Over the past decade, many therapies have received US Food and Drug Administration (FDA) approval for advanced prostate cancer, but there remains a need for additional treatment options, particularly for people who develop castration-resistant disease. At the ESMO Congress 2024, abstracts were presented from clinical trials evaluating emerging therapies for patients with advanced prostate cancer.

Following these presentations, featured expert Andrew J. Armstrong, MD, MSc, was interviewed by Conference Reporter Associate Editor-in-Chief Christopher Ontiveros, PhD. Dr Armstrong’s clinical perspectives on these proceedings are presented here.

The ARPIs darolutamide, apalutamide, enzalutamide, and abiraterone have really extended the lives of our patients with both metastatic castration-resistant prostate cancer (mCRPC) and metastatic hormone-sensitive prostate cancer (mHSPC). One of the interesting ARPI studies presented at the ESMO Congress 2024 was the PEACE-3 trial, which was designed back when we used ARPIs in the first-line mCRPC setting and tested whether the bone-targeting alpha emitter radium-223 could extend radiological progression-free survival (PFS) when added to enzalutamide and ADT as first-line therapy in patients with mCRPC who had at least 4 bone metastases (abstract LBA1). The study found that radium-223 plus enzalutamide significantly increased radiological PFS and interim overall survival (OS) vs enzalutamide alone. The use of bone-protective agents in this study mitigated the increased fracture risk that was seen with radium-223 plus enzalutamide.

While PEACE-3 was a positive trial, it is not particularly practice changing in the United States because we use ARPIs in the mHSPC or nonmetastatic CRPC setting, so, by the time a patient develops mCRPC, they have already been exposed to and progressed on an ARPI. However, I think that the PEACE-3 trial does provide very clear justification that it is safe to give enzalutamide with radium-223 in patients with mCRPC and bone metastases if you use a bone-protective agent. I may consider this in selected patients post abiraterone/prednisone who are choosing to receive radium-223 as their next line of therapy prior to docetaxel.

Although patients benefit from ARPIs, the development of cross-resistance is pretty inevitable in the metastatic setting. A major focus is on developing new therapies that have non–cross-resistant mechanisms of action. There is a lot of interest in bispecific T-cell engagers, CAR T cells, ADCs, and new radioligand therapies.

A phase 1/2 study presented at this year’s ESMO Congress that I would like to highlight is the oral abstract by Dana E. Rathkopf, MD, and myself on a novel, dual AR-directed degrader and antagonist called BMS-986365 in patients with heavily pretreated mCRPC post ARPI therapy (abstract 1597MO). We found that the use of this AR degrader can result in prostate-specific antigen responses that were sometimes very durable. The median radiographic PFS with BMS-986365 was 6.3 months, which increased to 16.5 months in patients who had not received prior chemotherapy. The drug was well tolerated with manageable toxicities. Interestingly, BMS-986365 was active in patients who had either wild-type AR or AR with ligand-binding domain mutations, which is a common mechanism of resistance to ARPIs. I have many patients who have been on BMS-986365 for 2 years now, and I expect this drug to continue in its development toward phase 3 trials. Toxicities were mild but still notable for prolonged QTc intervals, including grade 3 events at higher doses, as well as bradycardia, and these may limit the ability to dose this agent at high doses.

Xaluritamig, a STEAP1-targeting bispecific T-cell engager, is another novel drug on which data were presented at the ESMO Congress 2024. STEAP1 is a common cell-surface protein that is highly expressed in prostate cancer. Earlier this year, my colleagues and I published the results of a first-in-human study of xaluritamig. At this year’s ESMO Congress, we updated those results in 2 posters (abstracts 1610P and 1598P). In abstract 1610P, which I presented at the meeting, we showed that in 97 patients with heavily pretreated mCRPC, 54.7% of whom had visceral metastases, the median OS was 17.4 months. These are pretty remarkable results as compared with historical data for cabazitaxel or ¹⁷⁷Lu-PSMA-617, where the median OS was typically 12 to 15 months in the refractory setting. We showed that xaluritamig was associated with rapid reductions in circulating tumor cells and prostate-specific antigen declines, which were associated with better OS outcomes. Abstract 1598P showed that xaluritamig can cause cytokine release syndrome, which is rapidly reversible with steroids and/or tocilizumab. Step dosing and premedication with steroids also increase tolerability, and patients can be on this therapy for many months. Xaluritamig is now moving on in development and will probably be the first bispecific T-cell engager to be tested in a phase 3 randomized trial in prostate cancer.

Another abstract presented at the ESMO Congress 2024 that I thought was interesting was from the STAMPEDE and PATCH trial sites and tested transdermal estradiol patches vs LHRH agonists (abstract LBA69). This study showed that using estradiol patches is as effective as using LHRH agonist therapy. LHRH agonist toxicities differ from those of estrogens; for example, estrogen tends to cause fewer hot flashes and be more bone protective but causes more gynecomastia, which can be painful. So, I think that if you have certain patients who want to switch from LHRH agonists to something else due to side effects or because they have osteoporosis, these data suggest that you do not compromise efficacy by switching to estradiol patches. Prophylactic breast radiation would be necessary for those who opt for estradiol patches.