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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:

Scher, 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

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Two new cancer drugs approved – cabazitaxel and nilotinib

By MaverickNY 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 MaverickNY 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:

PSA is not a brilliant biomarker, but it's all we have for now.
Androgen ablation is not permanent.
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!

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

By MaverickNY 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:

Watchful waiting
Androgen deprivation therapy (ADT)
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.

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The lull before the Dendreon storm?

By MaverickNY 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.}

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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

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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