ASCO 2020: Updates in Prostate Cancer Treatment - Episode 5
Daniel J. George, MD: I want to move on. This is another narrative of prostate cancer. This is the nonmetastatic castration-resistant prostate cancer. We talked about the patient who has metastatic castration-sensitive disease. We pick them up by imaging, or they present de novo with widespread metastatic disease. It’s almost a different clinical path. In the patients who present with localized disease, they get localized treatment, at some point recur, PSA level rises, and they get put on hormonal therapy and respond for a long period of time. The natural history of these patients that evolve into nonmetastatic castrate-resistant disease might be 8 or 10 years.
We’re looking at a pace of disease that’s much more chronic yet largely neglected until recently. There’s been a series now of 3 large, international phase 3 studies to demonstrate an improvement and a new end point of metastasis-free survival. Ben, can you walk us through these studies—PROSPER, SPARTAN, ARAMIS—and what have they taught us about this disease’s biology? Tell us about some of the newer findings we’ll get to from ASCO [American Society of Clinical Oncology Annual Meeting] this year?
Benjamin H. Lowentritt, MD, FACS: Thanks. It’s interesting because this is a disease state that didn’t really name before. It was defined when we had options to treat it. These were the patients who had been put on ADT [androgen deprivation therapy] at some point purely because of a PSA, because of a biochemical recurrence, and because by definition, they didn’t have metastases. Some of them may have experienced early failure of treatment with radiation and had been on an ADT, but a lot of these were patients essentially treated for PSA levels before.
There’s a whole discussion to be had about whether we should have these patients much anyway. Should we have started them on ADT? That rewinds the clock a bit about who these patients are to begin with. That being said, eventually, many of these patients were failing. That’s when we had the head-scratching moment of looking at a patient and saying, “You don’t have metastases. I can’t find metastases. At this point, you’re on standard ADT, and I don’t really have anything else for you. It doesn’t make sense to offer you chemotherapy.”
Even the newer novel agents weren’t for this, at that time. It feels like a long time ago, but it was only 2 years ago when we had the readouts of several trials that were looking at the highest risk of those patients. These were not the patients who had a slow PSA, but those with doubling times of less than 10 months. All 3 studies use that same indicator, and that predicted that they were likely to show metastasis within the following year. All those patients are very high risk in this subset.
First was the SPARTAN trial with apalutamide, closely followed by PROSPER and enzalutamide, and then about a year later, it was darolutamide. They all showed a significant improvement in metastasis-free survival, or MFS. MFS made news because it was a new marker. It was an acknowledgement that to wait for overall survival is not practical if we’re trying to deliver on a treatment option for patients who have high-risk disease. Although now we know how long it would have taken to do that, at the time, it allowed for these studies to be framed in a more reasonable, although somewhat controversial, framework.
Metastasis-free survival was deemed to be a reasonable exploratory end point by the FDA, which allowed these trials to move forward. They all showed a significant reduction in the risk of metastasis with an approximate—all the data were relatively similar—2-year benefit over a placebo in metastasis-free survival, and hazard ratios that were 60% to 70% risk reduction. It’s a remarkable set of trials that showed an improvement that we don’t typically see, in a disease state that we knew was worrisome but didn’t have any options for before.
Daniel J. George, MD: It was groundbreaking from that perspective, to understand it, but it was a bit of an unproved end point. Tying that to overall survival, which is a very proved end point, has been the missing link until just recently.
Transcript Edited for Clarity