Androgen Receptor Inhibition in CRPC
In a roundtable discussion with multiple participants, Alicia K. Morgans, MD, MPH, discusses PSA doubling time and participant experience with androgen receptor inhibitors in castration-resistant prostate cancer.
A 75-year-old man presented with intermittent right hip pain, but his physical exam was unremarkable and he had a an ECOG performance score of 1. Clinical work-up of the patient showed he had a PSA (prostate-specific antigen) of 32.6 ng/ mL and his trans rectal ultrasound guided biopsy Gleason score was 4+4 in the 4 grade group. He had a negative bone and abdominal/pelvic CT scan and was diagnosed with stage T2N0MO prostate cancer. External beam radiation therapy and androgen deprivation therapy (ADT) were initiated and planned for 18 months. Six months after initiation of therapy he had undetectable PSA, was asymptomatic, and his testosterone was at castrate level.
Six months after this, he complained of increasing hip pain and urinary frequency. He had a PSA level of 29.4 ng/mL and testosterone level of 10 ng/dL. Another bone scan showed evidence of 2 osteoblastic lesions in his right hip at 0.8 cm and 1.1 cm. An abdominal/pelvic CT scan showed a 2.1-cm left pelvic lymphadenopathy and he is now considered metastatic and castration resistant.
ALICIA K. MORGANS, MD, MPH: The patients included in the nonmetastatic castration-resistant prostate cancer [nmCRPC] trials had to have a PSA that was at least 2. But the other PSA-related factor that they had to have was a PSA doubling time of 10 months or less, because those were the patients in other trials, particularly 1 of denosumab, that demonstrated a higher propensity or a higher risk to develop metastatic disease in their bones or elsewhere and die—or die of prostate cancer.
So this doubling time of 10 months was used to identify those patients at highest risk for all 3 of the clinical trials. If this patient had a doubling time of 15 months, so a much longer doubling time, despite being on ADT, what would you guys think about that? Would you want to add another drug if they were non-metastatic with a very long PSA doubling time? Would you wait until they had a shorter one?
TAREK SABAGH, MD: I go by the PSA in this situation. If it’s 2 or higher, I would consider treatment.
MOHAN NUTHAKKI, MD: I think we should go with what the studies have done. I think the NCCN also, if I’m not mistaken, mentions that 10 months is the cutoff where you decide to go on treatment or not. If it is more than 10 months, you observe. Less than 10 months, you treat.
SABAGH: Does it require both PSA of 2 and doubling in 10 months or less?
MORGANS: The labels do not have a 10-month requirement for the PSA doubling time. Nor do they have a PSA of 2 on the label that restricts the use of the drug. You can use, if you have nmCRPC, per the FDA, you kind of have an open label.1 But just like the NCCN, I tend to focus on patients who have a PSA doubling time of 10 months or less. Because these are the patients who might have the most chance of benefitting from an additional drug. At least per the trials that were done. I tend to start somewhere between a PSA of 1 and 2, usually, sometimes 2 to 5. Sometimes the PSA jumps, and you don’t have that window but I don’t say that patients have to get to 2 before I start. I do want to be able to be somewhat confident in their PSA doubling time, though. That is hard when the PSA is less than 1. It’s just not as reliable.
ARUN KUMAR, MD: Obviously, if some other drug has OS data, that is important.
EVAN LANG, MD: Yes, I agree. We like to put emphasis on OS, but I’m also very impressed with MFS for an average couple of years.
MORGANS: Between apalutamide and enzalutamide, does anyone have experience with both and could comment on whether there’s a big difference between these agents or do they seem relatively similar? Has anybody used both?
SABAGH: I used both with 1 patient, but at the end of the day, he quit treatment just because he didn’t see, to his own mind, a benefit. I’m not sure if that lack of tolerance to the apalutamide was real or not.
ELAINE BEED, MD: I have not used them. I guess I don’t even think of them as novel, because I answered the other question and just said that I’d use a second agent. The other ones, I don’t think anybody really treats with the older ones. I don’t think of these as novel, and I usually use the enzalutamide. I don’t use the other 2 a lot. I think that’s just because maybe it’s more familiar to the people in practice or something. I don’t really know. But the seizures are a thing that I know you have to look at.
MORGANS: I think of them as the AR antagonists of today, because you’re right, the other ones don’t have good data. But some people, particularly I think in the urology community, still cling to those for reasons that I’m still trying to understand myself. But you seem equally baffled.
Early intervention for patients who are nonmetastatic by bone scan and CT but have a rising PSA on ADT, castrate levels of testosterone—these are patients with nmCRPC. Early intervention can improve MFS, as we saw, by about 2 years and OS as well. Even when we’re hitting these patients over time even though we’re giving these patients additional therapies, we can never make up for that earlier intensification that appeared to be present as far as in our treatment arm. The placebo patients never made it up. They never made up that time. Three drugs are now approved: apalutamide, darolutamide, and enzalutamide.
Maybe we shouldn’t think of these as novel anti-androgens, these are the anti-androgens of today. We should use them. They’re distinct from each other a little bit in terms of their safety, their tolerability, seizure issues, drug-drug interaction issues, and their tolerability maybe by those adverse event profiles. But I think it’ll be important for us, as we continue to practice, to see which ones we feel comfortable with. Because as you said, familiarity is very important. We become more familiar by trying the drugs as you see patients, see what you think and continue to find the drug that works best for you and your patient.
BEED: If it’s earlier when we treat it, they do better, even if they don’t have a doubling time of 10 months. Even though we can’t see the things, this is the head of the parade, the tip of the iceberg. We know with these PSAs, there’s disease there. It’s just having to prove it. As soon as I see doubling times, I try to treat them as soon as I can talk them into it. Now these are expensive, though as we have to look at the fact, they are expensive and what people have to go through. But depending on their whole situation, I think the earlier, the better. Just because we can’t prove it on scans doesn’t mean it’s not there. The PSA is proof, in my mind.
MORGANS: I’ve been in multiple ad boards where people said the same thing, why are we calling this nonmetastatic, we know it’s there. It’s there, you’re right. It’s just not visible on our imaging. But we know it’s there. That’s why we’re able to make such a big difference, I think.
SABAGH: I’m asking the group: How do you measure the doubling time? How do you calculate the doubling time?
NUTHAKKI: Time interval, 10 months vs how long. I mean, if we take 1 to 2 to get 18 months, then that is more than 10 months doubling time. You repeat it in 3 months, and it is already double, then you know you have to treat the patient. Ten months, then it doesn’t need treatment.
SABAGH: I used to think of that in the 3-month or 6-month interval with the PSA. But then I realized there was a formula where you can go to online and calculate doubling time. So that’s why I wasn’t sure. That’s why my question to the group if just the old-fashioned way or if there is a formula which should be used.
MORGANS: A lot of people end up using the eyeball method, which is what they were just describing. There’s a Memorial Sloan Kettering PSA doubling time calculator [that I use] and then I write PSA doubling time calculator. Then I type, you can put in the date of your PSAs and you can do it back for a year or year and a half, whatever duration you want to put in there, then you put in the PSA value and it does calculate it for you. I find it most useful when I’m looking at low numbers that seem to be creeping. Sometimes they’re creeping more quickly than I realized.
1. Fizazi K, Shore N, Tammela TL, et al; ARAMIS Investigators. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Engl J Med. 2020;383(11):1040-1049. doi:10.1056/NEJMoa2001342