Latest metastatic castration-resistant prostate cancer (mCRPC) treatment advances
In a recent webinar, Massachusetts General Hospital’s Dr. Xin Gao explored the latest advancements and research in prostate cancer and key findings from 2024’s American Society of Clinical Oncology (ASCO) meeting. Watch the full discussion below.
Read on for a recap on recurrence and advanced prostate cancer transcribed from our conversation.
The following questions and responses have been lightly edited for grammatical purposes.
1) What are the signs of prostate cancer recurrence and what steps should be taken if it occurs?
With recurrence, I would assume that the patient has been treated previously with local therapy, like surgery or radiation. We typically monitor patients with PSAs and that’s a very reliable test after primary treatment. After surgery, a rising PSA greater than 0.2 is defined as recurrence and after radiation therapy, typically a rising PSA above 2.0 would trigger some evaluation for potential recurrence. That’s the most common way to identify things. Those PSA values are still quite low where it’d be pretty unlikely for somebody to have symptoms like urinary changes, bone symptoms, or anything else that would indicate prostate cancer.
In terms of what steps should be taken, typically these days, we’re getting PSMA PET scans. Again, they’re very sensitive and quite specific for prostate cancer. We’re trying to identify if we can see where the prostate cancer is. It might be localized to the pelvis after the primary treatment, in which case, if further radiation therapy is feasible, we oftentimes do consider that. If the cancer has spread more distantly, that can tell us it should be treated with medications as the foundation treatment. If there’s only one or two, or a limited number of spots of the cancer on imaging, we might think about radiation treatment for those as well.
2) Are there medications or other things that can influence the PSA levels or prostate cancer?
A large number of things can affect PSA levels, but if we’re talking about patients who had prior radiation or surgery, probably not so much. We never really act on one single PSA value alone. We see the trend and we repeat it a few weeks or even months later to see if that’s a real trend or if that’s just a blip affected by some other factor. It helps us understand the pace of increase in the PSA level.
I would say in general, a rising PSA after surgery greater than 0.2 is, unfortunately, probably related to cancer recurrence. There are some cases of residual normal prostate tissue that can be left behind after surgery, but in most cases, they shouldn’t be consistently increasing over time. Cancer grows and over time, it’ll make more PSA. Normal prostate tissue that’s left over shouldn’t progressively and consistently increase over time.
Sometimes after radiation-based therapy, the PSA values will fluctuate. Oftentimes, it will fluctuate a bit because the PSA isn’t the most precise test. There’s variability day to day, even if we were to check it daily. There’s some normal prostate tissue that’s still there since it’s not removed with surgery, which wakes up after radiation therapy and makes a little bit of PSA. Again, that’s why we have that higher threshold of 2.0 rather than 0.2 for post-radiation for recurrence.
3) Do we know much about PALB2 in prostate cancer? What treatment options may be available?
PALB2 is a gene involved in what we call DNA damage repair. Cancer cells, in general, they’re prone to mutations in their DNA and a lot of them can actually be deleterious or harmful to the cancer. They actually need ways to repair their DNA. If they’re already deficient in certain DNA repair genes like PALB2 or BRCA, which are probably the more common ones, if we give them certain medications called PARP inhibitors, it’ll help expedite the death of those cancer cells.
PALB2 is one of the genes that is being studied actively for prostate cancer. It’s not the most common gene, so there’s still relatively limited data. I would say most of the available data does show that for patients who have PALB2 mutations, the addition of a PARP inhibitor can be helpful in certain settings. Right now, the available data suggests that the PARP inhibitors are helpful for patients in what we call the metastatic castration-resistant prostate cancer setting and after a prior androgen receptor pathway inhibitor. This includes medications like apalutamide and darolutamide.
Ongoing randomized phase III clinical trials are trying to evaluate whether these PARP inhibitors are helpful earlier in what we call the castration sensitive setting. So that’s before the cancer has become resistant to ADT (androgen deprivation therapies) medications. We don’t have data from that yet, but I expect that in the next few years that should come out. There are smaller studies that are trying to look at these medications in earlier forms of disease, but again, we don’t really have a lot of data for that.
4) Would ARV-766 be a potential treatment for advanced prostate cancer?
I was actually involved in the clinical trial for this drug and a similar drug at Mass General during the phase I and II studies. It’s an oral pill, it’s a new class of medications. People call it PROTAC. What it does is it binds to the androgen receptor, the protein, that helps prostate cancers detect and sense androgens and drive its survival. It binds the AR, degrades it, breaks it down, and gets rid of it.
There was a presentation at ASCO on the early-phase I and II trials. It did show that for a subset of patients with androgen receptor mutations, it’s what we call ligand-binding domain mutations, if patients have an AR-LBD mutation, ARV-766 was associated with about a 43% rate of PSA 50 decrease. That’s a decrease in PSA by 50% or more, so there is definitely activity there, especially in the AR-LBD patients. We think that most of the data suggests that around 20% or so of patients with metastatic castration-resistant prostate cancer will have an AR-LBD mutation. It is something that we commonly test for these days. Oftentimes, we’re using a simple blood test called a ctDNA test or a circulating tumor DNA test. There are commercially available ones that are run by various genomics companies out there that will collect the tube of blood and give you the results, usually within a week or two. I think it is important to think about these types of drugs and clinical trials. Now, this drug is not ready for primetime yet. It is still in clinical trials, it may be tested in a phase III trial. There are other similar drugs that are coming down the clinical trials pipeline, but there’s certainly activity here.
Read the webinar recap on early-stage prostate cancer with Dr. Gao here.
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