DLL3 Targeting Bispecifics: A New Hope for Tough-to-Treat Prostate Cancer Patients - Rahul Aggarwal

March 6, 2023

Alicia Morgans hosts a discussion with Rahul Aggarwal about his ongoing research on DLL3 targeting BiTE therapy. DLL3 is expressed in an aggressive form of prostate cancer known as neuroendocrine prostate cancer. Dr. Aggarwal's study focuses on using an immunotherapeutic approach to target DLL3, using a compound developed by Amgen that enhances immune response. With 40 patients already enrolled in this phase II study, preliminary findings hint at a positive response rate, with some patients showing a sustained objective response. While considering the potential risks associated with immune-related side effects, Dr. Aggarwal remains optimistic about the promise of DLL3 as a target. The study aims to continue the exploration of DLL3 positivity in patients and potentially leverage DLL3 expression as a selection factor for future phases of research.


Rahul Aggarwal, MD Assistant Professor of Hematology/Oncology, Director of STAND Clinic, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, I'm so excited to be here with Dr. Rahul Aggarwal of the University of California San Francisco. Thank you so much for talking with me today.

Rahul Aggarwal: It's my pleasure.

Alicia Morgans: Wonderful. So I wanted to talk with you about an ongoing study. You are the PI. It's a really exciting DLL3 targeting BiTE therapy. Can you tell us a little bit about what this is? What is DLL3 and who are the patients where this might be important?

Rahul Aggarwal: Yes, absolutely. So this DLL is a target that's expressed in a particularly high risk or aggressive form of prostate cancer, what we think of as neuroendocrine prostate cancer. So in this high risk setting, we see about 75% of patients will have cancers that express DLL3 on the surface. And we're trying to figure out what's the best way to target this protein.

There were previous attempts looking at things like antibody drug conjugates that unfortunately didn't show a lot of activity and had a lot of side effects. We're now taking more of an immunotherapeutic approach to targeting DLL3 and really Amgen has developed a compound that has two headed antibody. One binds to DLL3 and the other binds to the T cells. And we're trying to really enhance the immune response for this particularly high risk form of prostate cancer.

Alicia Morgans: All right. So tell me a little bit about this. How have patients enrolled? Are you meeting your at least enrollment goals? And if you have any preliminary results, we'd love to hear them.

Rahul Aggarwal: Yeah, so the study initially was enrolled on the basis of a pretty broad selection category. So we define neuroendocrine prostate cancer either based on histology, so do we see small cell neuroendocrine with a biopsy. We also enrolled based on genomics. So if patients had two or more loss of tumor suppressor genes in TP53, RB1, and P10, or based on histochemical staining of neuroendocrine markers like hemogram and synaptophysin.

We didn't require a DLL3 staining in this first cohort to be eligible. So in that context, we actually enrolled the study quite briskly. So we had about 40 patients enrolled in a single arm phase II study. That just recently completed enrollment and we're still sort of cleaning up the data and trying to determine the overall response rate.

Anecdotally I've definitely had patients of mine that have had a really nice and sustained objective response who came in with platinum refractory neuroendocrine prostate cancer. So I think there's definitely activity there. The next step in is really to hone in on the DLL3 positivity and really select patients based on that and that's the plans for the next phase of the study that we're going to be enrolling hopefully within the next several months.

Alicia Morgans: Well, I think to that point, neuroendocrine is difficult I think just even to define as an entity. So at this point you've enrolled a broader population. Is it possible that you may see that DLL3 expression is enriched in this group or in that group? Perhaps it correlates. I would assume it correlates with response, but we don't necessarily know that yet, given this is the first assessment that we have the opportunity to look.

Rahul Aggarwal: Absolutely. So right now what's happening is we're retrospectively assessing DLL3 expression because we did collect tumor tissue on all the patients that were enrolled or the majority of patients enrolled. And we're looking at correlation with both clinical outcomes and response rate as well as those other factors like the genomics and clinical features that might correlate with expression.

I think at the end of the day when you have a surface target that you're going after directly like DLL3 nothing's better than a selection factor based on DLL3. So DLL3 expression by IHC or potentially eventually using PET imaging to select these patients as well.

Alicia Morgans: That would be a nice way to go too. So you'll have to keep us posted on that. So from an efficacy, at least in your practice standpoint, we had some patients who might have had some disease response. What does toxicity look like?

Rahul Aggarwal: So this is something we look at really closely with these bispecifics because there is a risk for immune related side effects, particularly cytokine release with the first one to two doses. And that's really just an activation in the immune system that can cause pretty significant low blood pressure and swelling and fevers and so forth.

Luckily, so far in the study we haven't seen high grade cytokine release. We've seen mostly grade one, occasional grade two, and it's been quite manageable. That being said, these patients are pretty closely followed, so they are admitted to the hospital for the first several doses for that inpatient observation just in case. And so I think as we move forward with these therapies, making it easier for patients and really looking closely at the toxicity profile is going to be important.

Alicia Morgans: Okay. Well any other closing thoughts as you continue to keep our excitement high for this approach?

Rahul Aggarwal: Yeah, we're excited about it. I mean, this is a tough to treat patient population. These patients unfortunately have cancer that's progressing after platinum-based chemotherapy and I think we really, really have such a high unmet need to develop new therapies. I remain very enthusiastic about DLL3 as a target and I think that a bispecific modality holds a lot of promise. So we'll see what the next phase of the study shows.

Alicia Morgans: That sounds great. So thank you so much. Keep us posted on upcoming advances and we appreciate your time and your expertise.

Rahul Aggarwal: Thank you so much.