As we all look forward to another prostate cancer awareness month, I find myself reeling with the advances the field has seen in the past year, particularly in the area of hormone sensitive metastatic prostate cancer. We learned that men may live longer if we can radiate the primary tumor if they have low volume metastatic disease. We also learned that enzalutamide and apalutamide prolong survival in mHSPC when combined with ADT as compared with ADT alone. Finally, we found that combining concurrent chemotherapy and enzalutamide with ADT may not add benefit in terms of survival, but does seem to increase toxicity. With all of these advances (and many others!), a good friend asked the other day, “Can we really go wrong?”The implication was that we could stop talking so much about systemic treatment for mHSPC because there are so many ways to do the right thing that we cannot go wrong. My response: Despite these advances, we can definitely still go wrong if we fall into a few simple traps. In this blog I will review each trap to ensure that we avoid these mistakes and treat each man with mHSPC to the best of our abilities, neither over or undertreating anyone, and incorporating men in treatment decisions along the way.

1. Undertreatment: Although we like to think that the findings from recent clinical trials has worked its way into every workflow in urology and medical oncology clinics, undertreatment still happens. Even in the most cutting edge practices, we can make this mistake. We make the mistake of undertreatment when we fail to talk about radiation to the primary tumor with men with low volume mHSPC, or fail to talk about clinical trials that are investigating this question for men with mHSPC more generally. There are many strong feelings around this treatment option, and some clinicians do not agree with the survival data presented in the subgroup analyses from STAMPEDE. However, we owe it to our patients to share the data and include them in the decision, as they may review the same information and disagree. With a mild side effect profile, they may think that radiation of the primary is at least worth a try, even if the data may be flawed.    

In a different scenario, we can also make the mistake of undertreatment when we don’t consider or talk about chemotherapy as an option for men with high volume mHSPC (per the CHAARTED definition). Abiraterone, enzalutaide, and apalutamide are all good options for combination treatment in this setting, but the patient in front of you may actually prefer to get chemotherapy out of the way now when he can do only 6 cycles rather than 10. He may also have lower financial toxicity with this approach, though if he loses time at work due to hospitalization or restrictions due to chemotherapy, he may not. It is up to us to talk with men and give each of them the choice. 

2. Overtreatment: I am the first to acknowledge that I am guilty of saying that combination therapy is the new standard of care for men with mHSPC. Given the compelling data of improved survival with androgen receptor directed therapy or chemotherapy plus ADT, why would anyone want treatment with ADT alone? Although I don’t talk about it often, for some men, ADT alone may actually be the best approach. The decision to avoid chemotherapy in frail patients is relatively easy, but why avoid AR directed therapies? Although they may be relatively rare in some practices, men with a limited life expectancy (<3 years) due to competing comorbid illness, and men with severe dementia may be overtreated if given combination therapy. Discussing this with patients and their families will likely take longer than if one simply prescribes abiraterone, but it is an important part of properly counseling patients who are more likely to suffer the consequences of progression of another illness than reap benefit from combination therapy. Importantly, our treatments could potentially harm men in these situations. Combination therapy could harm men who experience financial distress from a treatment that will not benefit them. It could also harm men who forget to take prednisone with their abiraterone, or who overdose on oral medications because they are not properly keeping track of medication use due to dementia. Not prescribing combination therapy is difficult to talk about, but it is our duty to discuss these hard choices, including not providing an extra medication if we truly do not believe the patient will live long enough to benefit.

We also make the mistake of overtreatment if we routinely combine chemotherapy with an AR directed therapy in addition to ADT (triple therapy). Fewer than 20% of patients in STAMPEDE and TITAN received combination docetaxel with abiraterone (STAMPEDE) or apalutamide (TITAN). When more patients received the combination of concurrent docetaxel and enzalutamide (~50% of patients) in ENZAMET, there was no apparent benefit to the addition of enzalutamide in the subgroup analysis of men receiving docetaxel. It is possible that with longer follow up a benefit will become apparent. It is also possible that the benefit of first line therapy, whether AR directed therapy or chemotherapy, is maximized with the addition of one systemic therapy to ADT. Perhaps there are subgroups of patients who may benefit more from one approach or the other. However, until that information is available, we can see clearly that the side effects of chemotherapy are compounded with triple therapy. PEACE-1 and ARASENS will help answer this triple therapy combination question. Until we have a compelling reason to use all three approaches in combination, we should avoid it. 

3. Not including the patient in the decision: This is a message that I will continue to share, especially because men will likely soon have at least four options for systemic treatment in combination with ADT for mHSPC. Each treatment has its own toxicities, co-pay, schedule, and optimal patient population. There will always be patient-specific preferences around what makes one treatment better or worse for an individual. We as physicians tend to believe that we are asking patients about their preferences and using them in decisions, but research suggests that we choose the treatments we are most experienced with using, and we project our preferences on patients assuming they will be similar to our own. None of this is done maliciously but is the nature of busy physician practices. As the list of options grows, I challenge each of us, including myself, to ask men what they want, review similarities and differences between medications, and help each man make the best choice for him. His buy-in will be enhanced, he may be more adherent to treatment, and he may have a better quality of life simply because he was part of the decision-making process.

4. Not considering a clinical trial: Finally, we make a mistake if we don’t encourage men to participate in clinical trials at some point along their prostate cancer journey. These can be trials of new medications, follow up studies to assess side effect profiles, or biomarker studies that seek to understand which patients will respond to treatment, and which will progress. Trials can be difficult as each center has access only to the trials locally, and they tend to require time and additional clinical support. However, studies like the IRONMAN registry and Count Me In are registry trials in which patients can participate remotely. Encourage men to do these and other studies. Encourage them to add their voices and experiences to quality of life studies, to add their DNA to genomic trials of disease risk and response, and to gain access to novel therapies in therapeutic clinical trials. Support them in their efforts, and congratulate them on giving back to the community of men with this disease. It is only with participation that we will understand this disease better, and eventually make it history.

Written by: Alicia Morgans, MD, MPH, Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois

Further Related Content:  A Million Faces: What Prostate Cancer Awareness Means to Me