Scott Tagawa: Yes. Thanks for inviting me. Very exciting for those of us who have been working on this for a while, and especially for our patients to have another option. So very briefly, targeting PSMA, a protein that's on the cell surface of most, but not all prostate cancer cells. We do have an imaging test to decide who or see which tumors have it or not to different degrees, and I think that's an important part of this kind of a platform. Previously approved in resistant disease, so APM-resistant disease, initially post-chemotherapy, and then pre-chemotherapy. But didn't make sense that it wouldn't work earlier, and in fact, maybe it would work even better earlier and in combination with hormonal therapy, and that was the origin of this study originally, just very briefly, back, actually, in 2018 with the US Cooperative Groups. Thanks to Endocyte at the time for agreeing to do that.
One question might be, well, what about chemotherapy? We actually decided we had an approved study, ADT abiraterone plus or minus docetaxel. We canned that study for this study. Sad we don't know that answer yet, but I'm very happy that we have this additional option for patients. So very briefly, patients that have metastatic disease on CT, MRI, or bone scan, PSMA-positive, these appropriate for ADT plus ARPI, which, I think, are the vast majority of patients that have metastatic disease, importantly at diagnosis for many of these patients. And they were randomized to the addition of up to six cycles of lutetium-177-PSMA-617 at the most standard, not optimal, but standard regimen, with the primary endpoint of radiographic progression-free survival at confirmed radiographic progression, like in PSMAfore, those that were on the control arm could cross over to the investigational arm.
And the primary endpoint was met, essentially leading to this new FDA approval for APMN or S, APMN meaning naive to any systemic therapy, or S, sensitive, meaning have recently started ADT and/or ARPI with this added in. And we'll get additional information, but at least what is in the label now is a 33% improvement in that endpoint of radiographic progression-free survival. Overall survival is not mature, but is trending with a 20% improvement with confidence intervals that still cross one, but barely 1.01. So getting closer. We'll see what happens. It's still early. But I think overall, a nice addition, if you will, to the armamentarium, and for our patients, something that's going to improve time until they need something else.
Alicia Morgans: Great. So let's talk some practical points here. We know that many patients have doctors who prefer one AR pathway inhibitor over others. That's the one they're comfortable with. They start most patients on that particular drug in combination with ADT. This study allowed any of the ARPIs to be used in combination with lutetium-177-PSMA-617, which is unique among some of the other combination studies that really required this or that ARPI. Can you speak to that, and whether or not that may be impactful when it comes to clinical practice?
Scott Tagawa: Yeah. I mentioned when this started within the US Cooperative Groups, it was tied to abiraterone, because at that time when we first started thinking about it in 2017, that's really what was there. But as it morphed, we recognized there were many choices, and it doesn't make sense to me that it would have to be tied to any choice. So what I like about this study design, what I'd say is a strength of the study design, it's a little bit more universalizable to a patient population that will sometimes have a preference for one or the other for many different reasons, et cetera, comorbidities or drug-drug interactions. So it's a nice thing that we can add this to any of those backbones.
Alicia Morgans: Absolutely. So one of the other things that I think is really important to unpack is that some people may view this as this is competition for docetaxel. And I'd wonder if you could speak to the general utilization of docetaxel in this upfront setting in the ADT-ARPI-docetaxel triplet combination, and whether it's widely used, whether this is really going to be replacing that utilization, or whether this may be actually giving an opportunity for more patients who may never have received a triplet type of a combination to receive that additional intensification and hopefully have a stronger chance to get to that very low PSA.
Scott Tagawa: So in this setting, I would say based upon level one data, we do not know that docetaxel adds anything to an ADT and ARPI backbone. And those of you that have it available, the SPARTAN study in the NCTN within the US Cooperative Groups hopefully will answer that question. That just happens to be a specific ARPI, but ADT plus ARPI with or without docetaxel.
That being said, I don't think it's absolutely wrong to give certain patients docetaxel, it's a good drug, or taxanes in general, whether it's docetaxel or cabazitaxel are clearly good drugs. We don't know that they're necessarily better or worse. I'd say the best available data says they're kind of similar in terms of at least looking at longer term data in terms of survival. But not everyone wants chemotherapy. Not everyone necessarily wants a radioactive particle either, but this clearly gives additional options.
Amongst those that have, I would say, the level one evidence adding to ADT and ARPI, we have PARP inhibitors, one that's approved and one that hopefully is going to become approved, we have an AKT inhibitor, and now we have lutetium-177-PSMA-617, all biomarker-selected. There are some preliminary data that maybe we can use biomarkers to select docetaxel, and also, hopefully we can prospectively validate it as well. Again, it's not necessarily wrong for someone to administer docetaxel or a patient to take docetaxel in the context of the overall data sets, but this is one of the three different types that really has level one evidence that is there. And frankly, I think that many patients would prefer this type of approach over chemotherapy.
Alicia Morgans: And I think that that's what's demonstrated in the utilization data, that it's unfortunately, or fortunately, I mean, however we want to interpret it, but the reality is only about 10% to 15% of patients end up receiving that triplet combination in that early setting. I use a lot of docetaxel for my patients, but I would not say that that's necessarily common, because of physician reasons, patient reasons, disease reasons, there are lots of different reasons. And I think it's always good to have another opportunity, another option for our patients to consider and potentially use to get to that ultra-low PSA.
And I think just to that point, I would love to hear your thoughts as we round out this discussion. There seems to be some pretty compelling data, that I'm sure contributed to this label approval, that this drug seems to work in this setting in patients with high-volume disease, low-volume disease, recurrent disease, de novo metastatic disease, and when utilized, does seem to get more patients to that PSA of less than 0.2, which we know is associated with better outcomes for patients, as compared to ADT and ARPI alone. Any comments or thoughts there?
Scott Tagawa: Yeah. Getting to that, so patients love for PSA go down, doctors love for PSA to go down, even though we say that's not everything. Overall, even the control arm, the PSA less than 0.2 rate was very high in this study compared to other studies. But as presented by Fred Saad at this most recent ASCO, less than 0.02 was actually about 65% compared to about 45% with just the doublet alone. And we're in the era with all these different, both tests, as well as treatments, recognizing that the older data sets that we said, okay, you have to be on continuous therapy, essentially starting and never stopping with ADT, that's in question. I don't have any real great evidence that we can stop, but we now have prospective evidence that we might be able to stop in terms of another cooperative study, A-DREAM, and a bigger percentage of patients will get there with this type of therapy.
The other thing that's a little bit different than the other molecularly-selected approaches, and this is like docetaxel, is it's a finite period of time. So actually, it happens to be the same number, up to six cycles, that we're looking at. I don't know that patients necessarily need the six cycles. This is just the way that the study was done. Many of us believe that we could safely stop earlier, particularly using a theranostic platform that we no longer see it, maybe we can pause. We'll hopefully prospective validate that. But it is a nice way that we can prolong time until progression without necessarily being on at least one of the three drugs on a continuous basis.
Alicia Morgans: Absolutely agree. Well, as we wrap up then, final words, I would love to hear your thoughts. What should we share with the audience on this relatively new approval?
Scott Tagawa: So first of all, anyone with metastatic disease, I think, really deserves at least two drugs. And now, it's looking like maybe the majority are going to be better served with three drugs, a triplet. Triplet does not mean only chemotherapy or docetaxel. There's several different options. And now, I think that this is... At least those that have access and a positive PSMA PET, this may become the most common option sometime in the hopefully near, but if not near, then somewhat distant future.
Alicia Morgans: Wonderful. Well, thank you so much for your time. Congratulations on the study, of course. And also, congratulations to all of us that we have the access and this newly approved drug to try to drive outcomes to a better place tomorrow. Thank you.
Scott Tagawa: Yes. Absolutely.