Crashing into progress: New findings meet old habits

In the last few weeks I have talked with numerous colleagues about the findings from LATITUDE and STAMPEDE presented recently at the ASCO Annual Meeting and published in the New England Journal of Medicine in June 2017.  We find ourselves in the process of integrating the findings into a treatment landscape that is still grappling with the findings of CHAARTED, data demonstrating a survival benefit from the use of chemohormonal therapy in a similar high risk population of men with metastatic hormone sensitive prostate cancer (mHSPC) first presented only a few years ago. 

For some of us it seems as if the CHAARTED “practice changing” data is still finding its footing in clinical care, with some urologists only recently feeling comfortable sending these mHSPC patients to medical oncologists for chemotherapy.  How will the data demonstrating that abiraterone prolongs life in the mHSPC population affect the practice environment in which we work? Will it affect medical oncologists and urologists similarly?  What about patients who are currently on, or who have recently completed, the CHAARTED chemotherapy protocol?  What do we make of the lower dose of prednisone used in the studies, particularly in light of the prolonged duration of exposure to therapy in men with mHSPC rather than the mCRPC population?  The answers to these and other questions these studies raise are fraught with individual, group, and local practice patterns, as well as restrictions by payers, and the beliefs and preferences of patients and loved ones. In this blog entry, I will address a few of the most pressing issues this data raises in my practice, and how we can rationally use the data to best improve outcomes for our patients. 

One of the first issues I considered when reviewing this data was whether or not the patients that benefit from docetaxel and abiraterone are the same, or whether the different therapeutic approaches affect different mechanisms of prostate cancer cell growth and resistance and therefore different populations.  The treatments may benefit a range of men with mHSPC, with some overlap in the populations benefiting from the two therapies, and some men benefitting from one treatment or the other, but not both. Because the inclusion criteria of STAMPEDE and LATITUDE were similar to CHAARTED (though not identical), the patients generally are similar clinically, but molecularly the men that responded in the separate studies may be very different. Efforts to demonstrate the molecular differences between responders to one approach to treatment or another are currently underway in the mHSPC population, and have been completed in populations exposed to other treatments.  Recent work by Zhao and colleagues suggests that prostate cancers may be classified into luminal A, luminal B, or basal cell subtypes at the time of prostatectomy by the PAM50 molecular classifier.  Luminal B patients appear to respond to treatment with ADT, while non-luminal B patients do not appear to reap the same benefit from treatment. Similar data in the mHSPC setting, using PAM50 or a separate molecular classifier, will be invaluable for identifying those men who will benefit from treatment with chemohormonal therapy or abiraterone, and for prognosticating outcomes in this molecularly heterogeneous but clinically similar group of patients.   

This brings us to a second question that arises from the LATITUDE and STAMPEDE data:  if we presume that there may be some populations that benefit from both docetaxel and abiraterone, while others benefit from one or the other exclusively, should we consider giving both treatments to all patients with a performance status suitable for chemotherapy, or should we avoid the side effects of chemotherapy in patients who will not benefit and simply give everyone abiraterone only? Since we cannot identify which patients fall into which category, this could be a complicated question to answer. From my perspective, the answer seems somewhat straightforward.  Until we demonstrate that one group of patients benefits from one approach but not the other, I will offer all interested patients with an acceptable performance status treatment with docetaxel, followed by treatment with abiraterone.  Part of this stems from my unwillingness to withhold a potentially beneficial treatment from anyone based on my assumptions that a patient would not be interested in chemotherapy.  It is clear that oncologists, and doctors in general, are not able to accurately predict patient preferences for particular side effects or treatments, nor are we able to correctly interpret patient understanding of the expected outcomes of treatment.  I believe it is important to at least present the options for both treatments to patients to allow them to think through their choices and help direct their care plan. The other reason I err on the side of offering more treatment to men in this patient population is that the survival benefit for each of these therapies is significant, and not something I can currently expect to match in the mCRPC setting.  If we can alter the disease trajectory more profoundly in a more limited metastatic setting, we should.  Thus offering docetaxel x 6 cycles to all men who are fit, followed by abiraterone per the LATITUDE and STAMPEDE regimens, is the way I have been approaching this conundrum in recent weeks.

In addition to these issues, I have been asked several other practical questions regarding the day-to-day administration of abiraterone in the mHSPC setting.  First, I have been asked whether the benefit of abiraterone in LATITUDE and STAMPEDE is related to abiraterone specifically, or whether the benefit may be similar for any of the androgen receptor directed therapies, including enzalutaimde, darolutamide, apalutamide, or others.  Although I am not certain which drug will ultimately be superior, it seems likely that there may be benefit to use of any of these in mHSPC patient population.  In the last few weeks since the data has been presented, our clinic has been successfully able to obtain abiraterone/prednisone for these patients without difficulty, as long as we cite the NEJM data suggesting a profound survival benefit.  However, this may not always the case, as different health plans may have varied restrictions on providing the drug in this setting.  If I was unable to obtain coverage for abiraterone, I would consider use of enzalutamide if that was easier to obtain for my patient.  Fortunately this should be less of an issue as abiraterone becomes a generic medication.  

I have also been asked whether I am starting all patients in the mHSPC setting on prednisone 5 mg PO BID, or whether I am now using prednisone 5 mg PO daily in this population given the LATITUDE data suggesting that it is generally well tolerated with an acceptable level of expected toxicity.  At present I continue to recommend prednisone 5 mg PO BID per the FDA approved label, but I do have a low tolerance to switch to prednisone 5 mg PO daily in patients experiencing toxicities related to steroids.   Toxicities that I consider most important in this decision include insomnia/sleep disturbance, weight gain, insulin insensitivity, and steroid-induced mood or personality changes.

Finally, I have been asked how long patients should undergo treatment with abiraterone and prednisone in the mHSPC setting.  In the mCRPC population, this is typically a relatively limited duration of time.  However, in the mHSPC population, the median time to discontinuation of treatment was closer to 3 years.  As a specialist in the complications of treatment, I would prefer not to have patients on steroids indefinitely, particularly if the patient has other complicated medical issues.  Work is ongoing to determine whether a more limited course of treatment with abiraterone may be sufficient, but this data is not yet available.  

Advances in treatment that improve patient outcomes are thrilling, and many of us are eager to bring new treatment options to our patients.  However, adoption of new therapeutic data is anything but immediate.  With the gradual integration of these data into medical oncology and urology practice in the upcoming years, I continue to wonder about how medical oncologists and urologists will use this data in their respective worlds.  Will treatment predominantly occur with urologists who feel comfortable with prednisone and abiraterone rather than in oncology clinics now that patients can achieve a survival benefit with an oral agent?  Will this new data in the mHSPC setting result in improved multidisciplinary coordination because of mounting evidence suggesting that treatment with more intense systemic therapy overall in the mHSPC setting may improve outcomes?  These questions will persist until future data guide our practice patterns more completely.  I am hopeful that the movement towards a multi-disciplinary approach to care in the mHSPC setting that was prompted by the CHAARTED data will continue.

Since I learned of them, I have been integrating the findings of LATITUDE and STAMPEDE into my clinical practice.  For men completing treatment with chemohormonal therapy per the CHAARTED protocol, I am offering treatment with abiraterone shortly after chemotherapy.  I believe that it is highly likely that the populations benefitting from docetaxel and abiraterone may benefit from both of these treatments, and feel strongly that all fit patients should be offered both options.  At present I am prescribing full dose prednisone (5 mg BID) unless patients experience side effects from steroid exposure, and I am then reducing the dose to 5 mg daily.  I encourage my colleagues in urology to consider multidisciplinary care for all of these patients to provide cohesive and complete cancer care.    

The LATITUDE and STAMPEDE data are practice-changing findings that deserve careful consideration and thoughtful integration into our existing treatment framework. In this way we can continue to push the boundaries of advanced prostate cancer care, integrating new findings with our old habits, and improving patient outcomes using a multi-disciplinary approach, one set of groundbreaking studies at a time.

Written by: Alicia Morgans, MD, MPH


Related Content: 

WATCH: A Clinical Conversation with Alicia Morgans and Charles Ryan: Considerations of ASCO 2017 LATITUDE and STAMPEDE

WATCH: Tom Keane's: ASCO 2017: Discussion of LATITUDE and STAMPEDE Trials

LATITUDE abstract from ASCO 2017

STAMPEDE abstract from ASCO 2017

STAMPEDE - Clinical Trial Information

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