Drug sequencing and combination therapy with newer prostate cancer therapies

There is an interesting report on the OncLive web site of a lecture by Dr. Robert Dreicer given just a few weeks ago and dealing with the sequential and combination use of new agents like abiraterone acetate, enzalutamide and others for the treatment of advanced and progressive forms of prostate cancer.

Dr. Dreicer’s presentation, given at the 6th Annual Interdisciplinary Prostate Cancer Congress in New York on March 16, made a number of interesting key points:

  • There are data from case reports showing that, in some cases, men with metastatic castration-resistant prostate cancer (mCRPC) who respond well to enzalutamide and then relapse can respond extremely well to salvage treatment with sipuleucel-T.
  • There are data suggesting a benefit from the combination of next-generation androgen receptor antagonists, such as enzalutamide, and testosterone-suppressing lyase inhibitors, such as abiraterone.
  • Both enzalutamide and abiraterone appear to delay time to first skeletal-related events in patients with mCRPC. So, do patents on these drugs really need to also be taking osteoclast inhibitors like denosumab or zoledronic acid?
  • Can we give radium-223 in combination with drugs like abiraterone and enzalutamide to treat men with mCRPC?
  • Given the activity and the mechanisms of action of these new agents, will the FDA be willing to consider clinical trial endpoints other than just overall survival?
  • Might it be possible, by confirming additive or synergistic activity between enzalutamide and abiraterone and using them early in the adjuvant setting — in high-risk, locally advanced patients — to “cure some patients that we didn’t cure before”?

The potential to better treat high-risk patients early and to further delay the progression of prostate cancer in many men with advanced forms of the disease hasn’t looked this promising in almost 50 years.

14 Responses


    I’m responding to Sitemaster’s second to last bullet, which in my view raises a critical point about the FDA’s prostate cancer treatment approval process, especially regarding drugs. Here’s my bottom line: it is imperative that we have trials that can reach their endpoints more rapidly, and probably also more flexibly.

    The FDA’s “problem” is that we prostate cancer patients, especially those of us diagnosed and treated in the US, now enjoy extraordinarily high rates of survival coupled with extraordinarily long periods of survival for the vast majority of that thankfully small proportion of us who ultimately succumb to prostate cancer. That’s a nice problem to have of course, but it is a huge complication for arranging and executing the kinds of clinical trials the FDA has traditionally depended on for approval of cancer drugs and other treatments.

    The FDA, for some sound reasons, strongly prefers overall survival as the primary scoring criterion, with quality of life also having persuasive credibility if the success pattern is strong. (Overall survival captures both disease-specific survival, the key point of interest to most of us, but also captures the impact of adverse side effects that might offset or even override advantages in disease specific survival.) In short, most trials depend on achieving a certain proportion of deaths in the randomized arms of the trials before conclusive analysis can be performed and success determined.

    Since so many prostate cancer patients do not succumb to the disease, clinical trialists focus on patients with a higher likelihood of dying, including those judged “high-risk” (by criteria like the D’Amico or NCCN criteria) like me, or especially men with well-advanced disease such as metastatic, castration-resistant prostate cancer. Dr. Dreicer’s report highlights developments that undermine the research effectiveness of trial patient populations that are in the latter, ideal category. As Sitemaster’s article noted, Dr. Dreicer’s report indicates that, at least in one case, Provenge had a standout impact after recurrence following Xtandi, suggesting synergistic potential, and it indicates that combination therapy with the new drugs abiraterone and enzalutamide appears promising, all in patients with mCRPC. These new treatment strategies could quite conceivably add several years of survival, or even more.

    Assuming these developments pan out (which seems likely to me, especially for the abiraterone/enzalutamide combo that resembles the “combined” part of androgen deprivation therapy using LHRH agonists or antagonist plus an antiandrogen that has worked so well for many earlier stage patients), deaths in trials would not accumulate as fast, and death totals would likely be lower until the effects of aging and co-morbidity ultimately had their way. For drug development companies, this means not only added trial expense for trials that are already enormously costly, but more market vulnerability to competitive treatments that are also emerging. (Think Provenge [sipuleucel-T], with it’s billion dollar investment just through the FDA approval date, with GVAX breathing down its neck, as well as some others, to say nothing of competitive strategies beyond the immune system such as Zytiga, Xtandi, etc.) The added research burden posed by the emerging environment of even longer survival and many now approved and emerging new treatments, assessment techniques and concepts could prove a show-stopper to some potential new drugs.

    Moreover, Dr. Dreicer focuses on the need for trials with combinations of drugs in contrast to single agents. Obviously, that complicates trial arrangements and execution. Furthermore, there is a synergy unfavorable to research with long-term trials for such combinations, as somewhat rigid trial protocol requirements are likely to be vulnerable to attractive new treatment and assessment technologies that emerge during the course of the long trials. For instance, for mCRPC patients who have been in existing trials for years for earlier investigational drugs, trial interpretation is going to be complicated as portions of those patients who recur after the trial treatments will be employing some of the advanced treatments (Provenge, Zytiga, Extandi, Yervoy), decision making tools (such as imaging), and concepts (such as potentially curable oligometastatic disease) that did not exist when the trials were launched. Use of those new resources – use which is clearly in the patient’s interest however much a problem for the researchers – certainly has the potential to somewhat confound the findings from the trials: were beneficial effects due to the treatment being tested, or were substantial portions of beneficial effects due to the new agents?

    Dr. Dreicer also made the key point that many of the new drugs are likely to work well “through the spectrum of disease,” meaning at earlier stages. That’s where I’ve been throughout the past 13 1/3 years despite being diagnosed with very high-risk disease, and it is crystal clear to me that overall survival, indeed even prostate specific survival, is not a criterion of much value in assessing the usefulness of agents and combinations for men at earlier stages, particularly those who are still responsive to ADT and not metastatic.

    I am convinced we need to move beyond overall survival and quality of life as the almost exclusive criteria for judging trial success. Fortunately, some emerging developments in bone and lymph node imaging (Na18F PET/CT scans for bone and [11C]choline and [11C]acetate PET/CT scans and feraheme USPIO 3-T MRI for lymph nodes) appear to have potential to at least partially fill this need, and, at least for earlier stage disease, PSA may be a satisfactory criterion. To reiterate, it is imperative that we have trials that can reach their endpoints more rapidly, and probably also more flexibly.


    The third bullet features the welcome news that the new drugs appear to delay the time to a first skeletal-related event (for example, a bone fracture) in men with mCRPC.

    However, I hope researchers will use quantitative CT scans to assess whether bone density is being preserved while on these drugs, rather than depending on trials that wait for bone fractures.

    I suspect that many researchers and doctors treating mCRPC patients still do not realize that bone density needs to be assessed and monitored, and that both the bisphosphonate class of drugs and denosumab have shown effectiveness in enhancing, protecting, or at least reducing the rate of loss of bone density.

    It is encouraging that abiraterone and enzalutamide may offer a way around the issue of bone density decrease for men on androgen deprivation therapy, but I see this as a matter of, to use an analogy, perfecting the wheel rather than re-inventing it.

    (Use of DEXA scans, Fosamax, and later Boniva appeared to have restored my bone density to a normal level, from osteopenia [with some osteoporosis] within a year of starting ADT, but a scan showing some osteoarthritis last year has thrown that success into question, with the arthritis possibly masking a lower level of bone density. I’m now on Vivelle transdermal estrogen patches to protect bone density, and I’ll probably switch to a quantitative CT scan rather than a DEXA for a better read on how I’m doing at the fourteenth year point.)

  3. Jim:

    It is easy to define potential endpoints for trials. What is a great deal harder is to demonstrate that these endpoints are actually clinically meaningful. That is where the breakdown comes. This topic has been endlessly debated. At present there are no demonstrably valuable surrogate endpoints associated with the relatively early treatment of prostate cancer.

  4. The Swedish government’s drug enforcers refuse to pay for certain uses of abiraterone acetate, aka Zytiga, for some men. The document states explicitly that it is not to be given to men of age X (I forget which, but at most 70) or over, because the costs outweigh the benefits to the patient, since the patient at that age is unable to return to work (i.e., he is economically useless and in fact a burden). If the article I read is correct and still relevant, this is being fought now, on grounds of age discrimination. Same thing in the Netherlands, but with less obviously offensive “justification.” I give up, especially since I got osteoporosis from ADT, without any warning at the very start of the treatment, as is recommended in the oncological papers I have seen. This got me so annoyed that I went over the head of the oncologists and complained to one of the two head doctors and another doctor who thinks like me. Thanks to this, urologists — not oncologists — have been instructed to give warnings at the start.

  5. A clinical trial using abiraterone and ipilumumab is about to kick off at UCSF; the principal investigator is Larry Fong, and a buddy of mine has been enrolled. He has previously received sipuleucel-T, and has just failed nilutamide.

    Watch this space!

  6. A similar (the same?) trial is already in place at three other centers, including Memorial Sloan-Kettering in New York. Click here for details.


    Hi Sitemaster, I’m responding to your response of 4/18 at 11:36 am to my post of 4/18 10:47 am regarding this issue.

    I have great respect for your view and perspective, but I have become convinced that the FDA needs to choose another way to score success in trials for relatively early treatment. This issue extends beyond prostate cancer, though we clearly are in the vanguard because of our long survival for most patients, even a clear majority of those with high-risk and advanced cases. As survival extends for other cancers, such as breast cancer, they too will face this research issue.

    It is simply impractical at this point for researching drugs for early treatment to use the traditional endpoints of overall survival and quality of life, leaving us with no way at present of convincingly scoring success. I believe we need to choose the alternatives that seem best and move out with them until proved wrong. Essentially, that is what happens informally now as oncologists try different things and choose those that seem to work in their individual practices. Unfortunately, with a few exceptions, that approach leaves the community with little evidence to work with.

    Perhaps the key phrase is “clinically meaningful”. Rather than signifying just death or substantial quality of life improvement, that phrase really covers or should cover other indicators. I believe that PSA, coupled with PSA kinetics, should be groomed as the leading indicator. That grooming would include confirmation as a seemingly valid surrogate with the bone and lymph node imaging technology that has recently become available.

  8. Dear Jim:

    The FDA has held multiple meetings about this. They would love someone to come up with a meaningful endpoint. To date, no one has succeeded. The problem is the disorder. For many other forms of cancer there is often a correlation between various types of progression-free survival and overall survival. It just isn’t the case for prostate cancer (to date).

  9. I think the UCSF trial may be separate, Mike. I spoke to Jedd Wolchok at the DC conference last September and he mentioned that Larry Fong was PI for a new trial coming up shortly. It so happens that Fong is also my buddy’s medical oncologist, and that trial is now enrolling.

  10. Hmmm … Odd … There’s no sign of this trial on ClinicalTrials.gov (that I can find). Dr. Peng had better get it up there or he won’t be able to publish the results in any reputable journal!

  11. K … I’ll make sure he does that ;-) … although it may help if you looked under Fong rather than Peng!!

  12. Oooopps … but actually I was looking under abiraterone and ipilimumab!



    Hi Sitemaster and fellow participants. This relates to Sitemaster’s post of 4/20 at 6:43 pm.

    I have been interested in “Ipi” since hearing Dr. Eugene Kwon (Mayo, Rochester) speak about it enthusiastically at the 2010 IMPaCT conference in March 2011 in Orlando. He described at as a potent immune system agent with activity against prostate cancer, but an agent so potent that it needed taming and careful use to avoid threats to the patient while the immune system was compromised. I’m excited to see that it’s being looked at already in combination with abiraterone.

    I’ve looked over the trial info, and I noted some interesting trial choices, not all of which make me happy. For one thing, while all the patients are intended to have castrate-resistant prostate cancer, the criterion for CRPC is a serum testosterone level of 50 ng/dl. While that is a typical research choice, none of the leading oncologists I consider experts in ADT believe that threshold is a valid indicator of resistance. Before deeming the patient castration resistant, they want to see the PSA rising at a threshold of 20 or lower, with concomitant very low DHT, and if testosterone or DHT is higher, they generally deem the ADT regimen inadequate and make adjustments, typically to the drugs used and timing (for example, LHRH agonists with a shorter than normal dosing schedule, or a higher dose of the antiandrogen).

    Inclusion criteria include ongoing ADT with a “GnRH analogue,” or bilateral orchiectomy, but no antiandrogen is permitted within 4 weeks and no concomitant antiandrogen use is allowed. To me, that is unfortunate as I am convinced that combined blockade, if not triple blockade that also includes a 5-ARI, is a superior regimen for many of us. At the least, with this choice to exclude an antiandrogen, DHT at a very low level should be an inclusion criterion. One of the medical oncologists I follow closely wants DHT to be 5 or below. I believe this trial will be enrolling some men who are in fact still responsive to the kind of ADT indicated but who will no longer be able to take advantage of that responsiveness during the period of the trial.

    I’m curious why enzalutamide (Xtandi) was not also excluded along with other antiandrogens. Xtandi is likely even more potent, probably much more potent, and it does not make sense to me that a patient on Xtandi would be allowed in this trial in view of the other exclusions. (However, as I said in the previous paragraph, I would like to have seen the potential of all the antiandrogens exhausted.) If patients on Xtandi are included, will not that compromise the ability of the researchers to draw conclusions regarding the role of antiandrogens in this trial setting? Similarly, how could findings about effectiveness, or even safety, be determined to be independent of Xtandi? I see potential for confounding, especially in view of the high interest in Xtandi at present and ethical imperatives to not harm patients, such as by depriving them of a promising therapy opportunity.

    I’m curious why the definition of lymph node metastasis in the inclusion criteria is so high: >= 2 cm if that is the only indicator of metastases. With emerging scans — [11C]choline PET/CT, [11C]acetate PET/CT, and feraheme USPIO 3T MRI — it appears that lymph node metastases as small as 2 mm, or even maybe 1 mm, can be reliably detected. I suspect the research choice was made because such technology is not practical due to its very limited geographic availability at present, as well as investigational status, especially for feraheme.

    In the exclusion criteria, the use of denosumab for bone metastases is permitted. I’m thinking that the use of zoledronic acid should also be addressed, ruling it either in or out. Also, since these patients will all be on a GnRH analog during the trial, as I understand it they should be getting some kind of bone density protection. If not denosumab or zoledronic acid, the choices would include the bisphosphonates and transdermal estrodiol (also with appropriate calcium and vitamin D3 supplementation and blood level monitoring, perhaps also with quantitative CT bone density scans). It seems this aspect should be addressed in the protocol.

    All this said, I expect we have a good shot at getting some very interesting information from this trial.

  14. Dear Jim:

    The information available on the ClinicalTrials.gov web site is only a summary of the trial protocol. Some of the issues you discuss above may well be addressed in the full trial protocol. However, many of the issues you address have never been formally proven in randomized trials and so are (“merely”) the opinions of a subset of medical oncologists as opposed to being accepted medical practice.

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