Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

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 Responses to “J&J unblind Zytiga phase 3 trial in pre-chemotherapy castrate-resistant prostate cancer”

  1. Lilmauwow

    This is a urology drug, DNDN will only care about what the urologists think as this is where they will succeed or fail.  You seem a bit biased about OS not being statistically significant.  If Provenge was stat sig, you’d be dumping all over it.  The argument isn’t whether the data is compelling or not, its whether OS is stat sig.  And as of right now when they unblinded it, its not.  stick with the facts.

    • maverickny

      Hello Lilmauwow and welcome to planet pluto aka my personal blog.  Blogs are not news sites, nor factual recordings, they’re opinion pieces.  If you disagree with the views or analysis expressed here, you’re more than welcome to put your views or counterpoint publicly on your own blog.

      That said, I have no skin or stocks in any of the companies mentioned, so there are no biases as such.

      From the pure factual perspective, Provenge was actually statistically significant for OS in the asymptomatic CRPC setting (by 4.1 months), that was one of the requirements for their approval.  Where I have issues with Provenge is that treating physicians tell me it’s very hard to monitor how well the therapy is doing in their patients as it has no impact on tumour shrinkage, PSA or bone pain.  Those are valid points in the community setting outside of a clinical trial.

      The 302 abiraterone trial actually has PFS and OS as joint endpoints, as does the MDV3100 trial.  If the monitoring committee decide that the data is compelling enough to stop early, then we have to believe the difference between abiraterone and placebo is sufficient enough to warrant stopping and switching from an ethical standpoint, at least from the PFS perspective. It’s a bit early to see a difference in OS at this stage and the challenge will be if the patients switch the arms crossover, thereby negating any easy calculation of OS later.  No doubt that will be a contentious issue for ODAC once filed.

      Until we see the data at ASCO or ESMO later this year, we can only speculate, but phase 3 oncology trials are rarely stopped early, unless the data is sufficiently compelling.

  2. Jae

    Hi Maverick, Thanks for timely information and nice discussion on its consequence.

  3. Lilmauwow

    The question is, have you ever seen a trial stopped because the data was so compelling before determining over survival was not stat sig as a primary endpoint?  If achieving a primary endpoint was a requirement, and you’re supposedly so close to that requirement that there’s a “strong trend”, that you would gamble and unblind your trial where it would be impossible to determine if that strong trend leads to OS?  I’ve learned alot of DNDN’s managmenet, if it doesn’t pass the smell test, its rotten!  BSR’s point is right where if it was a small biotech they would have been killed with this type of press release.

    I agree it does have joint endpoints.  It must be pfs AND os.  If one is missing from the other, the endpoint is not met correct? Again I point that i’m not arguing that Zytiga does not work or its useless because it didn’t meet OS stat sig. PFS stat sig met is enough to warrant the placebo patients to join in.  But it terms of taking the space of provenge on the NCCD, this news trends more negative than if no news came out at all.  Because everyone thought Zytiga was going to meet OS stat sig with ease, and now that’s a question mark.  


    • maverickny

      I’m going to wait until seeing the actual data, however to stop a trial early the committee would have to see a huge difference in PFS to allow switching to take place, otherwise it would just continue on to allow OS to be collected.  That there isn’t a significant difference in OS is a concern, but it could be more than 6 months at P=0.051 or something like that.  Until we see the presentation, we won’t know.  

      Personally, I would have preferred to see OS, but I’m not on the committee.  In the meantime, if PFS is met and OS is not, then all we can say is that one of the primary endpoints were met and we have no idea what was agreed with the FDA i.e. were both or either needed?  Sometimes the clinical trials database is hard to interpret.

  4. Mguiltinan

    It does come surprise me that Zytiga was not able to reach sig stat in OS with a 1000 patient trial that became fully enrolled 22 months ago. Currently we have Provenge with a OS effect but no PFS. Now Zytiga get sig stat with PFS but misses against OS. This gap could potentially allow MDVN to say they have the only drug in the pre-chemo mCRPC indication that significantly effects both PFS and OS. That could be a nice marketing tool for MDV3100.   

    • maverickny

      Agreed, Medivation and MDV3100 could well be the big winners in this if they get PFS and OS in pre-chemotherapy.

  5. guest

    Since these drugs figure squarely in the urologist market, I think urologists would prefer to sequence using drugs like provenge for a few months and see if anything happens. It reimburses well and is pretty benign to the patient. Plus, the 4.1 month advantage is likely longer– if i remember the placebo patients were offered to be crossed over in the study. it would have been interesting to see drug vs placebo only. longer OS?  also, urologists wont get much reimbursement for pills. they will get prescribed (especially mdv3100 assuming tolerable breast tenderness, no seizures) i agree that steroids would require urologists to become better prepared to handle the possible side effects.

    To me, abiaterone might not be as big of a winner and provenge might come out doing well too. medivation could be the big winner or maybe aragon’s related drug could be even better!

  6. Mguiltinan

    I’m curious if the Independent data monitors would make this decision on their own without 1st consulting with the FDA. Zytiga’s trending OS might have reached sig stat if the trial was left alone for a few more months. If the FDA rejects Zytiga for pre-chemo because it missed OS then the ethical decision to put all trial participants on the drug  could possibly prevent other patients from getting Zytiga. This doesn’t sound logical so I’m assuming the monitors checked with the FDA before making such an important decision. Anyone know?

    • maverickny

      Don’t know – that’s the very question I’ve been pondering since the announcement was made.  Trying to find out.

  7. Lilmauwow

    J&J announced in q1 cc Zytiga is not exhibiting the ‘strong trend’ towards OS and will not present as the ASCO.  The whole argument 
     it was unblinded so it must be doing good’ was just a PR stunt for those who don’t understand how the game is played.  They knew they weren’t going to make OS, so they need to find a blame ASAP to why it would NEVER meet OS.  Its not the drug, its the unblinding!!!!  

  8. Lilmauwow

    Michael Weinstein – JPMorgan: Just one question on ZYTIGA. When the independent data monitoring committee stopped the Phase 3 trial in pre-chemo metastatic castrate-resistant prostate cancer patients, they did so based on the primary end point which was progression free survival for them and I believe it was based on data that went through late last year. Do you know if at ASCO if we will see the follow up on patients up through the actual announcement of the halting of the trial? The question here is, whether we will see overall survival reached is still significant at the full follow up?
    Louise Mehrotra – VP, IR: You are correct Mike. It did include the information up until the end of last year. I think it was November of last year. I don’t believe that you are going to see the continuing trend on the overall survival as ASCO. You will see the results as we have them right now.  (p.2 of Q&A section)

Comments are closed.

error: Content is protected !!