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Investigational Therapies Target STEAP1 and DLL3 in Advanced Prostate Cancer - Rahul Aggarwal

November 28, 2025

Zachary Klaassen hosts Rahul Aggarwal to discuss therapeutic targets in metastatic castration-resistant prostate cancer, focusing on cell surface antigens including STEAP1, DLL3, PSMA, and KLK2. Dr. Aggarwal highlights Phase 1 data from the STEAP1-targeting bispecific T-cell engager xaluritamig, which demonstrated strong response rates in heavily pretreated patients. The discussion addresses DLL3 as a promising target for neuroendocrine prostate cancer, with 60-80% of these tumors expressing DLL3 positivity. Both physicians emphasize that metastatic CRPC exhibits significant heterogeneity, making dual targeting and combination strategies particularly attractive for future development. Dr. Aggarwal notes the advantages of different therapeutic modalities, including radioligand therapies' imaging capabilities for patient selection. The conversation concludes with Dr. Aggarwal predicting that combination and dual-targeting approaches will define future therapeutic directions in this evolving treatment landscape.

Biographies:

Rahul Aggarwal, MD, Medical Oncologist, Associate Professor, University of California, San Francisco, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor of Surgery/Urology at the Medical College of Georgia at Augusta University, Wellstar MCG, Georgia Cancer Center, Augusta, GA



Related Content:

PSMA and Beyond 2025: Beyond PSMA in Prostate Cancer: STEAP1, DLL3, and CD46

Exploring STEAP1 in Prostate Cancer: From CRISPR Screens to a Neoadjuvant Bispecific Trial - Carissa Chu

DARPin-Based Radioligand Therapy Targets DLL3 with Lead-212 for Cancer Treatment - Philippe Legenne

ASCO GU 2025: Beyond PSMA-Targeted Agents for Advanced Disease

ASCO 2025: Molecular and Clinical Characterization of KLK2 mRNA Expression in Prostate Cancer
Read the Full Video Transcript

Zachary Klaassen: Hi, my name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center. And we're joined on UroToday by Dr. Rahul Aggarwal, who is a medical oncologist at the University of California, San Francisco. Today, we're going to be talking about new emerging targets, particularly in the mCRPC setting, we'll be discussing some of the clinical implications of those. So Rahul, thanks for joining us on UroToday.

Rahul Aggarwal: My pleasure to be here.

Zachary Klaassen: So there is a huge number of new targets, DLL3, STEAP1, many others, just give our listeners where these came from, why they're important, and why they're seeing some Phase 1 data now.

Rahul Aggarwal: Yeah, absolutely. I think it's really been an exciting time in prostate cancer and mCRPC. We've really honed in on what are the top cell surface antigens that we really should be going after, and I think STEAP1, PSMA, KLK2, as we'll see some recent data on, and then in the more transdifferentiated and neuroendocrine subtype, DLL3, these are all very exciting targets.

Zachary Klaassen: So out of those, is there one you're particularly interested in? What do you think is going to be the first to maybe win that "race" for the new targets?

Rahul Aggarwal: Yeah. I think it really depends on what's your therapeutic modality of choice. Obviously, with PSMA and radioligand therapy, I think there, you're already seeing clear activity and regulatory approvals. I think for me, the exciting thing is how do we combine, how do we think about targeting more than one at a time, knowing that metastatic CRPC is inherently heterogeneous. So I'm really excited about some of the bispecific dual targeting agents that are coming down the pike, and hopefully more to follow.

Zachary Klaassen: I think too, you mentioned DLL3 neuroendocrine. We know neuroendocrine is getting some attention in the last couple of years, we know it's the end stage of prostate cancer. What are your thoughts on where that's going over the next little bit?

Rahul Aggarwal: Yeah. Well, it's interesting. I think when you actually biopsy patients with metastatic CRPC, and maybe you have some clinical suspicion that they may be having transformed disease, you actually find neuroendocrine prostate cancer in a reasonable percentage of time and not always at the very end. So I think key message, number one, we need to be looking for it. And when you find bona fide treatment-emergent small-cell NEPC, DLL3 certainly is one of the top targets, depending on the data series you look, it's probably somewhere in the 60%, 80% of those tumors are DLL3-positive.

Zachary Klaassen: Yeah. That's awesome. Focusing a little bit on STEAP1, it made some big waves last year at some of our big meetings in terms of some Phase 1 data, maybe just walk our listeners through the Phase 1 data.

Rahul Aggarwal: Yeah. I think STEAP1 is a great target in the adenocarcinoma, so the typical mCRPC patient. And the most exciting data we've seen is from the bispecific T-cell engager, AMG-509, or xaluritamig. Really, really impressive response rates in heavily pretreated patients that have had multiple AR pathway inhibitors, chemotherapy, increasingly radioligand therapy. Despite all that prior therapy, seeing a very impressive response rate, and many of those responses seem to be quite durable, so very exciting.

Zachary Klaassen: Yeah. And I think too, we've seen, in the last few years, a big explosion of data in RLT. It seems like it's coming with these new targets as well. How do you see the next two to five years going, Phase 2s, Phase 3s, et cetera?

Rahul Aggarwal: Yeah. I think you look at the different modalities of targeting a cell surface antigen, you have the radioligand therapies, you have the bispecifics, you have the ADCs, I think one of the fascinating things is how do we think about combining these different modalities of treatment, because they all have their different pros and cons. I think the radioligand therapy, the big, big advantage there is the ability to image, the ability to select patients. And I think with even lutetium-PSMA for mCRPC, we'll learn better how to select that therapy versus other things that may be coming down the pike.

Zachary Klaassen: Sure. I want to spin off that a little bit, you mentioned selective therapy. Biomarkers are obviously a great buzzword, but are there biomarkers for maybe which target of these is still too early in terms of what we should be looking at as we move forward?

Rahul Aggarwal: Yeah. I think with STEAP1, I think we are still looking for what's the right biomarker there, I think we don't have a STEAP1 imaging agent that's ready to use in the clinic. You can do biopsies in STEAP1 testing, but that's not really ready for clinical use. Perhaps PSMA PET is a surrogate for really detection of adenocarcinoma. But there's a situation where certainly biomarkers could help us.

Zachary Klaassen: For sure. Great conversation as always. Any take-home messages, concluding statements, for our listeners?

Rahul Aggarwal: Just look out for more combination data and dual targeting, I think that's the future here.

Zachary Klaassen: We'll be talking about it at almost every meeting, I think, for the next couple of years.

Rahul Aggarwal: Sounds good.

Zachary Klaassen: Awesome. Thanks, Rahul.

Rahul Aggarwal: My pleasure.