Toxicities Associated With Radioligand Therapy, Treatment Sequencing Considerations

A roundtable discussion, moderated by Michael Morris, MD, discussed the current landscape of radioligand therapy in prostate cancer, including recent trial highlights presented at ESMO 2023. Dr. Morris was joined by Tanya Dorff, MD; Evan Yu, MD; and Rana McKay, MD.

In the next segment of the roundtable series, the panel discusses treatment-related adverse events, including hematologic toxicities, xerostomia, and more.

Watch the next segment in this series.

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Dr. Morris: Let’s talk about what Tanya was alluding to in terms of sequencing and toxicity. Now, the hematologic toxicity for the PSMAfore trial is very different from that in the VISION trial. Low single-digit as opposed to double-digit hematologic toxicity. Indeed, if you were looking at Oliver [Sartor, MD]’s presentation carefully, thrombocytopenia didn’t even make the list, couldn’t fit it on the slide it was so low. Anemia was 6%, a high grade. How does that make you collectively feel about moving this earlier, and perhaps doing some of those combination and sequencing studies, now that you have those data. Rana, what’s your comfort level and how do you put that hematologic toxicity data into perspective?

Dr. McKay: I think these patients are not as heavily pretreated as the patients that were in the VISION trial. I think use of a radioligand therapy, probably when the patient has more reserve, I think is going to be… Those acute toxicities, we’re not seeing, but I do think about the long-term toxicity, because we don’t know what the long-term risk of myelosuppression is where you really can’t help that patient rebound, but acutely, in an individual who has not received extensive prior treatments, limited chemotherapy exposure, there does seem to be a mitigation. I think that’s also going to enhance the ability for patients to receive more therapy and then to speak about that adaptive design, it’s very provocative in this setting because actually, the PSA 50 response was upwards to 60%, 57% and change.

While it’s completely experimental at the present time to further preserve their marrow toxicity, they’re going to do well, they’re going to have a dramatic response. Can you protract the administration of the treatment and maintain quality of life but not compromise on efficacy? I think these are going to be questions that we try to answer. Just a little bit to the sequencing, I think, Tanya, you mentioned it a little bit about the NGS [next-generation sequencing] testing. It’s my understanding too that in the presence of PSMAfore, for those people that were BRCA1/2 mutated, they did receive olaparib prior. I think all of the data that we’ve seen thus far about the sequencing of the PARP inhibitors from TRITON and others is that the earlier that you can implement a PARP inhibitor for somebody that is addicted, particularly BRCA1/2, or that tumor is addicted, may make more sense for those particular individuals.

Dr. Morris: Worth pointing out that an exclusion criteria for PSMAfore was candidacy for a PARP inhibitor. The patient population that is HRD [homologous recombination deficiency] isn’t represented in that trial. Now, the trial didn’t require that patients be sequenced, but if they were known to harbor an HRD mutation, then it was felt that they would be better served by going on standard of care with a PARP inhibitor than going on to the study. It doesn’t really inform us on that population. Good point.

I think in terms of the toxicity, we probably, and I’m speaking generically now, not about a specific drug, not have sacred cows for modest therapies down the line. If we had a drug that we gave very early that prolonged life for, let’s say, years, we shouldn’t say, “But they couldn’t get chemotherapy,” which is a 12-week survival advantage later down the line. We just need to be careful about how we consider existing therapies. If we can’t give them, they’re not so good sometimes, that it’s worth not giving or doing trials of treatments upfront, knowing that it might render those patients ineligible for those later-line therapies since those are so modest. I think we shouldn’t be scared of bringing new things upfront, and we will have to learn what that risk and balance is.