Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

This month has brought a flurry of regulatory activity in the prostate cancer landscape with several companies seeing noticeable action in the new product development area:

For this specific post, I want to concentrate on the new trends in advanced prostate cancer, as last weekend I attended the 2012 American Urological Association (AUA) annual meeting, focusing on the basic research sessions hosted by the Society of Basic Urological Research (SBUR) and Society of Urologic Oncology (SUO).  It’s hard to ignore the clinical data though, with so much activity in going on in advanced prostate cancer!

While at the oral and poster sessions, I enjoyed informal chats with urologists and researchers. Many of the urologists I spoke to at AUA were very excited about enzalutamide, certainly much more enthusiastic than in the last two years when we saw the arrival of sipuleucel-T (Provenge) and abiraterone (Zytiga) in the pre- and post- chemo settings respectively. The reasons for this were varied, depending on the respondents, ranging from understanding the mechanism of action (MOA) clearly to ease of logistics to lack of concomitant steroid therapy. The fact that the initial overall survival of 4.8 months for enzalutamide in the post-chemo setting, which hints at a more potent and effective therapy, probably helped as well.

With that in mind, I spoke with Dr Neal Shore, one of the AFFIRM trialists about his perspective of the impact of enzalutamide on his patients.  Firstly, we discussed the expectations for patients who have received chemotherapy:

“Patients who typically have completed a course of docetaxel have historically a 6-12 month life expectancy depending upon… on how symptomatic or asymptomatic they are.”

Secondly, what was the impact of treatment with enzalutamide?

“In the treatment arm, those who received enzalatumide, they lived at the median 4.8 months longer than patients who received the control placebo.

So in fact their survival extended beyond 18 months. I told you that normally this patient population has a 6-12 month survival expectancy range, that to me is dramatic.

It’s a dramatic life prolongation effect.”

Emphasis mine.

One of the things that makes enzalutamide exciting for me is the ability to target splice variants. This may explain why the agent has slightly better efficacy in the post chemo setting than abiraterone, which demonstrated a 3.9 month overall survival advantage over placebo when it was initially approved. This figure has since improved to 4.7 months with more mature data, suggesting that the initial 4.8 months improvement we see with enzalutamide may also potentially improve further with time.

Previously, I discussed the splice variants with Dr David Hung, the Medivation CEO:

Dr David Hung on Splice Variants:

Another area where we may see changes in mCRPC is sequencing, combinations and different trial designs. While it seems logical that good old fashioned sequencing, as with ADTs in earlier disease, will prolong time to disease progression by managing PSA levels, it should be noted that I don’t think any of those agents have actually shown a significant improvement in overall survival in patients. Unlike oncology, urology tends to have looser endpoints and this is something that we may well see changes in going forward as more rigour is applied in the clinical trial setting.

Combination therapy is something that I think we will also see more of in the future if we are to see real shifts in meaningful outcomes. As Charles Sawyers noted in a previous interview, shutting down the AR pathway more comprehensively with dual inhibition and ‘big guns’ makes solid scientific sense. This doesn’t just mean the obvious though, such as determining whether dual upstream and downstream AR inhibition with enzalutamide plus abiraterone versus either alone would work, but also targeting cross-talk and adaptive resistance pathways such as AR inhibition plus a PI3K inhibitor. Some of these trials are already underway, at least in phase II to see what the safety and efficacy signals looks like.

The arrival of multiple new therapies that change the standard of care also means that once the current crop of new drugs have been approved (abiraterone, enzalutamide and alpharadin) it becomes more difficult to conduct placebo controlled trials with OS any more, as Dr Shore astutely observed:

Dr Shore’s point about surrogate markers of survival in advanced cancer is a highly relevant one given the increasing level of competition in this tumour type.

In the pre-chemotherapy setting, both abiraterone (302 trial) and enzalatumide (PREVAIL) appear to have progression-free survival (PFS) and OS as co-primary endpoints. It will be interesting to see how the FDA react if only PFS is significant while OS is not, as many commentators suspect from the rather vague and woolly press release that J&J put out for abiraterone.  I don’t know what was agreed beforehand with the FDA regarding the study design, but I can see an interesting and highly charged ODAC ahead here as well as much speculation prior to the ASCO presentation of the data in the prostate cancer oral session next month.

OS is a clear, but challenging measure because ultimately, as Dr Shore noted, the endpoint is death.  Remember, recent breast cancer trials discussed here on PSB achieved a significant OS of 6 months or more, precisely because crossover wasn’t allowed. These trials had an active arm as a comparator, not placebo, though. We don’t yet know if patients in the placebo arm who relapsed were allowed to crossover to abiraterone early (ie before the IDMC recommendation). If they did, then OS was doomed from the start and the trial design itself was flawed, but we will have to wait for the presentation to see before jumping to conclusions.

I really hope that’s not the case here, because once crossover does occur, it is very hard statistically, to sort out a true survival signal. If the placebo patients didn’t crossover before the IDMC recommended study stoppage, then it’s hard to see why OS wasn’t met (if truly the case) unless the patients had long term compliance and adherence problems as a result of the concomitant steroid therapy. I do find it hard to believe, however, that an IDMC would stop a trial early if a primary registration endpoint was not met, for that would be akin to regulatory hari-kiri!

Overall survival has long been the standard of care in advanced prostate cancer and several drugs have either received approval or will receive approval as a result of meeting that high hurdle. Future entrants will find it very hard to ethically justify using placebo in the comparator arm and will likely need to be compared to sipuleucel-T, docetaxel, cabazitaxel or abiraterone as the currently approved new standards of care and potentially other options will be considered that are seeking approval such alpharadin and enzalutamide in the near future.

This improvement in care raises the bar for companies considering advanced prostate cancer in several ways:

  • Increased costs (active comparator arm, prolongation of treatment)
  • Increased time to market (OS takes longer than PFS)

In the end, though, for men with prostate cancer it’s largely all good news as new therapies that clearly prolong life become available and make a difference to their lives, not just in terms of more time with their families, but also in terms of improved quality of life and symptom management.

7 Responses to “Update on advanced prostate cancer including enzalutamide (MDV3100) and abiraterone”

  1. Phys1

    What does she mean by urology has looser endpoints than oncology?These zytiga and mdvn studies were carried out by oncologists al la scer, shore etc..
     
    What does she mean by they (these new uro drugs)  dont affect overall survival–they do.  what does she think improvement of median survial means? For provenge, what does the 3 year survival show?

    • maverickny

      Hi Phys1,

      To answer your questions…

      1) by looser endpoints in urology I’m referring to the tons of weak, small (low n number) clinical trials largely run as post marketing studies by companies that get discussed at urology meetings in things like overactive bladder, ADT etc – I’ve sat through far too many of them and have despaired at the lack of scientific rigour.  To be clear I’m NOT referring to studies on chemotherapy, abiraterone, enzalutamide or sipuleucel-T in CRPC, all of which have been mostly oncology driven.  Urology is a broad church and advanced prostate cancer isn’t the only disease they treat.

      2) The comment on the lack of overall survival benefit refers to the many early -lutamide studies given as ADT in early prostate cancer – as far as I can tell from Pubmed, none of them has shown significant OS in a large scale RCT in phase 3 study.  Hence the many weak ‘puff’ studies that have sadly proliferated.The point of those comments is that these new generation therapies have now demonstrated a significant OS advantage in advanced castrate resistant disease so moving them up earlier in the continuum (in the ADT setting vs bicalutamide, for example) is potentially going to affect the ADT therapies in the future, especially since they have both an antagonist and agonist (stimulatory) effect, whereas enzalutamide does not.  

  2. Marie

    I think there is a completely logical explanation for why PFS was statistically significant for Zytiga in the pre-chemo setting when the trial was halted early, but OS was not….
    The trial, n=1000, was originally estimated to read out final results in Feb 2014*. Progression occurs within 2-3 months, whereas OS for this group will probably be 27-30 months for placebo, and even longer for Zytiga. Because hundreds of patients will have progressed, yet are still alive, there will be hundreds more datapoints for progression than for OS. Thus it would be anticipated that progression would show statistical significance before OS would, due to the much larger n. If the trial was continued until half the patients in both arms had died**, OS would very probably show statistical significance too, but the IDMC halted the trial because the PFS benefit was so impressive that it would be unethical not to offer Zytiga to placebo-arm patients based on the PFS benefit alone.
    * http://clinicaltrials.gov/ct2/show/NCT00887198 
    ** it’s a little more complicated than this, as drop-outs must be accounted for.

    • maverickny

      Hi Marie, completely agree the trial was stopped early at the interim analysis and if hugely different it would make it ethically difficult to continue with placebo.

      That said, in an ideal world the trial should have continued for longer (ie death) as that is the crude measurement of OS, blunt though it seems, because once you stop early and crossover it makes it impossible to obtain it later with any degree of certainty.  The issue we have seen in other tumour types with PFS is that a significant finding does not always translate to a significant OS later.
      The challenge going forward is will the FDA accept the data with only PFS and no OS, since that is the definitive standard in CRPC?  What happens if the FDA insists on attainment of both PFS and OS since they were co-endpoints but the company took the IDMC’s advice to switch the placebo arm?  This area is fraught with all sorts of conflicting issues in the medico-legal-regulatory environment that need to be addressed.Approving one drug on the basis of PFS opens a whole can of worms for future entrants and also makes it difficult to compare data based on different endpoints.  The ODAC and FDA response for abiraterone in the pre-chemo setting is likely going to be one of the most watched oncology events in a while.

  3. biobetter

    I wonder if part of the unusually long Affirm OS is due in part to Zytiga.  20.9% of the MDV3100 arm went on to use Zytiga and 24.4% of placebo ended up on Zytiga. If so then that and the adverse effects of long term steroidal use may add support for the use of Zytiga after MDV3100. Sally I’m curious if you heard any talk of specific combo treatments. I’d like to see a PTEN drug or a Cabo combo with MDV3100. It would be an interesting article if you could get Uros/Oncs to say what drugs they want to pursue in a combo and the reasoning behind that particular pairing? 4.8 months is a nice jump but still far too short. Nice article- Mike

    • maverickny

      Thanks, Mike.

      Yup, I certainly did wonder about the abiraterone impact after enzalatumide, but rather than speculate I thought it would be better to take a broad snapshot now, and then do a more in-depth update at ASCO next week after seeing the data and getting a feel for medical oncologists’ reactions to the data.  The general urologist reaction I heard at AUA (not Dr Shore’s I hasten to add, as he was very thoughtful and circumspect) tended to be (paraphrasing) ‘Ooh, a new hormone therapy I can use instead of ketoconazole, an abiraterone-without-steroids before I have to refer the patient to the oncologist’  Oncologists might have a different reaction in the post-chemo setting, so I hope to get some more granular reactions after they’ve seen the full presentation.  4.8 is the interim OS number, and it is not a home run but hopefully that will get a little better with more mature data.  To improve it further, we will need to figure out the adaptive resistance pathways to therapy as well as other drivers such as mutations that might be driving oncogenic activity.

      With regards to sequencing, it may well come down to personal choice, as RCC did initially, with some doctors in the sunitinib camp and others preferring sorafenib, at least until the OS data came out or perhaps one over the other as the urologists were clearly hinting at, since steroids was a definite disadvantage to them.  That said, I can see either enzalatamide or abiraterone being preferred after docetaxel and before cabazitaxel, rather than cabazitaxel first.

      Other combos is a hot topic that was much discussed at AACR with lots of interesting early basic research being done to look at logical combinations, including PTEN in early solid tumour trials to shutdown the AR and other pathways in concert.  There’s enough on that topic for another whole post when I have more time – remind me after ASCO to sum up the AACR data in the combinations :-)

  4. jessiedean478

    I do not work in the field of the medicine, but am extremely interested in the information and updates you are posting on here, and can not be more than happy to hear that researches are being made in finding ways the terrible prostate cancer to be treated more successfully!
    Houses

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