mCRPC | Biotech Strategy Blog

On finding new targets and boosting existing therapies

Science drives oncology new product development and the AACR special conferences are always a good place to look for insights into where the field is both emerging and also going in the future.

At the recent AACR Tumor Immunology and Immunotherapy conference, several presentations stood out for us as being noteworthy for either building on an existing story or the new perspectives they offered, some of which involved new targets we’d not heard before.

In this post, we take a take at some of the data presented, how it builds upon what we already know, and possible directions it may take us in. After all, the best way to predict the future is to invent it.

It’s time to shine some light on novel targets, biomarkers, and emerging combination approaches…

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ESMO19 Preview 2 – Targeting Synthetic Lethality and Immune Response in GU malignancies

We’ve been writing about PARP inhibitors since 2006! Who knew this target would have multiple legs over a dozen years on?

Barcelona

In this post we’re taking a look at some of the noteworthy presentations at ESMO19 around targeting DNA damage repair (DDR) and how they act through synthetic lethality and/or the generation of immune response to kill cancer cells in GU cancers.

It’s a fascinating area where we are seeing convergence between immunotherapy and genomic instability, one of the hallmarks of cancer.

The abstracts for ESMO19 are not yet available, so in this post we’re only providing context and setting the scene for some of the presentations we are looking forward to, as well as raising some key questions that we hope will be answered in Barcelona.

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Zytiga European Prostate Cancer approval may kill Jevtana sales

With the collapse of the Dendreon share price today following poor sales data (Adam Feuerstein on The Street has an excellent write up about this), attention has again focused on the prostate cancer market.

Zytiga (abiraterone acetate) was recently approved by the European Medicines Agency (EMA), following FDA approval earlier this year.

The EMA Committee for Medicinal Products for Human Use granted the marketing authorization for Zytiga at it’s July 2011 meeting. The approval noted,

“The poor prognosis of the target patient population represents a high unmet medical need while the novel mechanism of action of abiraterone has the potential to offer an alternative therapeutic option for these patients.”

What does this mean for sales of sanofi-aventis’ cabazitaxel (Jevtana), which was approved in Europe earlier this year?

Given that both drugs have approval in the same indication for metastatic castrate resistant prostate cancer (mCRPC) post-docetaxel chemotherapy, and the price is likely to be comparable, my guess would be that Jevtana sales will take a big hit.

After a sick prostate cancer patient has undertaken several cycles of chemotherapy with docetaxel, why would they not want to take an oral pill as opposed to another chemotherapy drug, which does have a less than stellar adverse-event profile. The answer is they will probably take a chemo-holiday and use Zytiga.

Jevtana simply came to the market too late in Europe, and Zytiga gained accelerated approval. It’s a reminder that we live in a dynamic pharmaceutical market place, as the news last night from Dendreon has also reminded us.

ASCO 2011 Cabozantinib (XL184) may be an exciting new prostate cancer drug

It’s hard to believe that the countdown to the 2011 annual meeting of the American Society of Clinical Oncology (ASCO) is now underway, but yesterday at 6pm, the ASCO abstracts were released.

Oliver Sartor at the recent annual meeting of the American Urological Association (AUA) highlighted the prostate cancer potential of cabozantinib (XL184), an oral inhibitor of MET and VEGF kinases, so it was interesting to see that new data will be presented at ASCO.

What makes cabozantinib interesting?

The preliminary data shows that it not only has an anti-tumor effect, but also has an effect on bone metabolism.

The data presented at EORTC last year and at ASCO GU this year confirms what was seen in animal models, in that it had both an anti-metastatic effect on soft tissue and blockade of bone lesions. Such dual action on both bone mets and the tumor microenvironment makes it an exciting new compound in prostate cancer.

By all accounts, the novel effect of cabozantinib on bone mets is unexpected.

At the forthcoming ASCO meeting, abstract 3010, whose lead author is Dr Michael Gordon of Pinnacle Oncology Hematology in Scottsdale, AZ will present data on:

“Activity of cabozantinib (XL184) in soft tissue and bone: Results of a phase II randomized discontinuation trial (RDT) in patients (pts) with advanced solid tumors.”

According to Dr Gordon in the ASCO press teleconference yesterday, the phase II data at ASCO for cabozantinib in prostate cancer will show:

Complete or partial bone scan resolution in majority of patients (86%), often accompanied by pain relief

Unprecedented bone scan improvement

On the basis of these promising results, according to Dr Gordon, “Exelixis plans to initiate the first pivotal trial in prostate cancer by the end of 2011.”

It will be interesting to see whether cabozantinib can impact overall survival (OS) in advanced prostate cancer, something that denosumab (Xgeva®) failed to show in the 147 trial that was just presented at AUA.

There are several abstracts on cabozantinib at the ASCO 2011 annual meeting. Another one that caught my attention was abstract 4516, whose lead author is Maha Hussein of the University of Michigan.

Dr Hussein will present data on cabozantinib in metastatic castrate resistant prostate cancer (mCRPC). The abstract’s conclusion is that:

Cabo showed clinical activity regardless of prior D in mCPRC pts, particularly in pts with bone disease, as reflected by high rates of b-scan resolution and pain relief, in addition to improvements in Hb and tumor regression.

I’ll be at ASCO in a few weeks time, so look forward to hearing more detail on the cabozantinib results. The data is still very preliminary, but cabozantinib (XL184) is certainly a drug to watch, and may be an exciting new prostate cancer drug in the future.

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AUA 2011 New Prostate Cancer products in development beyond the androgen axis

There is a lot of focus at the annual meeting of the American Urological Association (AUA) here in Washington DC on metastatic castrate resistant Prostate Cancer (mCRPC), and the recently FDA approved adrenal steroid inhibitor, abiraterone acetate (Zytiga®).

Drugs in development that target the androgen receptor, such as MDV3100, are also generating a lot of interest from urologists.

However, Oliver Sartor (Tulane) in the Saturday morning satellite symposia that I attended, focused on emerging therapies in CRPC, beyond the androgen axis. His hypothesis:

“Cancers are devious and some of the mechanisms of AR activation appear to be ligand-independent and resistant to all current androgen-axis targeted therapies.”

What this means is that focusing on adrenal steroid inhibition or blocking the androgen receptor may not be sufficient to prevent disease progression. If we are looking for a Prostate Cancer cure, then will it take multiple drugs, including those that target various stromal sites? That is the intriguing question that Sartor raised.

Indeed, if there is one take home from this meeting, it is that the “desert” of prostate cancer therapies has now blossomed into a multiplicity of potential new therapies and development, which will mean that urologists and oncologists will soon be spoilt for choice as abiraterone and MDV3100 are not the end of the story.

Sartor highlighted some interesting ones on the horizon to watch out for:

Alpharadin: This is a bone targeted therapy that uses radioactive Radium 223 to kill cancer cells. It is being developed by Norwegian company, Algeta in partnership with Bayer Schering Pharma AG. The 900 patient phase III trial completed accrual earlier this year in Jan 2011. Phase II data was published in the Lancet in 2007 by Nilsson et al. Data from alpharadin will be “coming soon” according to Sartor.

XL-184 (cabozantinib): Activated MET is highly expressed in prostate bone metastases. Exelixis XL-184 is a small molecule tyrosine kinase inhibitor that specifically inhibits both MET and VEGFR2.

Data from a phase 2 study of XL-184 in castrate resistance patients was presented last year at the EORTC-AACR-NCI Symposium on Molecular Targets and Cancer Therapeutics in Berlin by David Smith et al (Abstract 406).

Both XL-184 and alpharadin would be potential competitors to Amgen’s denosumab (Xgeva®).

Other new products in development “Beyond the Androgen Axis” that Dr. Sartor mentioned included Prostvac-VF, BPX-101 and ipilimumab. A phase III trial of ipilimumab, both pre- and post- docetaxel is now underway in mCRPC. A phase III trial of Prostvac-VF will start later this year with 1200 patients in a placebo controlled study with minimally symptomatic, castration-resistant metastatic prostate cancer patients.

Over the next few years a lot of data may emerge on exciting new treatment options. Coupled with the basic research that is going on, tremendous progress in the treatment of Prostate Cancer is already taking place.

According to Sartor “multiple drugs will be necessary to cure mCRPC and that is our greatest challenge today.” Major progress is now being made towards this.

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