Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘ASCO GU 2013’

Galeterone (Tokai Pharmaceuticals) is a new prostate cancer drug in development that has an interesting triple mechanism of action in that like abiraterone (Zytiga) it acts as a CYP17 lyase inhibitor, but it also acts as an androgen receptor (AR) inhibitor and is an AR degrading drug that decreases AR levels.

How effective it is compared to AR antagonists on the market such as enzalutamide (Medivation) or second-generation AR antagonists in development such as ARN-509 (Aragon Pharmaceuticals) or ODM-201 (Orion Pharma) is one of the many unanswered questions with this drug.

The poster (abstract #184) from Tokai scientists presented at the recent 2013 American Society of Clinical Oncology Genitourinary Cancers Symposium in Orlando (ASCO GU) showed preclinical laboratory work using cell lines whereby galeterone was a potent CYP17 lyase inhibitor. It may offer an advantage over abiraterone in not requiring concomitant administration of steroids.

Despite being a clinically focused meeting, no patient data using the new formulation of the drug was presented at ASCO GU; this was disappointing given the potential safety concerns that were raised with the original formulation.

AACR 2012 data showed drug-related rhabdomyolysis & acute renal failure, both Grade 4

Last year at the 2012 AACR annual meeting, Mary Ellen Taplin, MD presented data from the ARMOR1 clinical trial of galeterone in chemotherapy-naïve castration resistant prostate cancer (CRPC).

Of particular concern was the one serious adverse event of drug-related Grade 4 rhabdomyolysis and acute renal failure she reported. Some commentators have dismissed this as a “fluke” but it was clearly taken seriously by the company in the AACR presentation I saw with several slides discussing this and liver safety considerations.

Dr Taplin concluded her AACR presentation by stating that further work was planned to optimize the formulation of galeterone, and that a new phase 2 study with a better formulation was planned for later in 2012.

Critical clinical questions remain unanswered

As Professor Johann de Bono, who was the discussant at AACR 2012 noted, a future trial with galeterone has a number of critical questions to answer:

  • Can galeterone achieve sufficient exposure?
  • Can galeterone block CYP17? AR? Degrade AR?
  • Can galeterone reverse MDV/abiraterone resistance?

So why haven’t I written much about galeterone, as one blog reader recently wrote in to ask?  It’s largely because I don’t think there is enough data to make any conclusions yet and both the liver toxicity and rhabdomyolysis issues will overshadow its development until Tokai address this convincingly.

I certainly haven’t seen any pharmacokinetic data on the new formulation to show that safety and efficacy are acceptable, nor any data to show that it has a definite effect on disease progression over and above abiraterone or enzalutamide.

Tokai announced on December 13, 2012 that they had treated the first patient in the Phase 2 ARMOR2 trial, which will evaluate the safety and efficacy of the new formulation.

Hopefully, the clinical data from ARMOR2 will show no repeat of the drug-related grade 4 rhabdomyolysis and acute renal failure seen in the ARMOR1 trial.  Only then will we know whether this was a “fluke” or not as some commentators have suggested.

The company has shown a proof of concept but until we see more data, I don’t think we really can assess what potential galeterone may have in the treatment of advanced prostate cancer.

For those interested in the data on galeterone presented at ASCO GU, here’s a link to a PDF of the poster available on the Tokai Pharmaceuticals website.

Galeterone Commercialization Challenges

Some of the challenges that Tokai may face in bringing galeterone to market include:

1. Need for a new formulation has delayed drug development

There are multiple new prostate cancer products in development in what will before long be a much more competitive market than it is today.  Although galeterone received a fast track designation from the FDA , I can’t help but think that the company has lost a year as a result of the need to develop a new formulation. Given the market dynamics, this delay could impact Tokai and the potential market opportunity for galeterone.

2. Abiraterone patent expiration is on the horizon

The short patent life for abiraterone and prospect of the availability of a generic version in a few years, could negate some of the advantages of having a CYP17 “combination product”. Galeterone may not require the concomitant administration of steroids, but this benefit may not be sufficiently attractive on its own to justify a premium price when a generic version of abiraterone becomes available.

3. How good an AR antagonist is galeterone?

We don’t yet know how effective an AR antagonist the new formulation of galeterone is. At the scientific meetings I have attended, I have only seen one slide on the mechanism of action, and it’s unclear to me what effect galeterone may have (if any) on AR splice variants. Other questions that come to mind are:

  • Is galeterone a more complete antagonist of AR like enzalutamide or does it have antagonist and agonist properties like bicalutamide?
  • Will galeterone offer benefits over using an AR antagonist such as enzalutamide in combination with abiraterone?
  • Are the AR antagonist effects of galeterone better than second-generation AR antagonists in development such as ARN-509, ODM-201?

4. Randomized registration trials will need to be done against the standard of care

If your registration trial is not already underway, the days of placebo controlled trials in advanced prostate cancer are over. It would be unethical to give men an inactive placebo when effective new therapies are already available, especially in the post chemotherapy setting. Tokai will most likely have to do a randomized registration trial of galaterone against abiraterone. Will it be superior or only equivalent in efficacy and tolerabilty?

5. To charge a premium price, Tokai will need to show men live longer

The competitive landscape is moving fast, and I predict as the cumulative cost of prostate cancer treatment increases, the market will become more price sensitive as new drugs are approved. If Tokai desire to charge a premium price, then they will need to show that galeterone is superior to the standard of care i.e. men live longer when taking it compared to taking abiraterone or enzalutamide.

Abiraterone had the first mover advantage as the first drug to seek approval in the pre-chemotherapy CRPC setting. Johnson and Johnson obtained FDA approval based on the totality of the COU-AA-302 trial data, which included the absence of a significant overall survival advantage, although this would most likely have been reached had the trial not been stopped early. In future, I can’t see other companies being equally blessed. Medivation will most likely run their PREVAIL trial until a significant overall survival advantage is obtained, and in the process raise the bar for future competitors such as galeterone.

Other combinations may offer more benefit than galeterone

It is good news for men with advanced prostate cancer that new treatment combinations are on the horizon.  While I remain sceptical about galeterone, at least until they show compelling clinical data, I am excited about new treatment options such as radium-223 (Alpharadin) that will soon be approved by the FDA.

Professor Bertrand Tombal in his recent ASCO GU interview with Sally Church, PhD said the trial he’d most like to do is radium-223 + enzalutamide. I share his enthusiasm for this. If you haven’t already read the interview, here’s a link to it on Pharma Strategy Blog.

While I didn’t think galeterone was worth writing about from AACR 2012 given that it was headed back to the lab for a new formulation, a novel prostate cancer treatment that did catch my attention was AZD3514 from AstraZeneca. Here’s the link to my AACR 2012 post in case you missed it. This is one that I am watching, and I hope there will be phase 1 clinical trial data for AZD3514 at the ASCO annual meeting later this year.

My Conclusion

In my view, Tokai Pharmaceuticals have yet to show the new formulation of galeterone is safe and effective or that men with advanced prostate cancer live longer when taking the drug compared to taking abiraterone or enzalutamide either sequentially, or in combination. While galeterone may offer an innovative mechanism of action, it is too early to say whether this will translate into any meaningful clinical benefit in the treatment of advanced prostate cancer or whether it’s just another me-too drug in development.

It’s disappointing to learn from the ASCO 2013 GU symposium abstracts published today that Bristol Myers Squibb’s tyrosine kinase inhibitor, dasatinib (Sprycel), has failed in prostate cancer.

Dasatinib now joins a large graveyard of cancer drugs that showed promise in early clinical development in solid tumors, yet the data was not confirmed in a large scale randomized phase 3 trial.

The phase 1 / 2 trial results for dasatinib in advanced prostate cancer were published by John Araujo, MD and colleagues last year in the journal “Cancer” (Jan 1, 2012).

The paper concluded on the basis of two trials with 46 men that “the high objective response rate and favorable toxicity profile are promising and justify randomized studies of docetaxel and dasatinib in castration-resistant PC.”

Fast forward to the dasatinib phase 3 trial results published at ASCO GU 2013, where the data from a large scale randomized trial involving 1,522 men with advanced prostate cancer showed no significant difference in survival between men receiving dasatinib plus docetaxel (chemotherapy) versus men receiving docetaxel alone. The median survival between the two treatment arms was 21.5 vs 21.2 months (HR 0.99 P=0.90).

As the FDA comes under pressure to grant approval to promising cancer drugs based on early clinical trial data, the failure of dasatinib reminds us why large randomized trials are needed to show that a drug truly works, and the potential nemesis that may occur if phase 2 hubris alone is relied upon.

The news of dasatinib’s failure in prostate cancer is a disappointing result, but does not affect it’s role in CML where it is already approved.

Update Feb 13 – dasatinib may be effective in a subset of patients

I corresponded by email today with Evan Yu, MD, Associate Professor of Medicine & Oncology at the University of Washington School of Medicine and one of the co-authors on the dasatinib abstract presented at ASCO GU 2013.

BSB: Do you have any thoughts on why the phase 1/2 trial was promising yet the phase 3 trial ends up a failure?

Dr Yu: The challenge comes from identifying patients who have tumors that are being strongly driven by SRC.  The phase 2 monotherapy data was promising, but the greatest effect was on bone turnover.  And we know that SRC is expressed on
osteoclasts.  The phase 1/2 combination docetaxel with dasatinib trial also showed promising results.  However, it was a single arm trial without randomization.  The phase 3 trial was definitely solid, well-run, and BMS should be congratulated for running such an impressive trial.

BSB: Given there was a good scientific rational for targeting Src, any thoughts on what happened from a scientific perspective that might explain the lack of any survival benefit?

Dr Yu: One must ask whether overall survival was the right endpoint for this trial?  My suspicion is that the drug has potent effects in the bone for most patients, but significant direct antitumor effect for a small subset that is yet undefined.  Hopefully, smaller translational studies down the road performing tumor biopsy analysis and quantitative fluoride PET imaging will help identify those populations.

Dr Yu’s perspective highlights the challenge of oncology drug development, where increasingly companies need biomarkers to identify those patients who are likely to respond and to monitor the response to treatment. His comments add weight to the notion that companies need to spend more time in phase 2 development before rushing to costly, large-scale phase 3 trials. If you don’t know who is likely to respond to your drug, then you run the risk that those who don’t respond will turn your trial into a negative result.

Update Feb 15, 2013 – dasatinib fails to show a survival benefit in any subgroup

There is additional commentary from the presentation of the dasatinib READY phase 3 trial results in my piece on Xconomy about the prostate cancer drug winners and losers at ASCO GU.

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What’s hot in prostate cancer at the forthcoming American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) (twitter hashtag #GU13) that takes place in Orlando from February 14 -16?

That’s the question I was asked recently, and while the abstracts have not yet been published, (embargo lifts at 6pm ET on February 12, 2013) the titles of the posters and choice of oral presentations offer some insight into what may be newsworthy data.

In the oral abstract session on February 14, 2012 two of the presentations of particular interest to me are:

Bristol Myers Squibb dasatinib (Sprycel) Phase 3 Trial Data

Abstract #LBA8. Overall survival (OS) and safety of dasatinib/docetaxel versus docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC): Results from the randomized phase III READY trial.

Presenter: John C. Araujo, MD, PhD

I correctly predicted in my October 2012 blog post that the dasatinib phase III prostate cancer trial data would be at ASCO GU.

Bristol Myers ($BMY) stock has experienced an upwards run in the last few weeks, so we will soon see whether the company has a new treatment option for prostate cancer and one with a very different target (Src).

I have no thoughts on whether the data will be positive or negative. I hate to sit on the fence, but the impression I have is the results could go either way.

Aragon Pharmaceuticals ARN-509 

Abstract #7. ARN-509 in men with high-risk nonmetastatic castration-resistant prostate cancer (CRPC).

Presenter: Matthew R. Smith, MD, PhD

I recently wrote about the ongoing Medivation v UCLA/Aragon litigation on this blog. ARN-509 is a second-generation androgen (AR) inhibitor that along with enzalutamide came out of the work by Charles Sawyers and Michael Jung’s lab at the University of California Los Angeles (UCLA).

Irrespective of whether Medivation appeals the recent summary judgement decision in favor of Aragon, ARN-509 is of considerable interest. Sawyers observed in the preclinical testing that it may be a more complete AR antagonist than enzalutamide; see Sally Church’s Interview with Dr Charles Sawyers on Pharma Strategy Blog for further commentary.

At ASCO GU there is also an oral presentation on the pre-chemo data for abiraterone (Zytiga) from the COU-AA-302 trial that I wrote about from ASCO last year.

Without much fanfare, and without any significant overall survival data, abiraterone’s pre-chemo indication was approved by the FDA last December.  It will be interesting to see what new data is presented at the meeting.

There are also several interesting posters that did not make into the short oral session.  One to look out for is the first data for enzalutamide (Xtandi) in hormone-naive prostate cancer:

Abstract #18. Enzalutamide monotherapy: Phase II study results in patients with hormone-naive prostate cancer.

Presenter: Bertrand Tombal, MD, PhD (@BertrandTOMBAL)

It will be interesting to see how enzalutamide compares to bicalutamide, in what is a market segment with a very large potential.

Another poster of note is the pain analysis for radium-223 (Alpharadin) (Abstract#19).

I’m also looking forward to the poster on the use of chimeric antigen receptor (CAR) modified T cells to target prostate-specific membrane antigen (PSMA) (Abstract #72).  This is an emerging technology that was highlighted at ASH 2012.

For those interested in learning more about the potential of CAR based therapies, Sally Church, PhD (@MaverickNY) will be publishing a report in the not too distant future.

ASCO GU 2013 (#GU13) looks to have some interesting data in prostate cancer and I look forward to contributing to Xconomy from the meeting.

If you would like to receive information about my post-conference prostate cancer report and other insights, please sign up for an email alert.

Update Feb 12, 2013 – Dasatinib phase 3 prostate trial is a failure

Well, it’s gone 6pm and the #GU13 abstracts are now accessible on the ASCO GU Symposium website. The big news is that the dasatinib phase 3 trial data is negative!

According to the abstract, “The addition of DAS to standard-of-care chemotherapy in mCRPC pts did not improve OS.”

As commentators have already noted on Twitter, this is disappointing given the promise of the phase 1/2 trial results that were published in the journal “Cancer” on January 1, 2012 by Dr Araujo and colleagues.

Update Feb 15, 2013 – Winners & Losers at ASCO GU

Thanks to @ldtimmerman for editing my guest post on Xconomy. Here’s a link to my post about the prostate cancer drug winners and losers at ASCO GU 2013.

TBMS Sprycel Logohe results of the phase 3 clinical trial of dasatinib (Sprycel) plus docetaxel/prednisone versus placebo and docetaxel/prednisone in men with castration-resistant metastatic prostate cancer (CRPC) are expected soon.

BMS recently updated the clinicaltrials.gov website to show that the dasatinib phase 3 randomized prostate cancer “READY” trial (NCT00744497) of 1500 men completed data collection in August.

Data is expected before year end and, If positive, could be a late breaker at the ASCO Genitourinary Cancers Symposiusm (ASCO GU) in Orlando from Feb 14-16, 2013.

Dasatinib inhibits Src-family kinases (SFK)

Dasatinib is approved for Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia (ALL). It is a BCR/ABL, LYN and Src family tyrosine kinase inhibitor.

Src-family kinases (SFK) are involved with tumor proliferation and bone metabolism.

In the phase 1 & 2 clinical trials of dasatinib with docetaxel, many of the men with prostate cancer saw a decrease in PSA from baseline, reduction in tumor size and bone scan improvement and stabilization. Encouraging early results led to the start of a phase 3 randomized trial of dasatinib in combination with the chemotherapy, docetaxel.

However, the results for Src inhibitors in prostate cancer have been mixed to date, with not all agents generating positive data. Astra-Zeneca’s saracatinib (AZD0530), for example, showed little clinical effect on its own in a phase 2 prostate clinical trial.

It has been suggested by KOLs at numerous conferences that Src inhibitors may potentially be more effective in combination with other cancer agents. Data suggests that Src might be a resistance mechanism to enzalutamide (MDV3100), so it would be interesting to see whether a dasatinib/enzalutamide combination may be more effective than enzalutamide on its own.

Meanwhile, we await the data to see whether the combination of dasatinib with docetaxel generates a significant increase in overall survival over docetaxel alone. While some are “hopeful”, Dr Oliver Sartor, Professor of Cancer Research at Tulane Medical School noted in a prostate cancer session at ESMO 2012 that, “the docetaxel-combination graveyard is big!

Update Jan 26 2013: Dasatinib Phase 3 Data at ASCO GU

Results from the dasatinib phase 3 prostate cancer trial are a late breaking abstract at the 2013 ASCO Genitourinary Cancer Symposium (ASCO GU) in Orlando. The data will be presented on February 14 by John Araujo MD PhD, Assistant Professor in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston.

LBA #8: Overall survival (OS) and safety of dasatinib/docetaxel versus docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC): Results from the phase III READY trial.

Abiraterone Acetate Pre-Chemotherapy ASCO 2012Men with advanced prostate cancer want to know “if I take this drug, will I live longer?” Unfortunately, for abiraterone acetate (Zytiga®) in the pre-chemotherapy setting i.e for asymptomatic or mildly symptomatic men, doctors will only be able to say, “maybe” and tell the patient there is a strong trend towards an overall survival (OS) advantage.

You can read my Xconomy article published yesterday, on why I think it was a mistake for the abiraterone acetate COU-AA-302 trial (302 trial) in chemotherapy-naïve (pre-chemo) men to be stopped early.  The results were presented on Saturday at the American Society of Clinical Oncology (ASCO) meeting in Chicago.

Understanding the Lan-DeMets alpha spending function with O’Brien-Fleming boundary based on number of death events observed is challenging for non-experts.

However, the bottom line is that the 302 trial failed to meet the pre-specified hazard ratio for stopping early, and by so doing it failed to meet one of its co-primary endpoints. This is disappointing because the trial most likely only needed another 92 deaths to occur before it would have reached significance, and this would have occurred in a matter of months.

The co-primary endpoint of radiographic progression free survival (rPFS) was, however, met in the 302 trial. Whether rPFS reflects tangible clinical benefit is unknown.  The FDA have (to my knowledge) not approved a prostate cancer drug on the basis of rPFS , overall survival remains the regulatory standard.

I also learnt for the first time at ASCO about the problem of bone flare in patients receiving abiraterone. Charles Ryan, MD who presented the 302 data, discussed this is an ASCO educational session on prostate cancer imaging.

Bone scan flare is a spurious, “worsening” bone scan in the context of clinical response that reflects increased intensity of lesions, not new lesions.  In other words a brighter image on a bone scan may not represent disease progression.

In a previously published study, Dr Ryan showed a 43% incidence (10/23) of bone flare with abiraterone.  He advised attendees at the ASCO 2012 educational session to “look for, and CONFIRM new lesions before calling progression based solely on bone scans.”

Although the rPFS data for the COU-AA-302 trial was read centrally, and is therefore presumed to be more reliable as a result, I would have welcomed more discussion on the extent rPFS correlates with survival following the COU-AA-302 data presentation at ASCO.  I expect the Oncologic Drugs Advisory Committee (ODAC) will vigorously discuss this in more detail when Johnson & Johnson seek a pre-chemotherapy indication for abiraterone based on the COU-AA-302 data.

Bearing in mind overall survival has been the de facto standard in advanced prostate cancer, it will be interesting to see how the FDA and ODAC will view what is essentially a failed trial with a non-significant OS.  Will precedent be broken, opening the floodgates for future sponsor submissions based on PFS?

Update January 24 2013: FDA & EMA approve Zytiga Pre-Chemo in CRPC

With little fanfare and no ODAC, the FDA issued a press release on December 10, 2012 announcing that abiraterone acetate (Zytiga) had received approval “to treat men with late-stage (metastatic) castration-resistant prostate cancer prior to receiving chemotherapy.”

The press release states: “The FDA reviewed Zytiga’s application for this new indication under the agency’s priority review program. The program provides for an expedited six-month review for drugs that may offer major advances in treatment or provide a treatment when no adequate therapy exists.

The fact that there was an unmet need for prostate cancer treatments prior to chemotherapy was clearly key to their decision making. The press release notes that “patients who received Zytiga had a median overall survival of 35.3 months compared with 30.1 months for those receiving the placebo.”

However, the FDA in their carefully worded press release make no mention of the fact that the difference of 5.2 months in median overall survival failed to reach the pre-specified value for statistical significance.

In other words, although JNJ have expanded the label for abiraterone to include the pre-chemo indication, they cannot make the claim that taking abiraterone prior to chemotherapy definitely results in men living longer (overall survival). All we can say is that the data was trending towards a statistically significant overall survival advantage. To many this may seem academic, but overall survival remains the benchmark that drives cancer drug development and by which treatment effectiveness is judged.

As I noted in my post from ASCO 2012 for Xconomy, most likely statistical significance for overall survival would have been reached in a few months, which is why I and others thought the trial had been stopped too early. I would be surprised if other companies follow JNJ’s strategy, and expect Medivation will seek to show a significant overall survival advantage for enzalatumide (Xtandi) in their pre-chemotherapy PREVAIL trial.

Johnson & Johnson announced on January 11, 2013 that abiraterone has also received approval in the European Union for the pre-chemotherapy prostate cancer indication following a positive recommendation from the Committee for Medical Products for Human Use (CHMP) of the European Medicines Agency (EMA).

It will be interesting to see if there is any new data in the updated interim analysis for the COU-AA-302 trial (abiraterone pre-chemo) that will be presented at the 2013 ASCO Genitourinary Cancers (ASCO GU) symposium in Orlando next month.

 

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