Discussing Novel Radiopharmaceuticals in Development for CRPC

In a roundtable moderated by Tanya Dorff, MD, of City of Hope, panelists Michael Morris, MD, of Memorial Sloan Kettering Cancer Center; Benjamin Garmezy, MD, of Sarah Cannon Research Institute; and Yu-Wei Chen, MD, MS, of the University of California, San Diego discuss new treatments and therapy considerations in the field of castration-resistant prostate cancer.

In the final segment of this series, Drs. Morris, Garmezy, and Chen discuss the use of novel radiopharmaceuticals currently in development for the treatment of CRPC.

Watch this series from the beginning: PSMA/PET Scans and ADT in Patients With CRPC

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Dr. Dorff:
Certainly, some of the newer PSMA-targeted radiopharmaceuticals are being developed in part with the intent to spare salivary gland toxicity. But let’s talk about other novel radiopharmaceuticals in development and where we think they’ll play a role or how to best develop them in this landscape.

Dr. Morris:
Well, we have a couple of good targets. So there is hK2, it’s a human kallikrein and it is very similar to PSA. It is very different from PSA in the sense though that it not only has a soluble component but it has a membrane-bound component, which makes it a good theranostic target, also a target for other types of therapies such as bispecific antibodies, CAR T. But the theranostic is actinium-bound and preferentially binds to the membranous expression of hK2 as opposed to the soluble component. There is good phase 1 data that’s out there now that we presented at ASCO. This does have an adaptive dosing schedule. If you don’t dose it adaptively, you do get interstitial lung disease and you do get prolonged thrombocytopenia. So that’s an interesting target for your routine standard adenocarcinoma. But then we have to remember that 15% of our patients undergo lineage plasticity or their disease does after an ARPI yielding this mishmash of which we umbrella called neuroendocrine prostate cancer.

But not all of its neuroendocrine and it’s not… It’s frequently a composites of many different types of prostate cancer. And I think that new targets for theranostics for that population fall under DLL3, for which there is now a tracer. This was published by a fellow named Sal Tendler, a fellow at MSK in Lancet Oncology about three, four weeks ago. There’s an imaging tracer for DLL3 which can highlight the neuroendocrine diversity and heterogeneity in patients with neuroendocrine prostate cancer. And then Lisa Bodei, who’s a nuclear medicine physician, she now has an IRB-approved theranostic with lutetium, with DLL3 as a therapeutic to match that diagnostic. Then there’s the STEAP family of targets. So we know that STEAP1 has been credentialed both in terms of imaging and now with AMG 509 or abbreviated as XALU, I won’t even try to pronounce the full name, as an immunotherapeutic. But for a theranostic, there is a company that’s working on a STEAP2 theranostic that should be open within the next few months.

So I think that there are a lot of other targets that are up there. And as you pointed out, Tanya, the main issue with PSMA is with the small molecules salivary gland toxicity. But in a look of back to the future, actinium J591 is open and now accruing at centers and the large molecules. And J591 was the original granddaddy antibody against PSMA. That was the inception of the whole PSMA targeting field. And it does not bind to the salivary glands. So there are some old targets and old molecules also that look pretty good for sparing the salivary glands as we move into the alphas.

Dr. Dorff:
Well, speaking of older molecules also for neuroendocrine prostate cancer, which you mentioned and is a real unmet need, there is the ETCTN trial using lutetium dotatate. So trying to apply it now to this population, which I think will be very interesting. And at City of Hope, we are using a CEA actinium compound that we’re developing for neuroendocrine that expresses CEA. It’s great to see a proliferation of trials really targeting this population that I feel like we’re seeing a bit more frequently in the modern era, either because people are living longer or we’re just squeezing the AR pathway so strongly. But we don’t have time to get into all of that. I think this has been a great discussion, but I’d love to wrap up with a final thought. How can we best help our patients with metastatic hormone sensitive or CRPC based on what we’ve heard at ESMO and at this meeting?

Dr. Chen:
So I think that nowadays patients easily can just search those new information, new treatment options online. And I think it is our daily busy day in the clinic, it is our responsibility to really sit down with the patient to set up a clear goal. I mean, we can easily treat by intensification but make their life miserable, but we can also find a balance to reach the goal. I mean the goal not only live longer but also maintain their quality of life. I think that is the key takeaway for me, I think, is just to find a balance that maintain quality of life and make patients live longer as well in the clinic.

Dr. Dorff:
Yeah, that’s great. How about you?

Dr. Garmezy:
Yeah. So I’m going to look into the camera for this one and talk to all the community doctors out there that I’m representing today because you made a great speech about how we need to work together, and I think the ARASENS data set was perfect in the sense that how do we get urologists and medical oncologists in the community working together to share patient care in situations where there might be a Venn diagram of overlapping care. So it’s going to be unique in every locale, and we need to learn how to cross those bridges now, not just with urology and medical oncology, but more with radiation oncology because more ligands are coming down. So I think my biggest takeaway would be intensifying when it’s appropriate, de-intensifying when that’s okay, but to think about who needs to be involved and how to share that care.

Dr. Morris:
I would just echo everything that everyone has said. And I guess I would just add that this has been a year showing that what’s new is new and what’s old is new as well. And so I think it’s incumbent on us now to really figure out the sequencing question and the combination question so we can give our patients who I’m sure face this prospect of so many decisions to be made and really need advice on how to sequence. So it’s up to us to now generate those data. And so I think that with all of these really terrific years worth of discovery and results, we now have to really buckle down and figure out how to best give these drugs to the patient’s greatest benefit.

Dr. Dorff:
Absolutely. Well, thank you so much all for this wonderful discussion.