & Barentsz, J. (2011). Relationship between Apparent Diffusion Coefficients at 3.0-T MR Imaging and Gleason Grade in Peripheral Zone Prostate Cancer Radiology, 259 (2), 453-461 DOI: 10.1148/radiol.11091409

Hoeks, C., Schouten, M., Bomers, J., Hoogendoorn, S., Hulsbergen-van de Kaa, C., Hambrock, T., Vergunst, H., Sedelaar, J., Fütterer, J., & Barentsz, J. (2012). Three-Tesla Magnetic Resonance–Guided Prostate Biopsy in Men With Increased Prostate-Specific Antigen and Repeated, Negative, Random, Systematic, Transrectal Ultrasound Biopsies: Detection of Clinically Significant Prostate Cancers European Urology DOI: 10.1016/j.eururo.2012.01.047

Barentsz, J., Dickinson, L., & Sciarra, A. (2011). Re: Axel Heidenreich. Consensus Criteria for the Use of Magnetic Resonance Imaging in the Diagnosis and Staging of Prostate Cancer: Not Ready for Routine Use. Eur Urol 2011;59:495–7 European Urology, 60 (1) DOI: 10.1016/j.eururo.2011.03.013

Hambrock, T., Hoeks, C., Hulsbergen-van de Kaa, C., Scheenen, T., Fütterer, J., Bouwense, S., van Oort, I., Schröder, F., Huisman, H., & Barentsz, J. (2012). Prospective Assessment of Prostate Cancer Aggressiveness Using 3-T Diffusion-Weighted Magnetic Resonance Imaging–Guided Biopsies Versus a Systematic 10-Core Transrectal Ultrasound Prostate Biopsy Cohort European Urology, 61 (1), 177-184 DOI: 10.1016/j.eururo.2011.08.042

Barentsz, J., Richenberg, J., Clements, R., Choyke, P., Verma, S., Villeirs, G., Rouviere, O., Logager, V., & Fütterer, J. (2012). ESUR prostate MR guidelines 2012 European Radiology, 22 (4), 746-757 DOI: 10.1007/s00330-011-2377-y

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