Neal Shore, MD, FACS: Let’s move on to our third segment, which is mCRPC [metastatic castration-resistant prostate cancer]. We have several really important issues to talk about because of this plethora of new medications that started off early in mCSPC [metastatic castration-sensitive prostate cancer] and in nmCRPC [nonmetastatic castration-resistant prostate cancer]. How is this influencing our decision making and our discussions with patients when they are diagnosed with mCRPC? We’ve already touched significantly on the imaging conundrum that will befall us as we get more and more accurate and sensitive scanning, and how that changes our decision making. But at the end of the day, we have obtained so many life-prolonging agents since 2010. Pedro, this is a herculean request, but could you just review all the different therapies that have life-prolonging benefit in mCRPC?

Pedro C. Barata, MD, MSc: I’ll try to be succinct and summarize how I select therapy with a patient. We have a patient who progresses to or develops castration-resistant prostate cancer, which we often define by numbers, either PSA [prostate-specific antigen] progression or serological progression; new disease on scans, radiographic progression; or development of new symptoms.

Once a patient develops progressive disease, it doesn’t matter how you define it. There are 6 life-prolonging therapies approved in that space. You have 2 chemotherapies, both microtubule inhibitors. The older 1, docetaxel, has 2 phase III trials published in the New England Journal of Medicine that show survival benefit. You have cabazitaxel, which is a cousin of docetaxel with a different safety profile, and it’s approved after the use of docetaxel. The TROPIC data support their use. Then you have radium 223 dichloride, which is a novel bone-targeting agent. As a matter of fact, it’s the first bone-targeted agent to show a survival benefit in that space, which is quite remarkable and, for some of us, a little unexpected, right? But we can discuss those data.

We have a vaccine, sipuleucel-T, or Provenge. We’re going to talk a little later today about immunotherapy, but remember that we do have an immunotherapy agent approved for a man with asymptomatic or mildly symptomatic castration-resistant prostate cancer. We obviously have the AR [androgen receptor]—targeted therapies with abiraterone and enzalutamide. Historically, it is good to tell the story of how we developed all this, right? Back in the day, more than a decade ago, we had docetaxel, the first chemotherapy agent that made people live longer. And so we classify all the drugs we develop as prechemotherapy and post chemotherapy.

We showed with COU-AA-301 and AFFIRM that both enzalutamide and abiraterone would improve clinical outcomes, including survival, in that setting. Then we moved them early on in the course of the disease to the prechemotherapy space in the CRPC [castration-resistant prostate cancer] setting with COU-AA-302 and PREVAIL, and the same survival signal was present.

We have 6 life-prolonging therapies. There are a lot of therapies coming, and I know we’re going to touch on them later. But if I had to summarize it, I’d say we have different agents with different mechanisms of action that allow us to control the disease for a decent amount of time.

Neal Shore, MD, FACS: I’ll just say, some of us on the panel are old enough to remember when it was very nihilistic for patients with metastatic disease. It was ADT [androgen deprivation therapy] and nothing else. It’s great to see that we’ve had all these advances that are really giving us challenges. The treatment of patients has become that much more complex. There has to be a real dedication to treating these patients and understanding what the data are and what data are forthcoming.

Why does it matter? Of course, we’ve touched on these issues around comorbidities, the nuances and differences of the mode of administration, and the tolerability of these drugs. But before we get more into that, William, you’ve done such great work on this. We start using these drugs that are typically approved in the most end-stage disease because it’s been the pathway to approval with overall survival. You’re either alive or you’re not. Then we realize we have an opportunity to move these drugs up earlier in the disease continuum, but what’s the impact on the disease biology?

William Oh, MD: As you know, when we started out, Neal, these patients didn’t live much longer than a year or 2 at most when they developed castration resistance, and now they are definitely living longer. But there have been some interesting and concerning statistics. For the first time in the American Cancer Society statistics, we’re seeing a slight rise in the death rates of prostate cancer. That’s because we’re not curing these patients.

We’re using these therapies earlier. The men are living longer for sure. They have a better quality of life. I believe all those things. But the cancer continues to figure out ways to grow. It’s both frustrating and very upsetting because, despite of the advances, patients are progressing and, unfortunately, dying. The reasons probably have to do with biology. We are selecting for clones or subsets of cancer cells that figure out how to grow independent of androgen signaling, independent of the effects of chemotherapy, and independent of the bone-targeted effects. We did a small study where we looked at patterns over the last 20 years in patients present with metastatic disease.

When we started out—maybe on this side of the table—our patients had bone metastases 90% of the time. They still do have bone metastases often, but they have lymph node metastases 20% of the time. I remember some of the papers would say 20%. Now we know that it’s 50% of the time or more. We are shifting these patients to other sites of disease because we have better bone-targeted therapies, for example.

I think the biology will inform us. We have some new and interesting targets where drugs are being developed that are important. We’re going to talk a little about BRCA, but there are other targets of resistance, such as the neuroendocrine pathways. The problem is that the drugs don’t come fast enough. We may know that, for example, there are important biological drivers of some cancers, but we don’t have drugs that target them well. I do think that’s going to be the problem over the next 5 to 10 years. As these patients get all the therapies that Pedro just outlined, whether they’re receiving them very early on or in the CRPC setting, we basically have to stop every single pathway that these cancer cells use to grow. Otherwise, we’re never going to cure patients.

Neal Shore, MD, FACS: That’s a really good summary. How do patients become mCRPC? It seems that there’s a disproportionate number who progress into the mCRPC space. They come from 1 of 2 buckets, right? They either start off with metastatic disease, as we talked about earlier, and they progress; or they progress and receive a lot of other therapies before they get mCRPC. What’s the mutational effect on the adenocarcinoma cell, and how does it affect the aggressiveness of the biology and the resistance to different lines of therapy? And there are still the patients with biochemical relapse who receive ADT, progress to nmCRPC, and then move forward.

We’re starting to see data because we are screening less over with the USPSTF [US Preventive Services Task Force]. Where we historically identified around 5% of patients in the United States who presented with metastatic disease, we’re starting to see data that suggest it may be north of 10%. Clearly, in other parts of the world, it’s as high as 50% or 60%. It’s very interesting.

Transcript Edited for Clarity