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New developments in castration resistant prostate cancer – MDV3100

By MaverickNY on April 15, 2010

Last night I received an alert from Medivation announcing that an article would be published in today's online The Lancet regarding their prostate cancer agent, MDV3100. Sure enough, here's the article:

Although the trial is an early phase I/II study, encouraging antitumour effects were reported in 140 men, of whom 65 were chemotherapy naïve. Time to disease progression (TTP) was 47 weeks, which is decent considering the men in the study were all castration resistant and likely had advanced disease.

Obviously, it is too early to tell yet quite what Medivation and Astellas have here, but to put things in context, docetaxel (Taxotere), was approved for hormone refractory prostate cancer (HRPC) with prednisone in androgen independent (hormone refractory) metastatic prostate cancer with a median overall survival of 18.9 months (approx. 85 weeks) in a large phase III trial.

We must also remember that in another more recent trial, it was demonstrated that men who received cabazitaxel (sanofi-aventis' follow on taxane to docetaxel) lived a median of 15.1 months (68 weeks), compared with 12.7 months (57 weeks) for those who receive mitoxantrone, a difference that was statistically significant.

That said, the side effect profile of chemotherapy is certainly not benign, with significant risk of myelosuppression and infectious complications.

However, what was encouraging about the Medivation trial was early Kaplan Meier response curves, which demonstrated those men who had no previous chemotherapy generally did better than those who received it in terms of both PSA and radiological progression.

At the AACR Molecular Targets meeting last November, Charles Sawyers gave a keynote talk on prostate cancer and looked at the various opportunities for investigating new therapeutics in clinical trials for prostate cancer. He suggested that circulating tumour cells (CTCs) might be a more useful marker for disease status than PSA. In The Lancet study, the authors noted that:

"We recorded early post-treatment conversions from unfavourable to favourable in 75% of patients not exposed to chemotherapy and in 37% of those who were exposed. Decreases in PSA were generally associated with parallel falls (or no progression) in CTCs, but this finding was not consistent, suggesting that these measures assess different aspects of the malignant process. PSA decreases might in some cases be an indicator of the mechanism of action of MDV3100 as an androgen-receptor antagonist rather than an actual antitumour effect. However, the benefit of MDV3100 on several assessments, including CTCs and radiological time to progression, suggest that MDV3100 does have a true antitumour effect."

The other interesting observation that Sawyers made was that traditionally, early prostate disease is treated with oral hormonal therapies and once castration resistance sets in, the patient is referred to an oncologist for consideration of chemotherapeutic options. With the advent of new therapies with different MOAs in development such as MDV3100, abiraterone (Cougar/J&J) and Provenge (Dendreon), the lives of men with prostate cancer can potentially be extended further before stage IV metastases sets in.

At AACR last November, Sawyers also discussed the importance of androgen receptor signalling in the disease (previously discussed here with simple models) and the data from this trial seem to bear out his elegant theory. I'd like to see more analysis though and learn whether those men who had AR amplified prostate cancer did better on MDV3100 than those who did not?

All in all, this is an exciting time for men with prostate cancer. Dendreon's Provenge may well be the first new drug that fits between the hormonal therapies and chemotherapy, since the FDA PDUFA date is May 1st, although since that is a Saturday, we may well here the Go/No Go news on Friday 30th April.

In the meantime, the annual AACR meeting in DC this weekend can't come soon enough!

Scher, H., Beer, T., Higano, C., Anand, A., Taplin, M., Efstathiou, E., Rathkopf, D., Shelkey, J., Yu, E., & Alumkal, J. (2010). Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study The Lancet DOI: 10.1016/S0140-6736(10)60172-9

J&J's abiraterone shows promise for advanced prostate cancer patients

By MaverickNY on February 18, 2010

New results from a phase II clinical trial of the prostate cancer drug abiraterone suggest that it may help men with advanced disease who have tried standard treatments.

However, a Cancer Research UK clinician cautioned that there were still questions to be answered from ongoing studies about how best to use the drug.

Abiraterone was discovered in the Cancer Research UK Centre for Cancer Therapeutics at The Institute of Cancer Research (ICR) and is taken once a day as four pills.

The latest trial, which was led by the ICR and the Royal Marsden NHS Foundation Trust, is the first to investigate the drug in men with such advanced prostate cancer.

A total of 47 men were recruited for the trial, all of whom had late-stage castration-resistant prostate cancer, which means that their disease was advanced and their tumours were no longer responsive to androgen deprivation therapy. In almost all cases, the men's cancer had spread to their bones.

All of the participants had already received hormone therapy and the chemotherapy drug docetaxel, but were no longer responding to those treatments.

By the end of the study period, researchers found that around three-quarters of men had experienced a drop in levels of prostate specific antigen (PSA), which is often raised in men with prostate cancer and can be used to measure disease activity.

In around half of the men, PSA levels fell by at least 50 per cent, while three-quarters of participants also had a drop in the number of tumour cells circulating in their blood.

Three years after the start of the trial, five of the patients were still taking abiraterone and benefitting from the treatment.

via info.cancerresearchuk.org

New phase II data on abiraterone was reported this week in the Journal of Clinical Oncology from the researchers at the Royal Marsden.

Standard chemotherapy with docetaxel (Taxotere) improves survival by 2 to 3 months, so if the 6 months seen with abiraterone is repeated in a phase III trial, Johnson and Johnson (J&J) and Cougar could well have an approvable drug on their hands. The other benefit is that the side effect profile is much milder than chemotherapy, which can cause severe myelosuppression in the majority of patients receiving it.

It should be noted that these are advanced patients who have received already several hormonal therapies. The data from this trial will likely provide impetus for larger scale phase III trials, which could be used to seek regulatory approval from the US and EU authorities.

It is, however, obvious that the investigators are unsure yet what role and where abiraterone will eventually be used in the treatment paradigm, but traditional research approaches require that trials investigate advanced disease and then more up the continuum as more data and experience with the treatment is gained.

Of course, there is no guarantee that phase III trials will mirror promising phase II results, especially in the cancer arena, but now, it's nice to report on positive data after a bad run of disappointing trials in oncology of late.

Source: JCO (Abstract)

Posted via web from sally church's posterous

Reid, A., Attard, G., Danila, D., Oommen, N., Olmos, D., Fong, P., Molife, L., Hunt, J., Messiou, C., Parker, C., Dearnaley, D., Swennenhuis, J., Terstappen, L., Lee, G., Kheoh, T., Molina, A., Ryan, C., Small, E., Scher, H., & de Bono, J. (2010). Significant and Sustained Antitumor Activity in Post-Docetaxel, Castration-Resistant Prostate Cancer With the CYP17 Inhibitor Abiraterone Acetate Journal of Clinical Oncology DOI: 10.1200/JCO.2009.24.6819

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Update on Prostate Cancer therapies

By MaverickNY on February 2, 2010

It's been a while since I took a look at what's happening in the prostate cancer arena, but it seems a good time after the recent flurry on lung and colorectal cancers, especially as it's Groundhog Day :-).

There are three particular agents that I'm interested in:

MDV3100 (Medivation/Astellas)
Abiraterone (Cougar Biotech/J&J)
Provenge (Dendreon)

I'm going to spend most of this post talking about the first two, as much has been said on Dendreon already.

Dendreon filed their amended BLA on November, and the FDA have given a PDUFA date of 1 May 2010. The data from 512 patients showed an improvement of 4 months survival for Provenge over placebo, meeting the FDA's threshold.

We have, however, no idea how the vaccine would have done compared to standard chemotherapy such as docetaxel plus prednisone, and therein lies the rub. Normally, in oncology trials we compare the standard of care with and without the new agent or compare the standard therapy to a different regimen. Placebo controlled trials have not done well with ODAC and the FDA, as J&J, Vion and Genzyme all learned with placebo controlled trials in elderly AML patients.

Regular readers of Pharma Strategy Blog will know I'm not a big fan of either placebo trials in cancer or vaccines, so we'll wait and see what the FDA decide. My expectation is that it will receive approval this time round having jumped through the extra hoops.

Cougar Biotech and J&J are developing abiraterone in advanced prostate cancer. A phase III trial in asymptomatic or mildly symptomatic patients with metastatic castration-resistant prostate cancer began enrolling this month.

It's estimated to complete in April 2014 and the primary endpoint is overall survival, but initial results should be available in April 2011 for progression free survival at 12 months from what I can see, so perhaps there will be some data around ASCO in 2011. Based on that data I can't see a filing much before the 2nd half of 2011 at the very earliest, possibly not until 2014.

Looking at J&J's analyst presentations, I found the following timeline for their pipeline:

Now, many drugs are lumped together in the 2011 timeframe across 3 columns. It isn't clear whether each column represents 2011, 2012 and 2013 or it's a random list of drugs that will be filed in that period. Either way, it's hard to see abiraterone getting accelerated approval so my assumption for now is abiraterone will be filed in 2013, with approval in 2014.

It's not going to be a fast development: Cougar is very inexperienced and J&J are relatively weak and slow in oncology.

The asymptomatic nature of the patients will also complicate things because it's a high risk study that may not show much in the end. If it works, great! That said, I'm not sure how well the results will fare in what looks like a fluffy trial design comparing abiraterone plus prednisone to placebo plus prednisone. Patients are specifically excluded if they have received prior chemotherapy. Well then, why not compare abiraterone to docetaxel, which is the current standard of care in castration-resistant disease, given that this is a front-line trial?

Recently, at the AACR Molecular Targets meeting in Boston, I had the pleasure of listening to a most excellent talk from Dr Charles Sawyers (MSKCC), one of may favourite researchers. He covered a lot of ground on the lessons learned in targeted agents, principally in CML and prostate cancer.

With regards to prostate cancer, he showed a graphic similar to this one (from Medivation):

Clearly, there are a number of opportunities to explore for the development of new drugs for the disease after hormome therapy ceases to work. This is where traditional drug development for chemotherapies typically starts.

What was interesting about Sawyers talk is his discussion about the androgen receptor (AR) and whether or not it is important in castration resistant disease.

Previously, AR was thought to be irrelevant in this situation because it is not expressed in 2 common prostate cancer cell lines, but Sawyers argued cogently that this shows a failure to appreciate the potency of inhibition because AR is restored through PSA production. Several reasons have been evaluated for this, including AR amplification, mutation and alternative pathways among others. AR is also overexpressed in castration resistant xenograph models, and can confer castration resistance.

What followed was an elegant discourse showing that MDV3100 is distinct from bicalutamide, whereby it has a greater affinity, binds AR selectively, without displaying agonism in AR overexpressing cells and has more potent antagonistic activity.

In the end, Sawyers argued that what was important was not AR overexpression per se, but AR amplification because prostate cancer cells with natural AR amplification are more sensitive to AR knockdown than AR single copy prostate cancer. Minor AR knockdown is sufficient to inhibit growth of AR amplified disease. All of this leads us logically to an important question:

Are AR amplified prostate cancers a different (and important) patient subtype?

Clinical trials with MDV3100 have demonstrated that at least half of prostate cancer patients remain AR dependent, suggesting that this is indeed the case. Clearly, if you can keep patients hormone sensitive or at least responding to therapies using different approaches, then the opportunity to delay time to metastasis and late stage disease may well exist with these novel approaches.

Time will tell.

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Abiraterone in prostate cancer

By MaverickNY on September 25, 2008

Dr Johann de Bono, whose group presented the phase I data that generated so much recent interest, has been captured on video at the Prostate Cancer Foundation Scientific Retreat.

In the talk, covers the background behind the drug's development in prostate cancer, as well as explaining the data so far in patients who have failed standard docetaxel chemotherapy.

You can view the videos here and here.

There is more information on a previous post about how abiraterone works in prostate cancer. The drug is now in phase III development and new trials in breast cancer are expected to start soon.

Will abiraterone impact survival in advanced prostate cancer?

By MaverickNY on July 22, 2008

Prostate cancer, the most common carcinoma in men, is characterised by malignant cells that are both androgen-dependent and androgen-independent. In the cells that are androgen-dependent, a critical level of androgen is required to activate a sufficient number of androgen receptors (ARs), so that death-signaling genes are repressed. Ninety percent of androgens are produced by the testes, with 10 percent produced by the adrenal glands or the cancer cells themselves.

Image: Two prostate cancer cells dividing from Cancer Research UK

Prostate cancer treatment is loosely divided into three phases based on the stage of disease; early stage disease, followed by a hormone therapy phase and finally an advanced cancer phase also know as stage IV, which usually leads to metastasis i.e. spread of the cancer cells to others areas of the body.

Early phase disease (stage I and II) can be picked up from an annual physical exam and involves surgical removal of the prostate gland, radiation therapy with or without hormone therapy, and "active surveillance", also known as watchful waiting.

The hormone therapy phase (stage III) is treated with primary androgen deprivation therapy, which may include castration and therapeutic disruption of the normal androgen production regulatory pathways.

Advanced metastatic prostate cancer (stage IV) is where the cancer cells can become androgen ablation insensitive (also called hormone refractory prostate cancer or HRPC). As the patient becomes insensitive to the hormone therapy, the levels of prostate specific antigen (PSA) increase. Chemotherapy is considered the standard of care for advanced stage disease. There are only three drugs approved by the FDA to treat HRPC; docetaxel, mitoxantrone, and estramustine, all of which have noticeable side effects, but show an increase in survival over best supportive care by approx. 18 months.

Recent therapies in the clinic have had a difficult time with FDA approval. Abbott's atrasentan (Xinlay) was found by the FDA advisory panel to be lacking in clear evidence that it prolonged survival despite significant drops in the PSA levels. Ditto for GPC/Spectrum's satraplatin, although it was approved by the European authorities.

More recently, Dendreon's Provenge (sipruleucel) was reviewed by the panel and more data was required because the trial just missed significance (0.052). This vaccine used a technique called Antigen Presenting Cells (APCs) to alert the patient’s T cells to attack the cancer and will likely be available for patients at some point in the next 12 months.

There are several drugs in development for prostate cancer, including AstraZeneca's endothelin receptor antagonist, Zibotentin, Genentech/Roche's Avastin and Merck/Ariad's mTor inhibitor, deforolimus.

In February this year another biotechnology company, Cougar, announced some promising data. Results of a phase II trial abiraterone in chemotherapy naiive patients demonstrated a 50 percent drop in PSA in 61 percent of patients. A phase II trial in patients having failed first-line chemotherapy with docetaxel showed 48 percent of patients having 50 percent decrease in PSA and 53 percent experiencing on-going stable disease. Additional phase I and II studies show similar promise with patients who have failed other treatment regimens including chemotherapy, leutenizing hormone analogs and other hormonal therapies. It remains to be seen, however, whether the falls in PSA will lead to a demonstrable improvement in survival (witness the atrasentan and satraplatin experiences).

So how does abiraterone work? In simple terms, it works by blocking the androgen sex hormones that fuel the cancer. Ten percent of the normal levels are produced in the adrenal glands, but theories point to cancer cells producing their own testosterone, thereby fueling the tumour's growth.

Abiraterone interferes with the cell's mechanisms for adrenal steroid synthesis through two very specific pathways, P450 enzymes 17-alpha hydroxylase and C17,20-lyase. This approach is thought to result in far fewer side effects and also inhibits androgen synthesis with tumour cells, although the data is still immature.

The latest study, reported in the Journal of Clinical Oncology, is a small one based on 21 patients with advanced, aggressive prostate cancer treated with the drug, but data has been collected on a total of 250 worldwide. It found significant tumour shrinkage, and a drop in tell-tale levels of a key protein produced by the cancer in the majority of patients.

To date, no patient has taken the drug for longer than two-and-a-half years, and so it has not been possible to determine exactly what the effect of the drug on life expectancy will be. These findings need to be reproduced in larger scale clinical trials, but the results so far look promising for advanced stage prostate cancer.

News Sources:

BBC News

Reuters

This article is part of the Cancer Research Blog Carnival being hosted by the
Sciencebase Science Blog.

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