Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘CRPC’

J&J unblind Zytiga phase 3 trial in pre-chemotherapy castrate-resistant prostate cancer

By on March 8, 2012

The big cancer news that hit the news wires this morning was not entirely surprising:

“Janssen Research & Development, LLC today announced that it has unblinded the Phase 3 study of ZYTIGA (abiraterone acetate) plus prednisone for the treatment of asymptomatic or mildly symptomatic patients with metastatic castration-resistant prostate cancer (CRPC) who have not received chemotherapy.”

Source: Press Release

Given the accelerated approval of abiraterone in the post-chemotherapy setting last year, the results in the pre-chemotherapy setting were widely expected to:

  1. Be even better in earlier stage than the 3.9 months OS advantage already seen
  2. Likely to have an early study halt

Zytiga already has Compendia listing through mention in the NCCN Guidelines with level 2a evidence in the pre-chemotherapy setting, essentially listed with ketoconazole.  Several industry friends with access to market data have mentioned that the pre-chemotherapy share for abiraterone is already around 20-25%, not bad at all given it doesn’t have full approval prior to docetaxel use and has been on the US market less than a year.

No clinical details were provided by the Data Science Monitoring Committee (DSMC), but the data are expected to be presented at a clinical meeting later this year (Adam Feuerstein of The Street speculated that ASCO was a likely target).  I do hope so, but that would suppose an abstract was sent in with no data by the late breaking deadline of Feb 1st.

The company did state that:

“The company plans to submit for regulatory approval in the United States and around the world beginning in the second half of 2012.”

At this rate, J&J should receive the new indication in the first half of 2013, based on the 302 trial data, depending on whether the filing is accepted as an accelerated, priority or regular review.  No doubt this information will be apparent after filing has taken place.

One challenge with early stoppage of trials based on progression-free survival (PFS) is that determining whether patients truly live longer, as judge by overall survival (OS), becomes much more difficult, if not impossible.  Once patients on placebo are offered the active drug, there is a crossover effect confounding any subsequent data analysis.

The news today will impact several other companies in the advanced prostate cancer landscape

Medivation and Astellas are expected to file MDV3100 in the post chemotherapy setting soon based on the phase 3 AFFIRM study.  This agent has several attractive advantages over abiraterone in that:

  • no concomitant prednisone or steroid administration is required (hence less puffiness and related side effects) and
  • it targets splice variants as well as the AR, which may lead to less drug resistance.

Based on the post-chemotherapy data we’ve seen so far (MDV3100 saw a slightly longer improvement in OS, which may be related to the above), we can expect that the phase III PREVAIL trial prior to docetaxel to also show a similar trend to the Zytiga study.  It won’t surprise me at all if the interim analysis also leads to the DSMC recommending early unblinding.  Based on the Zytiga data, it wouldn’t surprise me if the interim analysis for MDV3100 came up as early as mid next year, which would be earlier than expected.

Two drugs that will be impacted by these developments with hormonal agents are Dendreon’s Provenge, which is approved prior to docetaxel and Sanofi’s Jevtana (cabazitaxel), which is approved after docetaxel.

The immunotherapy sipuleucel-T (Provenge) is an unlikely partner for combination with abiraterone given that steroids suppress the immune system, while many older men with metastatic would much rather take a pill than undergo the debilitating side effects of myelosuppressive cytotoxics such as the taxanes.  Certainly my Dad was in that category, as are many men in their 70’s.  Once approved, Alpharadin (radium-223) may well offer a useful option for that subset of patients, especially of they have already tried ADT and seen biochemical relapse with rapidly rising PSA levels.  Provenge is likely to be negatively impacted by Zytiga approval pre-chemotherapy.

Approval of Zytiga in the pre-chemotherapy setting will likely increase its share there, since many oncologists are somewhat sceptical about Provenge in terms of how it works, how effective it is, how to monitor patient progress on it (it doesn’t seem to affect pain, PSA or any of the usual markers of disease) and the hefty price tag ($93K for 3 infusions) doesn’t help either.  MDV3100 would likely have an even stronger impact, since urologists dislike using steroids and managing the complications, plus Astellas have a solid franchise in urology already.

At this rate, Jevtana will be pushed further out down the treatment paradigm and reserved for salvage therapy in the younger, fitter patients.  Its biggest challenge is competing with it’s fellow taxane, docetaxel, since many oncologists will re-challenge with the generic if the patient previously did well on it.  Any delay (through improved survival with newer, earlier treatments) will delay time to cabazitaxel uptake.  This will likely get worse once MDV3100 is approved, and oncologists can sequence them.

At what point will we see placebo trials go away?

I’m not a big fan of placebo-controlled trials, except where there are no standard of care or alternative clinical options for patients.  Until recently, the advanced prostate cancer market was relatively immature with few approved therapies, so placebo trials were de rigeur.  Going forward though, new entrants to the market will face the ethical dilemma of how can placebo-controlled trials be justified in a market where drugs such as abiraterone (or MDV3100 and Alpharadin, if approved) have a proven survival advantage?  It will push the bar for new market entries higher (and more costly).  Millennium’s TAK-700 (orteronel), which is similar to abiraterone but may or may not need steroids, may well have just made it into clinical trials in time before that window shuts off.

And finally…

The good thing is that after a decade of not much happening in the advanced prostate cancer market, we are seeing a lot if new therapies, often with different mechanisms of action, being developed for this disease.  There are others I haven’t mentioned here, including custirsen (Oncogenex) and cabozantinib (Exelixis) which are also undergoing clinical trials and we await those results too.

As more drugs for castrate-resistant prostate cancer (CRPC) are approved, sequencing and combinations will also come to the fore to determine optimal strategies for improving outcomes for men with prostate cancer.  It’s an exciting market to be following given the rapid progress over the last year or so, but hopefully, this is just the beginning and there will be much more yet to come.

14 Comments

Is ARN-509 (Aragon) potentially better than MDV-3100 (Medivation) in advanced prostate cancer?

By on February 2, 2012

Many readers will have noticed that the advanced prostate cancer market is rapidly becoming crowded with three new therapies (cabazitaxel, sipuleucel-T and abiraterone) already approved and several more in late stage development, including Alpharadin (radium-223) and MDV3100, both likely to file this year. In addition, others are focused on bone complications, such as denosumab, which is expected to have a tough ODAC meeting this month, and cabozantinib, a multikinase inhibitor currently in phase III trials.

Unlike breast cancer, where progression-free survival (PFS) is a used as a surrogate measure of survival, in advanced prostate cancer, overall survival (OS) has pretty much become the gold standard by which prostate cancer trials are reviewed. This makes it much easier to judge whether the drugs are having a positive effect on true efficacy, i.e. do patients live longer as a result of treatment.  PFS is particularly difficult to measure in prostate cancer, so it’s not surprising this approach has evolved as the standard measurement.

Interestingly though, Health Authority approval does not always mean reimbursement coverage, as NICE showed yesterday in declining to approve abiraterone in the UK on the grounds that it is too expensive. The BBC quoted a patient who had been on abiraterone for only three months, with a positive impact:

“I have my life back. I have a lot more energy and no pain. My quality of life is excellent. I wouldn’t even know I have cancer now, it’s that good.”

The BBC also quoted his wife, who had an excellent point:

“We know NICE has to take a lot of things into consideration, but when you have a terminal illness an extra four months is very precious.”

Source: BBC

Of course, it’s very much a case of balancing available resources with potential benefits and unfortunately, advanced stage patients will inevitably take the lion’s share in terms of budget for disease management. Post EMA approval, some local UK health providers permitted the drug to be used on an individual basis, raising the old contentious issue of the rather unfair post code lottery (zip code for Americans).

Going forward, no doubt there will be much political posturing and pressure, as you can see from Cancer Research UK, who helped fund the research, but hopefully a deal can still be struck between NICE and Janssen, the manufacturer, on price to enable British men broader access to the drug.

One of the things that has struck me lately, though, is how prostate cancer is attracting serious research focus, such that a heterogeneous disease is slowly being more segmented based on the underlying biology of the tumour. Examples include Arul Chinnaiyan’s superb work on the TMPRSS2-ERG fusion gene and Charles Sawyers’ work on the Androgen Receptor.

Thanks to Sawyers work we now know that the old terminolgy ‘androgen independent’ prostate cancer is an incorrect way of descibing advanced disease because as Clegg et al., (2012) described Scher et al’s original research findings in 2005:

“Despite administration of androgen-depleting therapies, continued androgen receptor (AR) signaling is a common feature of CRPC, attributed to AR gene-amplification, AR gene mutation, increased AR expression or increased androgen biosynthesis in prostate tumors.”

In other words, the AR is very much an oncogenic driver of the tumour’s survival.

This week, we saw promising data for MDV3100, an AR antagonist in the post chemotherapy setting but what of the pipeline beyond abiraterone and MDV3100?

Previously, we came across Aragon’s ARN-509 AR antagonist, which is much further behind in phase I/II clinical trials. Sawyers and Michael Jung, the co-inventors of MDV3100 while at UCLA also developed (along with several other scientists) additional AR compounds, the most promising of which became ARN-509. Aragon is a privately held company formed out of the UCLA discovery with the intent of developing and commercialising this compound.

The obvious question arises – is it a ‘me-too’ or potentially better than MDV3100?

Preclinical data has just been published in Cancer Research by Clegg et al., (2012) addressing this issue. They argued that, based on their findings:

“In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100.”

Of course, preclinical data doesn’t always translate to the clinical setting, but my first reaction was ‘Whoa!’

Let’s take a look at the agent in more detail.  ARN-509, like MDV3100, is a pure antagonist of the androgen receptor, unlike bicalutamide (Casodex), which has both agonist and antagonist properties.  The idea behind this is that there will be less resistance and greater therapeutic potential for more comprehensive binding with the receptor.

We know from work in Sawyers lab that MDV3100 targets splice variants, which have been shown to cause resistance in CRPC, but we don’t yet know how ARN-509 will fare on that front.

So why did Clegg et al., (2012) suggest that ARN-509 might be superior to MDV3100?

“Maximal therapeutic response in this model was achieved at 30 mg/kg/day of ARN-509, whereas the same response required 100 mg/kg/day of MDV3100 and higher steady-state plasma concentrations.

Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists.”

In other words, it’s much more potent and has a greater therapeutic index; these things are important clinically. It also has a longer half-life:

“ARN-509 exhibits low systemic clearance, high oral bioavailability and long plasma half-life in both mouse and dog, supporting once-daily oral dosing.”

Androgen deprivation therapies are more commonly used in castrate-sensitive disease, so this begs the question of whether there is anti-androgenic activity in the non-castrate setting:

“At higher doses of 30 mg/kg/day, robust tumor-regression (>50% reduction in starting tumor volume) was observed in 6/8 ARN-509-treated animals, similar to regressions observed in mice castrated on the day treatment initiated.”

The promising results led the researchers to conclude that:

“ARN-509 is a next generation anti-androgen selected for pre-clinical and clinical development based on its efficacy and pharmacodynamic profile in mouse xenograft models of CRPC.”

They also stated that:

“Unexpectedly, given a similar in vitro profile, ARN-509 is more efficacious per unit dose- and per unit steady-state plasma-level in mouse models of CRPC than MDV3100.”

In other words, ARN-509 is a next generation AR antagonist with a good efficacy and PK profile in mouse xenograft models of CRPC.  It’s clinical development, although further behind abiraterone and MDV3100, will be well worth watching over the next few years.

In summary…

While there has been a lot of activity in the advanced prostate cancer market lately with new approvals making a difference to the lives of men with prostate cancer, there are also several other promising near term agents in development, as well as some potentially more potent and effective treatments in early clinical development.  What we have seen to date is merely the beginning of new advances in R&D.

The early and advanced prostate cancer markets are likely to see some significant changes over the next 24 months, as new products based on rational drug design and an improved understanding of the biology of the disease make it to market.

More on prostate cancer coming soon!

All this new data is very timely, considering on Monday I’m off to the AACR Special Conference on Prostate Cancer, jointly chaired by Drs Chinnaiyan and Sawyers.  I’ll be interested to learn what new events are emerging as biological targets and what factors can help us predict response to treatment.  If you’re going to this meeting do stop and say hello, it’s always good to meet new people in the field.

References:

ResearchBlogging.orgClegg, N., Wongvipat, J., Tran, C., Ouk, S., Dilhas, A., Joseph, J., Chen, Y., Grillot, K., Bischoff, E., Cai, L., Aparicio, A., Dorow, S., Arora, V., Shao, G., Qian, J., Zhao, H., Yang, G., Cao, C., Sensintaffar, J., Wasielewska, T., Herbert, M., Bonnefous, C., Darimont, B., Scher, H., Smith-Jones, P., Klang, M., Smith, N., de Stanchina, E., Wu, N., Ouerfelli, O., Rix, P., Heyman, R., Jung, M., Sawyers, C., & Hager, J. (2012). ARN-509: a novel anti-androgen for prostate cancer treatment. Cancer Research DOI: 10.1158/0008-5472.CAN-11-3948

Scher, H. (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

3 Comments

Update on Medivation’s MDV3100 in advanced prostate cancer

This weekend heralds the annual American Society of Clinical Oncology (ASCO) Genitourinary (GU) meeting in San Francisco, although ASCO held their press briefing today to provide an update on some of the key topics.

For those of you interested in Alpharadin (radium-225) in castrate-resistant prostate cancer (CRPC), check out the update of Dr Oliver Sartor’s presentation, which is covered on Biotech Strategy Blog.

The key topic that most interested me though, was Dr Howard Scher’s update on Medivation’s Androgen Receptor antagonist, MDV3100, in CRPC.  Previously, Medivation announced that the data showed an improvement in median overall survival (OS) of 4.8 months and this is still solid (Note: J&J’s abiraterone was approved by the FDA based on an OS of 3.9 months in the same population and must be taken with prednisone).

Three new things were important in this presentation though:

  1. There has been some previous concern about the risk of seizures, after they were reported in an earlier trial, but that was at much higher doses.  In this study, the now standard (and much lower) 160 mg dose of MDV3100, demonstrated low levels of seizures (0.6%), which is very reassuring and not something I think many will worry too much about.
  2. MDV3100 has a nice effect not only on OS, but also median time to confirmed PSA Progression, i.e. 8.3 months vs. 3.0 months for placebo (HR 0.248, P<0.0001). Yes, I had to do a double take at that HR – it’s quite phenomenal!
  3. Aside from PSA drops, patients often like to know if their tumour is shrinking or not as evidence of activity and progress. Dr Scher showed the soft tissue response by CT/MRI imaging. There was a 28.9% response rate with MDV3100 compared with 3.8% for placebo (P<0.0001).

From this data we can definitely say that patients lived longer, saw a positive impact on their PSA levels, and felt better compared to placebo. In terms of serious adverse events, there were fewer in the MDV3100 arm (28.4%) versus the placebo arm (33.6%). There were also slightly more discontinuations in the placebo (7.0%) than MDV3100 (3.8%) cohort.

Overall, I wasn’t at all surprised when the host, Dr Nicholas Vogelzang (Medical Director of the Developmental Therapeutics Committee of US Oncology) exuberantly said he had only one comment to Dr Scher’s presentation of the MDV3100 data,

“Wow, that’s very impressive! It’s unprecedented.”

For once, I thought that ‘impressive’ was actually an understatement to apply to a cancer drug.

I also talked to Dr David Hung, CEO of Medivation afterwards. Many readers will remember my interview with Dr Charles Sawyers, the co-inventor of MDV3100, last year about the science behind the development. It was nice to see Medivation’s side of the R&D story, which has gone pretty rapidly so far.

PSB: Are you going to be filing soon based on this data?

David Hung: We are having a pre-NDA meeting with the FDA. Once we have that meeting we will be able to give much more concrete guidance on when we will be filing.

PSB: Some of the pre-chemo trials have started, would they be due to report some data soon?

David Hung: We haven’t given any timelines on any of our other trials.

PSB: When I interviewed with Charles Sawyers previously, he said that many pharma companies were not interested in what is now MDV3100. What did you see in it when many others said “no”?

David Hung: Charles didn’t approach me. I found him! I had read, with great interest, his work on the AR. I was very familiar with his Nature Medicine publication in 2004 showing that overexpression of the AR is a significant molecular change in patients with castration resistant disease. While I think a lot of people thought that targeting the AR would create just another AR antagonist, like casodex, the data suggested to me there was more here.

Because, in Charles’ lab by being able to over-express the AR, we were able to much more carefully assay and screen compounds for their ability to block androgen receptor signaling very thoroughly. And we found in the process that a number of compounds in the series that we were testing had ability to not only block just AR binding by testosterone, which is something that Casodex does, but unlike Casodex these compounds were able to inhibit nuclear translocation as well as DNA binding and activation by the AR.

I am an oncologist by training and was pretty familiar with this area, so when I saw the compounds and saw the data in more detail, I didn’t agree that it would just be another casodex like molecule. I thought the mechanisms suggested that this drug could be special, so when I went ahead and licensed the drug back in 2005. We then took the program forward rapidly through development. We had to do all the standard pharmacokinetics, metabolism, tox, formulation work, then take it into a clinical trial as quickly as we could, led by Howard Scher. So, we were able to develop the molecule very quickly.

One of the differences with MDV3100 over weaker AR antagonists such as bicalutamide, is it’s ability to target splice variants. This was a surprising but important finding. I asked Dr Hung about them:

PSB: Does that potentially mean that the patients in the current trial data presented by Dr Scher, may actually do better over time or is the 4.8 months OS probably going to be the final number?

David Hung: Well, I won’t know the answer to that until I unblind the PREVAIL trial. What is very interesting from our phase 1 / 2 data is that the time to PSA progression in post-chemo patients in that data set is about 203 days. Yet, the time to PSA progression in the pre-chemo patients was 4x longer than that, 812 days, suggesting that the drug may have even more robust activity upstream than it does downstream. Downstream it already has robust activity. We will be greatly looking forward to seeing the PREVAIL data, because that is the pre-chemo population. If we can recapitulate our phase 1 / 2 results, that would be great news for patients.

PSB: At AUA last year, I heard from Charles Sawyers that if you inhibit the androgen receptor, you often activate the PI3-Kinase pathway. His colleague Neil Rosen had also noticed that if you inhibit PI3K, you activate androgen receptor in prostate models. So Charles was saying in their joint paper that the logical thing to do would be to combine an androgen receptor inhibitor and a PI3K-inhibitor to potentially reduce the resistance and hopefully improve outcomes. Is that the kind of combination you might consider in the future?

David Hung: We actually are. You point out exactly the kind of things that we think about. We look to see how our drug works and we look to see what mechanisms might possibly complement our drug. That is the way we think about potential combination studies that we might do.

All this is very exciting news for both Medivation (and commercial partner Astellas), as well as patients with advanced prostate cancer. I hope that the discussions with the FDA go well and we will see a filing, perhaps even with Accelerated or Priority Review in the near future. Based on the data so far, the data clearly shows that MD3100 can make a difference to the lives of men with advanced prostate cancer.

Next week, I’ll be at the American Association for Cancer Research (AACR) Special Conference on Prostate Cancer, jointly chaired by Charles Sawyers (MSKCC) and Arul Chinnaiyan (Michigan) to learn more about the biology of prostate cancer. It promises to be both a timely and exciting meeting!

References:

ResearchBlogging.orgChen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, & Sawyers CL (2004). Molecular determinants of resistance to antiandrogen therapy. Nature medicine, 10 (1), 33-9 PMID: 14702632

Carver, B., Chapinski, C., Wongvipat, J., Hieronymus, H., Chen, Y., Chandarlapaty, S., Arora, V., Le, C., Koutcher, J., Scher, H., Scardino, P., Rosen, N., & Sawyers, C. (2011). Reciprocal Feedback Regulation of PI3K and Androgen Receptor Signaling in PTEN-Deficient Prostate Cancer Cancer Cell, 19 (5), 575-586 DOI: 10.1016/j.ccr.2011.04.008

6 Comments

Excellent news in Advanced Prostate Cancer – Medivation's MDV3100 meets primary endpoint

By on November 3, 2011

It’s not often that you wake up to really exciting news in the cancer field, but that’s what happened this morning with Medivation’s announcement on the interim analysis of their androgen receptor (AR) antagonist, MDV3100:

“As reported by the IDMC, MDV3100 produced a 4.8-month advantage in median overall survival compared to placebo.

The estimated median survival for men treated with MDV3100 was 18.4 months compared with 13.6 months for men treated with placebo. MDV3100 provided a 37 percent reduction in risk of death compared to placebo (Hazard Ratio=0.631).

The IDMC further determined, considering the observed safety profile, that MDV3100 demonstrated a favorable risk-to-benefit ratio sufficient to stop the study.”

The 4.8 month improvement in OS in post-chemo setting is superior to that previously reported for abiraterone (Zytiga), which had a 3.9 month advantage over placebo and received regulatory approval in the US and EU earlier this year.

This is great news for patients, for Medivation and also for Charles Sawyers at MSKCC who originally invented the MDV3100 compound. If you are interested in the MDV3100 story, you can read my interview with Dr Sawyers posted earlier this year.

There are several points to note about these results:

  • MDV3100 does not require concomittant steroid therapy as abiraterone does, this is huge for urologists who as surgeons do not generally want to manage side effects.
  • Given the excellent results in the post chemotherapy setting, I would expect the survival advantage in the pre-chemotherapy session for both therapies to be more than 6 months.
  • Ultimately, as hormone therapy, I can see the real advantage for MDV3100 being as a more potent and complete inhibitor of the AR than bicalutamide, so there is a huge potential for MDV3100 as ADT therapy in the earlier stages of disease.

With regards to filing, Medivation announced that:

“Medivation and Astellas plan to hold a pre-NDA meeting with the U.S. Food and Drug Administration (FDA) in early 2012 and will provide an update on regulatory timelines for MDV3100 subsequent to that meeting.”

At this rate, I would expect to see MDV3100 approved sometime in 2012.

The future is looking very bright indeed for patients with advanced prostate cancer – these new therapies offer the potential with sequencing to extend lives significantly.

2 Comments

Custirsen – a new treatment for castrate resistant prostate cancer?

By on August 8, 2011

I’ve been following the development of Oncogenex’s custirsen for a while based on various posters presented at meetings such as ASCO and AUA, but with the publication of phase II data in prostate cancer, it seems a good time to discuss the compound in more detail.

According to Oncogenex:

“OGX-011, also known as custirsen sodium, inhibits the production of clusterin, a protein that is associated with treatment resistance in a number of solid tumors, including prostate, breast, non-small cell lung, ovarian, and bladder cancers.”

Essentially, I think of it a chemo-enhancer, although more technically, it seems to help delay the onset of resistance developing by targeting clusterin (CLU).  CLU is a stress-activated cytoprotective chaperone.  It is upregulated by a several cancer drugs and confers resistance when overexpressed.

Low levels of CLU are therefore more desirable and may be useful as a predictive biomarker of response.

Previous data on custirsen from the phase II front-line trial showed an encouraging shift to the right in the survival curves, validating the hypothesis that resistance is delayed:

The current phase II clinical trial received support from both Sanofi and Oncogenex. Results were reported by Saad et al., (2011), who assessed the weekly administration of custirsen in combination with either docetaxel or mitoxantrone in second-line metastatic castrate resistant prostate cancer (CRPC).  Patients had previously been treated with a minimum of 2 cycles of a docetaxel-based chemotherapy regimen and progressed during or within 6 months of discontinuation of docetaxel treatment.

Overall, patients (n=42) were randomized to receive either docetaxel + prednisone + custirsen (DPC) or mitoxantrone + prednisone + custirsen (MPC).

What did the data show?

Given that the preclinical in vitro and in vivo models have demonstrated the potential of custirsen to enhance chemotherapy and reduce docetaxel resistance, I was keen to see how the concept would pan out in humans.  We all know that preclinical evidence is no guarantee of success in clinical trials!  Although the primary goals of the trial were to measure safety and tolerability, the effects on tumour response and disease progression were interesting.

DPC (n=20):

  • Received: median of eight cycles
  • Overall survival:15.8 months
  • TTPP: 10.0 months
  • 10 of 13 (77%) evaluable patients had pain responses
  • Three of 13 (23%) evaluable patients had objective partial responses
  • PSA declines of ≥90%, ≥50%, and ≥30% occurred in 4 (20%), 8 (40%) and 11 (55%) patients, respectively.

MPC (n=22):

  • Received a median of six cycles
  • Overall survival was 11.5 months
  • TTPP was 5.2 months
  • 6 of 13 (46%) evaluable patients had pain responses
  • No objective responses were observed
  • PSA declines of ≥50% and ≥30% occurred in 6 (27%) and 7 (32%) patients, respectively.

Based on experience, we would expect the results with docetaxel chemotherapy to be better than mitoxantrone, since the latter is only palliative at best.

Additionally, custirsen treatment was shown to significantly decrease levels of the target protein, CLU, and low serum CLU levels during treatment demonstrated superior survival.

Two phase III trials in combination with docetaxel are now ongoing in both the first and second line setting in CRPC.  The trials are currently enrolling patients, so results will not be available for a while, ie 2013 at the earliest.

Many of you will remember the video discussion from the American Urological Association meeting earlier this year, where we highlighted the potential for custirsen in combination with an AR antagonist such as MDV3100 from Medivation/Astellas.  For those interested, the initial data from the custirsen/MDV3100 combination is shown in the short vlog.

In the meantime, the results look most encouraging, although there is a-ways to go yet, since phase II data is no guarantee of phase III performance.

{Update: Luke Timmerman from Xconomy posted about the slow recruitment to the phase III trials and the protocol amendment to include Sanofi’s cabazitaxel (Jevtana).

References:

ResearchBlogging.orgSaad, F., Hotte, S., North, S., Eigl, B., Chi, K., Czaykowski, P., Wood, L., Pollack, M., Berry, S., Lattouf, J., Mukherjee, S., Gleave, M., & Winquist, E. (2011). Randomized Phase 2 Trial of Custirsen (OGX-011) with Docetaxel or Mitoxantrone in Patients with Metastatic Castrate-Resistant Prostate Cancer: CUOG Trial P06c Clinical Cancer Research. DOI: 10.1158/1078-0432.CCR-11-0859

2 Comments

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

$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}

#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
error: Content is protected !!