Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘abiraterone’

Making a difference to the lives of cancer patients: An interview with Dr Charles Sawyers

Advanced prostate cancer has been quite a hot topic lately, with several new and relatively late stage compounds in the pipeline garnering attention from promising data. One of those agents, abiraterone acetate (Zytiga) only just received FDA approval on Friday and has been designated for accelerated review by the EMEA.

Following on from previous interviews in the Pharma Strategy Blog “Making a Difference” series with Dr Sue Desmond-Hellman (Chancellor of the University of California, San Francisco), Alain Moussy (CEO of AB Sciences) and Dr Ross Camidge (University of Colorado), it seemed most timely to extend the next round of the series to prostate cancer.

It was therefore a pleasure to talk with Dr Sawyers about his current research in the prostate cancer last week and discuss how he approaches some of the challenges involved with incorporating translational medicine into clinical research.  He is co-inventor of two drugs currently in clinical trials for prostate cancer, namely MDV3100 (Medivation) and ARN-509 (Aragon Pharmaceuticals).

Charles L. Sawyers, MD is Chair of the Human Oncology and Pathogenesis Program at the Memorial Sloan-Kettering Cancer Center (MSKCC), and an Investigator with the Howard Hughes Medical Institute.  In 2009, he received the Lasker-Debakey Clinical Medical Research Award along with Drs Brian Druker and Nick Lydon, for their work on molecular targeting that led to the development of imatinib (Gleevec/Glivec), a drug that revolutionized the treatment of Chronic Myeloid Leukemia (CML) and turned it from deadly cancer into a manageable, chronic disease.

In full disclosure, I had the great privilege of working with Drs Sawyers and Druker while bringing imatinib to market at Novartis Oncology.

Pharma Strategy Blog: Charles, you and I have known each other for over ten years, when we first met you were at UCLA. What made you move to the East Coast and MSKCC?

Dr Sawyers: Harold Varmus who was the Director here at MSKCC, before he moved to the NCI, made me a job offer I couldn’t refuse.  Memorial had built up an impressive cadre of basic scientists, but there was this missing piece of physician scientists who could capitalize on translational opportunities. He was able to convince “the powers that be” to build a new research tower with 21 floors of lab space, that opened in 2006.  He offered me 3 floors and the opportunity to be Director of a brand new program called “Human Oncology.”

My mission was to recruit the best and brightest physician scientists either locally or around the country.  I also saw, after my imatinib work, that the most important contributions I could continue to make from my laboratory work were not going to be in CML, and I wanted a new challenge.  I had started to work on prostate cancer for many reasons, mostly scientific, and I needed to be at a place where clinical care and clinical trials infrastructure was much more integrated than it was at UCLA.  So, it was not that hard a decision to make the move.

Pharma Strategy Blog: One of the drugs that you discovered at your lab was MDV3100, what are you thoughts on when this may be used?

Dr Sawyers: I am very much involved in asking translational questions about MDV3100 and whether it works beyond castrate resistant disease.  Does it work up front in the neo-adjuvant setting, prior to surgery to shrink the tumor? Would it synergize with radiation? All kinds of interesting questions are coming up that we are working to answer.

Pharma Strategy Blog: Why does MDV3100 block the androgen receptor better than bicalutamide?

Dr Sawyers: The most interesting property that MDV3100 has, and what I think is the most likely explanation for its superior performance, is that when you treat cells with this compound the androgen receptor is completely incapable of binding DNA.  We have shown this recently using ChIP-Seq technology that is very powerful at annotating all the binding sites for any transcription factor across the genome.  With bicalutamide, the androgen receptor still binds with the drug very tightly on many thousands of binding sites, whereas with MDV3100, we cannot find it binding anywhere.  It has a profoundly different effect on the receptor.

Pharma Strategy Blog: How did the discovery of MDV3100 come about?

Dr Sawyers: We had been using mouse models to understand why the tumor became resistant to castration and bicalutamide.  What came out of that was the level of expression of the androgen receptor was consistently up, about 3 to 5 fold, in the castrate resistant sub lines of otherwise sensitive tumors.  Then we showed by either over-expressing the androgen receptor at about that level or knocking it down in castrate resistant lines, that it was both necessary and sufficient for this resistance phenotype. Quite dramatically, when you overexpress the receptor at that level and treat cells with bicalutamide, bicalutamide is now a weak agonist rather than antagonist.  So, you can trick the cell into responding differently just by manipulating the level of the androgen receptor.

All of that led me to approach a couple of companies that were interested in prostate cancer, with the idea that we should do a screen for compounds that are selected based on their ability to inhibit androgen receptor signaling in this context of higher expression.  Everybody that I talked to in the pharma industry pretty much thought that the androgen receptor was not really all that relevant a target in castrate resistant disease.  There seemed to be a mindset, that had built up over decades, that castrate resistant disease was really androgen independent disease, and therefore hormone therapy is no longer going to be effective.

That’s why we had to do it academically, and the approach that worked was based on a friendship that I had made with a chemist at UCLA named Mike Jung.  Rather than do high-throughput screens, he said there’s tons of chemistry already done on the androgen receptor, let’s explore that literature and try to find compounds that bind with extremely high affinity that others have described that aren’t antagonists and then do some SAR to figure out how to make them antagonists.  He found this compound that was described in an old patent that has extremely high binding affinity for the androgen receptor, never went anywhere because it is a potent agonist, but it was about two orders of magnitude tighter than bicalutamide.  So he made it, we tested it and of course it didn’t work.  Then we started making derivatives of that compound, tested 200 over a year and half, and stumbled upon MDV3100.

Pharma Strategy Blog: What is the current state of development for MDV3100?

Dr Sawyers: MDV3100 is now in a phase 3 registration trial that is fully accrued and is supposed to read out later this year, maybe early 2012.

Pharma Strategy Blog: What do you think of Circulating Tumor Cells (CTCs) as a surrogate marker in prostate cancer instead of PSA response?

Dr Sawyers: Measuring CTCs using a standard Veridex platform is very nice, the answer that is not so clear is whether a CTC drop is predictive of a long-term clinical benefit?  There are a number of clinical trials in prostate cancer moving along with traditional survival endpoints in which the CTC data is being collected in parallel.  Hopefully, over another a year or two these kind of correlates can be drawn to see if it is a surrogate marker of response that could lead to faster registration.

Pharma Strategy Blog: Could CTCs replace PSA as a measure of response?

Dr Sawyers: I think in the case of MDV3100 we are targeting the androgen receptor, which regulates the expression of PSA, so it is almost a given that if your drug is engaging the target effectively you have to see a PSA drop.  If you don’t you probably haven’t hit the target correctly.  In essence, PSA is a pharmacodynamic endpoint.  If you are able to sustain PSA down for 12 weeks, with a drop of at least 50%, that is considered a pretty significant effect that is likely to be predictive of some other longer-term benefit.  Not many drugs have done that in the past, so I wonder if PSA actually might be more valuable than we give it credit for, if we just set the bar higher for what we call a PSA response.

Pharma Strategy Blog: Can you tell us more about the other prostate cancer compound that came out of your lab that is being developed by Aragon?

Dr Sawyers: “Son of Medivation” is what some people call it.  It came out later than MDV3011 and is more potent, and has what we think is a better safety profile. It is called ARN-509 and is in the clinic now. It is still in the dose-escalation stage of a phase I study at Sloan Kettering that Howard Scher and colleagues are running. There is a lot of excitement around it and we are pushing as fast as we can.  The challenge now is that the prostate cancer space is becoming crowded.

Pharma Strategy Blog: Does ARN-509 have a similar mechanism of action to MDV3100?

Dr Sawyers: Yes, very similar. We don’t yet know if ARN-509 will work in those patients who don’t respond to MDV3100 or have resistance to it. If it does work in that setting in the clinic, then it is a straightforward path to approval.  What I think is more likely is that ARN-509 will work in a similar same patient population as MDV3100 but might produce a higher percentage of responders or maybe longer duration of response. It will take at least a year if not a little more to know with confidence what those numbers are for ARN-509 compared to MDV3100, and by then Medivation will be approved.

Pharma Strategy Blog: How do androgen receptor antagonists such as MDV3100 and ARN-509 compare to abiraterone acetate (Zytiga) that was recently approved by the FDA?

Dr Sawyers: Abiraterone is targeting the androgen receptor pathway differently. Even though all these men remain on a testosterone lowering agent, testosterone is still produced primarily by the adrenal gland.  Abiraterone targets the enzyme Cyp17 that is critical in maintaining that residual level of testosterone. It is the same target of ketoconzole, a drug that has been used in this space, but has a fairly unpleasant side-effect profile. Abiraterone is looking great and showed a survival advantage in the same kind of trial as the Medivation one.  A very obvious question is whether it would make sense to target the androgen receptor pathway at two points i.e. abiraterone plus MDV3100.  Scientifically it makes beautiful sense and I think that combination trials will happen.

Pharma Strategy Blog: Would it make sense to potentially sequence them?

Dr Sawyers: I am always a believer of going up front with your best shot, so scientifically favor using a combination.

Pharma Strategy Blog: What are some of the challenges that remain in prostate cancer?

Dr Sawyers: We have a good understanding of the prostate genome, but it is very challenging to obtain tissue from patients in trials so that we can subset them into molecular subgroups.  The benefit of that is so crystal clear in other tumor types. It is a challenge that we are still struggling how to execute in prostate. One reason for this is that the trials are typically done with end-stage patients with bone disease, so tissue is not easily obtainable.  Even if patients give consent, technically, it is a challenge to isolate the tumor and analyse it.

Pharma Strategy Blog: It is a very exiting time to be in this field.  Hopefully, we will learn more at the AACR special meeting on Prostate Cancer that you are organizing in Orlando next year.  Thank you, Dr Sawyers, for sharing your thoughts and insights.

 

References:

ResearchBlogging.orgScher, H., & Sawyers, C. (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

Watson, P., Chen, Y., Balbas, M., Wongvipat, J., Socci, N., Viale, A., Kim, K., & Sawyers, C. (2010). Inaugural Article: Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor Proceedings of the National Academy of Sciences, 107 (39), 16759-16765 DOI: 10.1073/pnas.1012443107

 

10 Comments

Abiraterone now approved as Zytiga by the FDA in castrate resistant prostate cancer

By on April 28, 2011

Abiraterone (Zytiga)This afternoon the FDA approved Ortho Biotech’s abiraterone acetate (Zytiga) in combination with prednisone for the treatment of castrate resistant prostate cancer in patients who have received prior chemotherapy with docetaxel.

Abiraterone was filed on December 20th, 2010 and received fast track designation, so the FDA approval comes 2 months ahead of the expected PDUFA date of June 20th.

It represents another exciting advance for this disease after what Dr Bernard Tombal described as a “Grand Cru” year for prostate cancer in 2010 following the successive launches of cabazitaxel (Jevtana), sipuleucel-T (Provenge) and denosumab (Xgeva), the first since docetaxel (Taxotere) was approved back in 2006 for chemotherapy naive metastatic disease.

I’ve written much about the clinical data from various oncology meetings over the last nine months such as ESMO last September and EAU in Vienna last month.  You can check out the data in the related posts below.

The big question on everyone’s mind, though, has been price.  Docetaxel is now generically available, Sanofi-Aventis’s cabazitaxel is around $6K per cycle (assumes ~$48K if 6 cycles are completed), Dendreon’s sipuleucel-T is $93K for three infusions.

Ruth Coxeter of CNBC Health Sciences was the first to tweet the confirmed abiraterone price of $5K per month, with a median of eight months of therapy.  This gives a treatment price of  ~$40K, which I think is very fair, although some patients will obviously take it for longer than that.

Ruth Coxeter, CNBC Pharma's Market

For those interested in the press release, you can read more here.

What does this approval mean?

abiraterone acetate (Zytiga)

For men with castrate resistant prostate cancer (CRPC) who have previously received chemotherapy, there is now a new treatment option for them to choose other than more chemotherapy with cabazitaxel in the form of easy to take pills (four per day).

The data from the 302 trial in the pre-chemo setting is expected later this year and is expected to be better than the 3.9 months overall survival benefit seen in the post chemotherapy setting reported at EAU last month.

In the analysis for the FDA approval, the overall survival benefit had increased further according to Ortho Biotech:

“In an updated analysis, results were consistent with those from the interim analysis with a 4.6 month difference between the two arms in median survival (15.8 months vs. 11.2 months [HR = 0.74]).”

At the European Association of Urology meeting earlier this year, Dr Johann De Bono (Royal Marsden) told a packed audience that the data for the circulating tumour cells (CTCs) would finally be available at the ASCO annual meeting in June.  It will be interesting to see whether this is a better surrogate measure of response than PSA. With the American Urology Association meeting coming up in a few weeks in DC, not doubt there will be more to discuss then.

All in all, it is good to see new treatment options emerge for the treatment of castrate resistant prostate cancer.

7 Comments

$JNJ files NDA for abiraterone in castration resistant prostate cancer

By on December 20, 2010

At the recent European Society of Medical Oncology (ESMO) meeting, J&J and Centocor OrthoBiotech announced that they planned to submit the filing for abiraterone by the year end, following the presentation of the phase III data by Johann de Bono from the Royal Marsden.  That moment finally came today with a press release announcing the news within the last half hour or so.

The filing, in castration resistant prostate cancer (CRPC) after treatment with a taxane (such as docetaxel), has apparently taken place in both the EU and US.  For men with the disease in the US, approval of this agent could come within six months or even less, but the EMA will likely take a little longer, as they do not have an official priority review process.

It’s mixed blessings for me – too late to help my Dad or my friends Fathers, but hopefully it will represent good news and a new option for other men in their situation who have advanced disease and are too frail for chemotherapy.

You can read more about the data from ESMO here.

{Hat Tip to my buddy @adamfeuerstein of The Street for alerting me promptly to the news}

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

By on December 1, 2010

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

References:

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

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

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


1 Comment

#ESMO 2010 round-up #2

By on October 12, 2010

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

  Master Yoda

 

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

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

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

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

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

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

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

The results were interesting, to say the least.

The overall survival (OS) was as follows:

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

The PSA response also favoured the treatment arm:

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

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

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

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

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

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

2nd line metastatic setting:

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

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

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

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

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

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

 

1 Comment

Mechanisms of castration resistance in prostate cancer

By on September 6, 2010

Over the last few weeks I've received quite a few questions relating to castration resistance and how it happens.  After all, while we have several therapies now approved once androgen deprivation therapy (ADT) fails, if we could keep men hormone sensitive for longer, then overall outcomes would likely improve.

Writing about prostate cancer is always a tough topic for me after my Dad passed away 10 years ago from the disease. He was sadly diagnosed in stage IV so there wasn't much that could be done really. It took only 18 months or so for a series of hormone therapies to fail and he developed castration resistant prostate cancer (CRPC). He subsequently declined chemotherapy on the grounds that he wanted to go with dignity on his own terms, nor did he want to put my Mother through hell either.  I rather respect that kind of mature and sensible approach in the face of a very difficult situation.

Ever since then though, I've always wondered what could we do inhibit androgen receptor (AR) signalling better and how could we improve on the therapies we have?After all, bicalutamide and similar therapies are not particularly effective agents because eventually, they all stop working and cycling through multiple therapies is very much the norm.

A new paper in Clinical Cancer Research attracted my attention recently (see journal link below).  The authors took a look at various possible methods of castration resistance and defined the main ones from the literature as:

"(i) AR activation by androgens converted from adrenal androgens or synthesized intratumorally via the de novo route

(ii) hypersensitivity of ARs due to overexpression of AR proteins and/or changes in cofactor expression levels

(iii) promiscuous activation of AR signaling by various ligands following AR mutation

(iv) constitutive activation of AR signaling by truncated ARs lacking ligand-binding domains."

A prior article by Harris et al., in Nature Reviews Urology defined 6 potential pathways slightly differently, including:

"(1) Tissue and tumoral steroidogenesis contribute to synthesis of testosterone and DHT, and might lead to persistence of tissue-level androgen despite castration.

(2) Mutations in the AR allow activation by alternate ligands or increased affinity for androgens.

(3) Amplification increases AR abundance.

(4) Ligandindependent activation of AR through ligand-independent modifications or cross-talk with other pathways, including phosphorylation of AR leading to hypersensitization and increased nuclear translocation.

(5) Change in the balance of coactivators and corepressors augment AR activity.

(6) Bypass pathways functioning independently of AR activity through upregulation of antiapoptotic molecules, such as Bcl-2."

These were also described graphically in the following picture, with the source referenced below:

17,20 lyase pathway

Source: Medscape

A lot of people have been asking how the 17,20 lyase inhibitors work. 17,20-lyase is essential for androgen and testosterone synthesis in both the adrenal glands and CRPC tissue, so the inhibitors have been developed to target this mechanism in both organs.

There are a number of 17,20 inhibitor in the oncology R&D pipeline including:

  1. abiraterone (J&J/Centocor) – phase III
  2. TAK-700 (Millennium-Takeda) – phase II
  3. TOK-001 (Tokai) – phase I/II

However, resistance to these therapies have already been observed in clinical trials, so while they may inhibit AR signalling for a period, they may not be the final answer.

The other drug in development that has garnered a lot of attention is MDV2100 (Medivation and Astellas).  This agent works via a completely different mechanism. Rather than acting through the adrenal cortex or CRPC tissues, it may operate in the cell nucleus on the AR regulated genes, essentially acting through the “intracrine” production of androgens from adrenal androgen or intratumorally, blocking the the interaction between androgens and AR.  The first generation agents such as bicalutamide, flutamide and nilutamide are not very effective because they have agonistic activity for CRPC so what is needed is a drug with more complete antagonist AR activity, especially against mutant ARs that develop over time.

What is particularly interesting in the new agents being developed to target advanced prostate cancer is what a poor marker of activity PSA is.  New studies with circulating tumour cells (CTC's) may well ultimately help us learn more about the underlying biology of the disease.

I'm also looking forward to hearing more about TMPRRS2-ERG, a recently discovered fusion by Tomlins et al., (2005) of an androgen-controlled serine protease, TMPRSS2, and the erythroblast transformation-specific (ETS) family gene ERG by chromosomal rearrangement. Together with phosphoinositide-3 kinase (PI3K), this fusion gene is now thought to be involved in the pathogenesis and progression of prostate cancer.

The authors noted:

"By using fluorescence in situ hybridization, we demonstrated that 23 of 29 prostate cancer samples harbor rearrangements in ERG or ETV1."

Once you have a fusion gene identified, you have a potentially druggable target that may play a causal role in cancer.  It will be interesting to see if what happens with this and how long it takes for a new agent to hit clinical trials targeting this aberration in prostate cancer.  

Maybe there is already one out there and I missed it!?

 

References:

ResearchBlogging.org Yamaoka M, Hara T, & Kusaka M (2010). Overcoming persistent dependency on androgen signaling after progression to castration-resistant prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research, 16 (17), 4319-24 PMID: 20647476

Harris, William P, Mostaghel, Elahe A, Nelson, Peter S, & Montgomery, Bruce (2009). Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion nature clinical practice UROLOGY, 6 (2), 76-85 DOI: 10.1038/ncpuro1296

Tomlins, SA, Rhodes, DR, & Perner, S (2005). Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science, 310, 644-648 DOI: 10.1126/science.1117679

1 Comment

Two new cancer drugs approved – cabazitaxel and nilotinib

By on June 18, 2010

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

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

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

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

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

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

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

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

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

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

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

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

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


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


#AUA2010: new perspectives and learnings in prostate cancer

By on June 2, 2010

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

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

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

What alternatives are there to PSA?

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

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

Androgen ablation therapies are not particular effective

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

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

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

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

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

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

What's next?

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

1 Comment

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

By on May 30, 2010

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

Why is this?

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

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

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

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

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

How are things changing?

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

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

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

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

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

What other compounds are there?

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

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

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

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

3 Comments

The lull before the Dendreon storm?

By on April 29, 2010

Today's post is going to be relatively short as I'm knee deep (literally) reviewing poster handouts from the recent AACR meeting, but while reading translational medicine data I came across a poster on sipuleucel-T basically explaining that it engages the immune system and activates or stimulates priming of T-cells in asymptomatic disease.  

Like many out there I'm quietly wondering what will happen tomorrow with Dendreon's PDUFA date due on Saturday May 1st.  We can reasonably assume a response on sipuleucel-T (Provenge) might be forthcoming on either Friday or Monday.

Given the gap in available treatments between castration resistance (CRPC) and stage IV metastatic disease, I'm hoping Provenge receives approval on the basis of the four month survival advantage after a somewhat rocky path along the journey.  Approval could well kick off what may well turn out to be a new era, with other therapies also in late stage development, namely OrthoBiotech/Cougar's abiraterone and Medivation/Astellas' MDV3100, which are both seeking to test their efficacy and safety and in phase III trials for CRPC.

Non-approval could well be a disaster for a company who has invested so much into immunotherapy as their lead product, investors will likely be very unhappy and Monday could turn into a blood bath.  I'm more inclined to be positive though, and my educated guess is that approval will be forthcoming given Dendreon met the pre-defined FDA targets.

We shall see.

{UPDATE: The FDA officially approved Dendreon's Provenge today 29-4-10, see comments below for FDA links and materials including the PI.}

4 Comments
error: Content is protected !!