Read the Full Video Transcript

Evan Yu: I'm Evan Yu, a medical oncologist at the Fred Hutch in University of Washington. We're going to talk today about combination of agents and sequencing of agents, more sequencing of agents because we don't have a lot of successes just yet with combinations for the metastatic castration-resistant prostate cancer disease state. So, it's a lot of stuff, so I'm going to blast through it. Here are my disclosures.

And so here's how we're going to break it down is we're going to do it really practically, how I think about a patient when I see one. So this is first the traditional pathway, which is before we add all this treatment intensification up front for hormone-sensitive disease, for M0 castration-resistant prostate cancer, what did we generally do for first-line metastatic castration-resistant prostate cancer? Now some patients got [inaudible], but more commonly people got put on a novel hormonal therapy agent like abiraterone or enzalutamide.

So how do I think about it after somebody progresses on that, and how do we sequence them? You can see the green are kind of the top choices. The red is not so great. And the purple is if you have select patient populations. So in general, if you have patients that have, let's say, mismatch repair alterations, hypermutation, microsatellite instability, pembrolizumab could be used here. If you have patients with DNA repair deficiency like BRCA2, olaparib could be used here. But generally speaking, I go with docetaxel or radium-223 if the patient has bone metastases and symptoms. Novel hormonal therapy switch, just not preferred, and I'll talk a little bit about it here.

So this is a nice study from University of British Columbia where they took patients and randomized them from abiraterone to enzalutamide or enzalutamide to abiraterone. And they looked at progression free survival by composite criteria and group A, which was abi followed by enza, did better. Group A also had better response rates to the second agent. So enzalutamide, 36% PSA response rates. abiraterone after enza, only 4% response rates. So with that being said and done, if you're going to go back-to-back hormones with sequencing, probably abi followed by enza is most ideal.

Now the next question is, what about radium-223 or chemotherapy? I said radium you can give to patients who have bone mets and who have symptoms. Here are some considerations. Well, radium you can't give to patients who have visceral mets. Radium also has very stringent criteria for your CBC, your hemoglobin, your platelet, your white blood cell count, ANC. And, as time goes on with prostate cancer, you can get marrow involvement, and you can get myelosuppression from that. You can obviously get myelosuppression after chemotherapy, as well. Radium requires pre-authorization. Chemo with docetaxel doesn't, and you can get all six cycles in. If there's data that shows that the earlier you start, the more likely you are to get all six cycles in. So for pragmatic reasons, I kind of like the idea of trying to use Radium before chemotherapy if you can do it, and the patient meets the criteria.

Now here's my summary for this traditional pathway. You get first-line abi or enza for metastatic castration-resistant prostate cancer, precision therapy when possible. Not back-to-back novel hormonal therapy agents because it yields poor results, but if you have to do it, it's better to go abi then enza, rather than enza then abi. Vice versa is not as good.

Radium can be administered before docetaxel. There's a survival benefit either before or after docetaxel, but of course the patient has to have bone mets, lack visceral mets, and have some sort of symptoms, as well. However, if your patient has rapidly progressive disease, PSA shooting up real fast, you re-stage them, their disease is really exploding on scans, docetaxel is your best shot at response and should be the most frequently relied upon pathway.

Now you can see that the considerations are different depending upon how you enter into resistance to novel hormonal therapy agents. If you start off with M0 CRPC, you received an AR antagonist. abi is not FDA approved in this situation. So it's apalutamide, enzalutamide, or darolutamide that are FDA approved, and although many the options are the same, I think about things a little bit differently. So, again, precision therapy when possible. The difference here is I never do back-to-back hormonal therapies.

Occasionally, I do the abi to enza as I mentioned earlier, but I'll never go to abiraterone in this situation just 'cause you saw how abysmal the response rates are of abiraterone after a prior AR targeted therapy. Again, radium can be used here before docetaxel if the patient has bone mets, lacks visceral mets, and has symptoms. But again, docetaxel is your best shot at response, especially if the patient's progressing rather rapidly.

Now what about the setting where Dr. Morgan just talked about for metastatic hormone-sensitive prostate cancer, and they received a novel hormonal therapy agent? Not triple combination therapy yet, we'll get to that, but let's say they had either abiraterone, enzalutamide, or apalutamide. How do I think about that? Okay, so similar options again, but again, for novel hormonal therapy switch, it's more acceptable if they received abiraterone previously, then you can switch to another AR targeted therapy versus if they start with an AR targeted directed therapy like apalutamide or enzalutamide.

So again, precision therapy when possible, radium for select patient populations, docetaxel is your best shot at response. However, again, occasionally I will switch these patients from abiraterone to enzalutamide, although not preferred. The reason to switch them is, if you think about how patients progress, they have hormone-sensitive disease, now they're starting to progress to castration-resistance. They're coming in every three to four months for their Lupron shots, let's say, and you're checking the PSA. The vast majority of these patients are going to progress asymptomatically. They're not progressing symptomatically, and a lot of them don't want to move on to chemotherapy or IV therapies. So I do this kind of switch a little bit more often from abi to enza, but again, I wouldn't do it if they were on enza to abi, vice versa, okay.

So now this is the newest state. What if they received triple combination therapy so they, like Dr. Morgans described, somebody, let's say, has high-volume de novo metastases, gets ADT and either abiraterone + docetaxel or ADT and darolutamide + docetaxel, very different thought considerations here.

Okay. You could re-treat with docetaxel, but the thing about it is, in oncology usually we say, "Oh, a patient goes six months, 12 months since they last received the treatment, we can re-treat again," I don't think about it here like that. Why? Because if you just give somebody androgen-deprivation therapy, they have about a median of two years before they develop castration-resistance, even longer if you've treatment intensified them, potentially three years.

So I have to see a really, really long duration of response before I go back to docetaxel re-treatment here. Sure, you can go on to cabazitaxel. Sure, you can go on to radium-223 if you have the right patient population with bone mets, no visceral mets, and symptoms. And you can also do the newest approved agent, which is Lutetium-PSMA-617. We'll talk more about all these sorts of things.

I am not a fan of novel hormonal therapy switch here, mostly because their data from the CARD trial. This patient population would fit there. They receive prior novel hormonal therapy agent. They receive prior docetaxel chemotherapy. We know cabazitaxel does better than novel hormonal therapy switch, okay? So again, precision therapy when possible. Radium-223 for select patient populations. Docetaxel re-treatment if the patient had at least a decent response from the initial ADT and docetaxel, that means an undetectable PSA. And for me, I got to see at least two years, if not longer of a duration, before they develop castration-resistance.

What I really rely on would rely on here is either cabazitaxel or lutetium here. I might lean a little bit more towards lutetium just because there's that TheraP study that was no overall survival benefit, but there was a superior PSA decline rate, composite progression free survival, better adverse event profile to lutetium over cabazitaxel. No overall survival, but again, it wasn't powered to show that. And again, novel hormonal therapy switch here should really just be discouraged because there's so many other good options that we know will work better here.

Now when it comes to combination therapy for metastatic castration-resistant prostate cancer, we've unfortunately had lots of negative studies. But there are some positive ones recently to talk about, and we have some slides that we can pull up later when we do the cases and discussions, etc., but I know we're running short on time, but I'll just quickly summarize.

MAGNITUDE, first-line mCRPC, abiraterone plus niraparib for patients that had DNA repair deficiency that showed a PFS benefit for the biomarker selected population, not overall and not for the negative population. PROPEL. This is in a biomarker unselected population, abiraterone plus olaparib had an rPFS benefit over abiraterone alone. The subgroup analyses looked positive for both the biomarker positive and the biomarker negative population. Very, very interesting there.

TRITON3, recently pressed release. We haven't seen all the details yet, but rucaparib and enzalutamide also have an rPFS benefit over enzalutamide in the BRCA1/2 population, and the intention to treat population that includes ATM. But, that being said, and then we haven't seen the breakdown of biomarker positive versus biomarker negative. Growing data here to support these kinds of combinations of PARP inhibitors and abiraterone or enzalutamide even potentially in the DNA repair proficient population. Overall survival data is not mature yet, so we have to wait and see, okay?

So what are unanswered questions in this combination field? So what I want to know is, okay, you have BRCA2, should I give them niraparib and abiraterone if and when it becomes available? How do I know that that combination's better than sequence, since there's only rPFS data now? Of course, if there's survival data that might help answer that, but right now, I don't know. What's the biologic rationale for benefit for the biomarker negative population? Is it off-target effect? Maybe PARP inhibitors have cell cycle inhibition effects. Maybe there are DNA repair genes that we're just not smart enough to know about yet, and patients have those predispositions. Might be one of those things. Unclear.

And the question really is, will this data be enough to drive regulatory approval and use? There's a little bit of stuff happening right now outside of the US. We'll see what happens here in the United States.

So my take home points, combination therapy for metastatic castration-resistant prostate cancers generally been unremarkable. Early hints for combining novel hormonal agents with PARP inhibitors. Many options for patients who progress on a novel hormonal therapy agent. But it depends upon what setting you received it, when it was administered, whether docetaxel has been given or not, and how all that goes into the equation of how it affects the downstream options in sequencing. There's no definitive pathway. Patient individualization, comorbidities, all these and your clinical judgment needs to be applied here to every single situation.

But one thing generally doesn't lead to good outcomes and that's switch from novel hormonal therapy agent from one to the next. You do better if you go abi-enza versus vice versa. And of course, we always encourage clinical trial accruals. Standard care is going to continue to change because of this, so we thank you all for your accruals and the patients for going on. Thanks so much.