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If a therapy in castrate-resistant prostate cancer (CRPC) shows an improvement in progression-free survival, but not overall survival, should that change practice? The topic is top of mind for us this month based on the results of the ACIS study presented at the ASCO GU 2021 Genitourinary Cancers Symposium by Dana Rathkopf of Memorial Sloan Kettering – and I’ll explore it here. To briefly recap, ACIS compared abiraterone to abiraterone plus apalutamide in men with chemotherapy naïve CRPC.

By all accounts outside of our world of prostate cancer, 2020 was a pretty bad year. That much has been decided and agreed upon by just about everyone in the world. With that said, 2020 was not a horrible year in the progress against prostate cancer. Several new developments arose and progressed in the past year that can give us hope and new options for patients. Along those lines, it can give us an optimistic look at 2021 as well, as the developments of 2020 are but a precursor to some of the moments that may await us in 2021.

I am grateful to UroToday for giving me the platform that this Center of Excellence allows. I have dedicated my career to the care of men with metastatic castration-resistant prostate cancer (mCRPC), the development of therapies to treat it, and (hopefully) thoughtful analysis of the biological, clinical, and even societal factors that characterizes it. A forum to generate and share ideas is a gift.  

"When does a radical prostatectomy save a life?" is a question that has been asked in the medical literature. Studies from Scandinavia1 reported long term outcomes of a randomized trial of immediate radical prostatectomy versus observation and deferred treatment. The study evaluated the outcome of overall survival (OS) and showed that OS curves remained superimposed until the timeframe of year 10-15, suggesting that the ‘saving a life’ prostatectomy was occurring around year 15.

The tumults of 2020 have put racial disparities front and center for the nation at large and health disparities are now viewed with increasing intensity, if not clarity. Prostate cancer patients and the treating community have struggled with the question of racial disparities in outcome for some time, and recent events bring this closer to the front of our dialog.

I was confronted with a decision in the clinic this week about whether or not to use radium-223 for a patient with metastatic castration-resistant prostate cancer (mCRPC). He was on the older side, mid to late 80’s and his performance status was declining rapidly. He had persisted for quite some time with relatively low volume disease, in fact, just pelvic lymph nodes. As those progressed, he developed urinary outlet obstruction (even though the nodes weren’t that big) with multiple urinary tract infections (UTI) and, during a several month period marked by brief hospitalizations, relatively rapid failure of next-generation androgen receptor (AR) antagonists, all amidst the COVID-19 (SARS-CoV-2) pandemic, metastatic disease in the bone blossomed in multiple sites, and it was associated with relatively mild pain.

Recently, those of us who treat prostate cancer have become comfortable with testing for Breast Cancer Gene 2 (BRCA2) and acting on the results. It’s now time we took a slightly deeper dive into this gene and how knowing more can help us counsel our patients better and design better clinical trials.

With two poly ADP ribose polymerase (PARP) inhibitors on the market, we expect to see many patients on these therapies in the coming years, most likely with great benefit for a substantial proportion of them, prolonging life and delaying or preventing further misery from this disease.

June 26, 2020, marked the 20th anniversary of the publication of the first working draft from the Human Genome Project. At a special White House event to commemorate the results of this 10-year public effort (it was really more like 50 years since the discovery of DNA, but I digress), then-President Bill Clinton called the project “the most wondrous map ever created by humankind”, and touted its promise to detect, prevent, and treat disease.  Obtaining that first sequence from one human cost about $2B and resulted from a massive global public/private partnership.

Another advance in hormonal approaches to controlling prostate cancer is available for our consideration. The results of the HERO trial demonstrate efficacy and safety advantages of oral relugolix when compared to standard of care leuprolide, given via intramuscular injection every three months. The results open up two areas for discussion: 1) is an oral ADT feasible, effective and necessary and 2) do LHRH antagonists confer cardiovascular and disease control benefits compared to LHRH agonists? It provides us with choice and a lot to ponder in terms of how this treatment may alter patient outcomes, practice patterns, and the future of our approaches to many stages of prostate cancer. 

In the summary slide of one of my 'go-to' talks I pose the question “Have we reached the limits of androgen receptor (AR) targeting?”. Of course, I don’t know the answer, which is precisely why it is framed in the form of a question on a summary slide. But I think about it a lot. So, let’s ponder this question a little.

As a medical oncologist, I may rely a little less than my radiation or urology colleagues on the Gleason score for prognosis and treatment decision making. Most of our decisions are based on the pace of disease and extent, and of course whether it is castration-resistant or castration sensitive. However,  I do look at it and in particular, it factors into the data ‘stew’ that one creates within an individual case and how we approach it.

Chemotherapy improves survival when given to patients prior to radical prostatectomy.

It is the latest, and potentially the last, piece of data in the decades-long march of this important and interesting (but much-maligned) therapy. Will this news change practice?

The clinical development of therapies targeting DNA repair pathways in prostate cancer is now well underway. It is a hopeful on-ramp for prostate cancer into the world of molecular oncology. We are beginning to see the emergence of consistent data and some surprises. There is a significant reason for hope, for example, that the poly ADP ribose polymerase (PARP) inhibitors will become a standard of care for patients with BRCA1 or BRCA2 alterations.

A highly practical and interesting study, CARD, was recently presented at ESMO and published in the NEJM. It’s a study that answers a lot of questions, creates a few others, and can be translated into the clinic relatively quickly.

The CARD study randomized patients with castration-resistant prostate cancer (CRPC) to either treatment with cabazitaxel  ( taxane chemotherapy) or a second ‘sequence’ of androgen receptor (AR) targeted therapy (ARTT) – enzalutamide in patients with prior abiraterone exposure, or vice versa.

Treating cancer is hard. Its even hard when you have years of experience and are considered an expert. 

Communication with patients is always a challenge, as is gathering all the information you need to make an informed decision. Then there’s the energy and time that are required to keep up with the clinical literature in your space, and the scientific/basic literature of it if you are so inclined. 
I continue to be surprised by the biology of prostate cancer, and how much guessing we are still doing. The good news is the number of tools in the tool chest is increasing. Also, even in situations where they don’t direct our actions, our ability to gain an understanding of the molecular underpinnings of the disease may inform our discussions with patients.
I recently followed a minor twitter based jousting match between various cancer treating specialists about how we present the goals of care to patients. The conversation went something like this (on Twitter):

1. Dear Surgeons - stop telling patients “We got it all” signed, Medical Oncologists.
2. Dear Medical Oncologists – please inform your patients that your treatments for metastatic disease are palliative, not curative. Signed, Surgeons and Radiation Oncologists.
I have been thinking a lot about the outliers, the exceptional responders, those rare patients for whom we have cracked the code and end up with a PSA of zero after we treat them with abiraterone, immunotherapy or other treatments - and what to do about them.
I have stated many times in this forum before that treating castration-resistant prostate cancer (CRPC) is analogous to trying to hit a moving target. The better we get at treating it, the more the disease is able to evolve and adapt and acquire new mechanisms of drug resistance and lethality.
I love the year-end lists and the person of the year articles that always come out at this time. whether it is TIME magazine or Sports Illustrated or even People magazine (…not that I follow the worlds sexiest man and woman contest that closely), they help us give a perspective of the shifts in our world that occur within a year.

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