Emerging Strategies in Prostate Cancer: Molecular Glues and T-Cell Engagers

The therapeutic landscape for advanced prostate cancer is expanding beyond traditional hormonal blockade into the realm of “molecular glues” and multi-specific T-cell engagers. Following his attendance of the 2026 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, Benjamin Garmezy, MD, highlighted the promising activity of MRT-2359, a novel GSPT1 molecular glue degrader.¹

While initially studied in MYC-driven tumors, early phase data revealed significant efficacy in patients harboring androgen receptor (AR) ligand-binding domain (LBD) mutations. By degrading the GSPT1 protein, MRT-2359 disrupts critical oncogenic translation and AR signaling, offering a potent combination strategy with enzalutamide (Xtandi). Garmezy additionally noted that while hematologic adverse effects like cytopenia require careful intermittent dosing, the regimen remains manageable and highly targeted.

Beyond AR-targeted therapy, the focus is shifting toward neuroendocrine prostate cancer (NEPC) management via gocatamig, a trispecific T-cell engager targeting DLL3.² Unlike earlier assets, gocatamig has shown encouraging stable disease rates and tumor reductions in a notoriously heterogeneous patient population. Garmezy emphasized that identifying these aggressive variants early through visceral biopsies, particularly of liver metastases, is essential. Detecting molecular signatures such as loss of PTEN and RB1 and TP53 mutations can guide the timely introduction of DLL3-targeted agents after traditional chemotherapy, marking a pivotal step toward precision oncology in refractory disease.

Garmezy is the associate director of genitourinary research and executive cochair of the Genitourinary Cancer Research Executive Committee at Sarah Cannon Research Institute (SCRI) and a medical oncologist at SCRI Oncology Partners, specializing in genitourinary cancers.

CancerNetwork: Why is the combination of MRT-2359 and enzalutamide specifically effective in patients with AR LBD mutations compared with wild-type AR-expressing patients?

Garmezy: MRT-2359 is an innovative GSPT1 molecular glue degrader—a class of molecules we don’t yet have much of in the clinic. While initial hypotheses suggested it would be most effective in MYC-driven tumors, phase 1 data has led us in a different direction.

GSPT1 is a protein critical for the translation and driving of certain oncogenes. By degrading GSPT1, we can prevent oncogene-driven cellular signaling. We observed that patients with prostate cancer harboring AR LBD mutations responded incredibly well to the combination with enzalutamide. Five patients with these mutations showed responses in this early phase study.

We believe GSPT1 degradation intersects with the AR signaling pathway. In patients with LBD mutations, signaling persists from the cell exterior into the nucleus, where AR conjugates with DNA to drive transcription. While the biomarker enrichment is encouraging, our data suggest the drug doesn’t strictly require an LBD mutation to work. Perhaps we’ll also look outside of AR mutations as well because we don’t think that this drug requires an LBD mutation to work.

You can see that, in fact, we have data that was presented ASCO GU in patients without LBD mutations. Now, of course, the percentages were enriched in those patients with that biomarker, which may simply be a surrogate for the specific intracellular signaling we are capturing with this combination.

What are the most significant adverse effects observed with this combination, and how are you managing hematologic toxicities?

We see fatigue, but the primary focus was on hematological toxicities, specifically cytopenias. This was managed quite easily. We changed the dosing schedule. We moved to an intermittent schedule of 21 days on and 7 days off. This schedule has proven much more manageable and helps prevent high-risk cytopenia in some patients. We will not need delaying growth factors for the majority of patients under this current schedule. The other adverse effects we see are some gastrointestinal [adverse] effects, such as nausea and diarrhea. Those are quite easily managed the way we would manage them with other assets.

Given that MRT-2359 is an oral agent, what are the challenges in finding the sweet spot for intermittent vs continuous dosing to maximize GSPT1 degradation while minimizing cumulative adverse effects?

That’s what we struggled with initially, trying to come up with the different dosing schedules. This 3-week-on, 1-week-off schedule, or giving it 75% of the time, is probably going to be effective. There’s still some tweaking to do. There always is. That’s why it’s not a regulatory phase 3 [trial yet].

Given that DLL3 is highly expressed in any prostate cancer, but not normal tissue, how does the efficacy of gocatamig in NEPC compare with its performance in other neoplasms like small cell lung cancer (SCLC)?

Gocatamig is a trispecific T-cell engager, which distinguishes it from other DLL3 assets like tarlatamab-dlle (Imdelltra), which is FDA-approved for SCLC. We had tarlatamab data presented at a prior conference, and while there’s activity there, the response in prostate cancer hasn’t historically been as robust, which means we need to [conduct] further development.³

The current data for gocatamig are encouraging, where this asset comes in that’s being developed, with response rates near 20%. [This is] obviously not as high as tarlatamab is in lung cancer and not as high as we think this asset might be in other areas as well. But it goes to show the heterogeneous nature of NEPC. Interestingly, we saw responses in both DLL3-low and DLL3-high tumors. The other thing is, if we’re only hitting the DLL3 clones, is there something else going on in the heterogeneous nature of those traditional adenocarcinoma cells? There’s no specific cutoff that this had to be a 100% small cell prostate cancer population. We’re still learning about that.

We’re seeing encouraging signals, and while that response rate seems relatively modest, many additional patients achieved a mild reduction of tumor [size], not hitting the 30% threshold for a response. When you look at the [disease control] rate, a significant number of patients are benefiting. It’s early, and there’s still some work to be done, but we need to do it because this asset does look like it has good activity in NEPC.

When is the optimal time to introduce a DLL3-targeted agent, and should clinicians be performing earlier repeat biopsies to catch neuroendocrine transformation?

That is the answer. Any patient who develops liver metastases should have a biopsy of that visceral disease. That’s a relatively easy thing to get out there. If you have a biopsy of a lesion in the liver, we should be doing that upon hormone resistance. Neuroendocrine and small cell prostate cancers have a predilection for the liver. We should be performing these biopsies at the first sign of hormone resistance.

For true small cell prostate cancer, the paradigm is to treat it with platinum/etoposide chemotherapy, possibly with immunotherapy. DLL3 assets could then layer in as a second-line option. It’s more complex for patients transitioning from adenocarcinoma to neuroendocrine disease. Once they have progressed through chemotherapy regimens like carboplatin and cabazitaxel, that is the time to consider a DLL3-targeted agent.

I’m intrigued and excited about where these assets can go. We cannot rely on blood draws to indicate neuroendocrine histology; we need tissue samples. However, molecular signatures—such as the loss of PTEN and RB1 and TP53 mutations—can serve as “aggressive variant” indicators that a patient is likely harboring neuroendocrine elements due to cell-cycle dysregulation. It’s hard; it’s not one size fits all. The easy solution is, if you have a liver metastasis, biopsy it.

References

1. Parikh RA, Herzberg B, Stein MN, et al. A phase 1/2 study of MRT-2359, a highly selective oral GSPT1 molecular glue degrader (MGD), in combination with enzalutamide in metastatic castration-resistant prostate cancer (mCRPC) harboring AR ligand binding domain (LBD) mutations. J Clin Oncol. 2026;44(suppl 7):161. doi:10.1200/JCO.2026.44.7_suppl.161
2. Beltran H, Cooper AJ, Sankar K, et al. Efficacy and safety of the DLL3 T-cell engager gocatamig in participants (pts) with neuroendocrine prostate cancer (NEPC) and other neuroendocrine neoplasms (NEN). J Clin Oncol. 2026;44(suppl 7):182. doi:10.1200/JCO.2026.44.7_suppl.182
3. Aggarwal RR, Rottey S, Bernard-Tessier A, et al. Phase 1b study of tarlatamab in de novo or treatment-emergent neuroendocrine prostate cancer (NEPC). J Clin Oncol. 2024;42(suppl 16):5012. doi:10.1200/JCO.2024.42.16_suppl.5012