Treatment of Nonmetastatic Castration-Resistant Prostate Cancer - Episode 6
Judd W. Moul, MD: In M0 CRPC, the patients currently do not have visible metastasis. In plain English, that means you can’t see metastases on a classic CAT scan or bone scan. And so, the endpoint of treating that condition is when the patient develops metastases. We certainly know that men who have M0 CRPC, if nothing is done, are going to continue to progress with that cancer, and eventually you’ll see metastases on those scans. The whole rationale behind these trials with apalutamide and enzalutamide and darolutamide are to use them in these men who have M0 CRPC to see if we can significantly extend the time until that patient has metastases. So, that’s called time to metastatic disease.
In all of the FDA regulatory requirements for using these drugs in the M0 space, time to metastasis seems to be the endpoint that the FDA is most comfortable with in working with the pharmaceutical company and saying “Look, if you meet this endpoint with this product, we’re going to consider that for FDA approval.” In other words, what the FDA seems to be saying is that time to metastasis in M0 CRPC is a surrogate for cancer-specific survival.
The biological difference between prostate cancer that metastasizes and prostate cancer that doesn’t metastasize is the $64,000 question that we’re all wanting to answer. Why is it that a patient will have prostate cancer and live seemingly forever, or for his entire natural life, without developing metastasis, and the next gentleman who starts at about the same point develops metastases in a couple of years? That we don’t know, but we’re working hard through molecular biology and molecular genetics to sort that out.
Up until recently, we would have shrugged our shoulders and said, “We have no idea,” but I think we’re on the verge of being able to potentially discover a whole series of prostate cancers based on their molecular pedigree. And I would imagine in 10 years, maybe even sooner than that, we will start to manage advanced prostate cancer based on a patient’s molecular signature. And that molecular signature will help determine the time to metastasis, or why one patient biologically is going to take a long time to develop metastasis and the next patient has a different molecular signature and may develop metastasis in a short period of time.
Julie Graff, MD: Prostate cancer typically metastasizes to the bone. It’s a very bone-tropic disease. So, 90% of the metastases go into the bones, followed by lymph nodes, then followed by the liver and lung. Visceral metastases are typically those in the liver and the lung. People with metastases in the liver in particular do very poorly, and in some clinical trials those patients were actually excluded from being tested.
Charles J. Ryan, MD: When one looks at metastasis-free survival, we’re looking at the prevention of metastases and how that might correlate with overall survival. The hope would be that if we are giving a therapy that’s going to prevent metastasis, we might also be helping that patient to live longer. It would probably not be effective to give that therapy if it only prevented metastasis and the death that followed that was rapid.
The good news is that the studies that have been done by looking at several thousand patients, I think over 100 studies, demonstrate that metastasis-free survival is highly correlated with overall survival with a correlation coefficient of about 0.9, meaning that they’re very, very tightly linked. And so, if we took a population where we were to improve their metastasis-free survival and a population where we didn’t, we would expect that those who had the improvement in the metastasis-free survival would also enjoy a longer overall survival.
The future design of clinical trials in prostate cancer will learn a lot from current studies that are studying metastasis-free survival and are exploring the nature of therapies in the nonmetastatic castration-resistant patient population. In general, we want oncology, specifically the treatment of prostate cancer, to become a more proactive endeavor. We don’t want to be waiting for bad things to happen before we intervene with an effective therapy. And I think this is a really good example where an earlier intervention by preventing a complication may actually lead to an improvement in the overall outcomes of a substantial margin of patients with this disease.
As I think about the treatment of patients with prostate cancer, I have 3 goals that I summarize with the expression, “the 3 Ps.” I want to preserve quality of life, I want to prevent complications and progression, and I want to prolong life overall. I talk to patients about that, and I think that the use of a treatment that’s well tolerated in the nonmetastatic setting by preventing metastasis is actually a really important and effective treatment. It would be a really important step towards that preservation and that prevention and that prolongation of life.
Transcript Edited for Clarity