Personalized treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) has become increasingly important in the face of an ever-evolving treatment landscape. The 2026 ASCO Annual Meeting highlighted potentially practice-shaping data from key clinical trials in the metastatic setting, including the TALAPRO-3, PLUDO, and ARACOG studies.

Following these presentations, featured expert Rana R. McKay, MD, FASCO, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Clinical perspectives from Dr McKay on these findings are presented here.

At ASCO 2026, some of the most important data presented on treatment personalization in metastatic prostate cancer were the top-line data from the phase 3 TALAPRO-3 trial, which were presented by Neeraj Agarwal, MD, FASCO (abstract LBA5007). TALAPRO-2 investigated talazoparib/enzalutamide in the frontline mCRPC setting, while TALAPRO-3 looked at this combination in the frontline metastatic castration-sensitive prostate cancer setting in patients with HRR alterations. Overall, TALAPRO-3 was resoundingly positive, demonstrating an improvement in progression-free survival (PFS). Overall survival (OS) is still immature; however, in the exploratory analysis, we are seeing the hazard ratio favoring the combination. Ultimately, this tells us that patients with HRR-mutated tumors, namely BRCA1/2-mutated tumors, really seem to derive benefit from early PARP inhibition. Overall, I think that these data will be practice changing.

Another key presentation at ASCO 2026 featured the results from the phase 2 ARACOG (AFT-47) study (abstract 5005). Here, Alicia K. Morgans, MD, MPH, FASCO, presented the first report from this study looking at the cognitive effects of enzalutamide vs darolutamide using the computer-based platform CANTAB (Cambridge Cognition) to monitor change in cognitive function. Overall, this was really a positive trial that met its primary end point. There are nuanced differences between these agents; each carries a different side-effect profile, and this is the first time they have been looked at in the context of a single study. Going forward, I think that this is going to be an important consideration for clinicians as they prescribe medications.

The phase 2 PLUDO trial (Canadian Cancer Trials Group [CCTG] PR21), which was presented by Kim N. Chi, MD, at ASCO 2026, is another really important study to consider (abstract 5019). In this trial, patients with mCRPC received either ¹⁷⁷Lu-PSMA-617 or docetaxel, with crossover permitted at radiographic progression. The primary analysis of this trial was first presented at the European Society for Medical Oncology (ESMO) Congress 2025 in Berlin, showing no significant difference in the primary end point of first-line radiographic PFS (rPFS) between the 2 arms but a statistically significant OS advantage favoring the patients who were randomized to docetaxel first.

The data presented at ASCO 2026 reported the results of a planned crossover analysis. In the top-line data, there was not a tremendous difference in rPFS between the patients who received docetaxel followed by ¹⁷⁷Lu-PSMA-617 vs those who received ¹⁷⁷Lu-PSMA-617 followed by docetaxel. However, interestingly, there were more patients who crossed over from docetaxel to ¹⁷⁷Lu-PSMA-617, and there was an improvement in OS in patients who received the docetaxel-to-¹⁷⁷Lu-PSMA-617 sequence vs those who received the ¹⁷⁷Lu-PSMA-617-to-docetaxel sequence. This is due to more patients who started with docetaxel crossing over to a second life-prolonging therapy (ie, ¹⁷⁷Lu-PSMA-617). Most individuals really have an aversion to chemotherapy, so many of those who started with ¹⁷⁷Lu-PSMA-617 did not go on to receive a second life-prolonging therapy.

Dr Chi also reported on the second-line rPFS, rPFS2, OS, and OS2 data. Like the top-line results, the efficacy outcomes were nearly the same for both crossover sequences, but, again, I think that there were fewer patients who crossed over from ¹⁷⁷Lu-PSMA-617 to docetaxel. Ultimately, this tells us that, regardless of the sequence in which these treatments are received, patients derive benefit.

I think that the clinical science symposium titled, “Radiation Re-Imagined: Radioligand Innovation in Prostate Cancer,” chaired by Andrei Iagaru, MD, and Sophia C. Kamran, MD, was eye-opening. There is currently a lot in the pipeline. For example, lutetium is a beta-emitting prostate-specific membrane antigen (PSMA)–targeted RLT, but there are also several alpha-emitter RLTs being developed. Overall, I think that this is going to be an evolving area.

One such alpha-emitter RLT is ²²⁵Ac-PSMA-617. At ASCO 2026, Louise Emmett, MD, PhD, MBChB, FRACP, presented the phase 1 AcTION clinical trial in patients with PSMA+ mCRPC with or without prior ¹⁷⁷Lu-PSMA-617 exposure (abstract 5010). This was an important dose-escalation study, and it identified the recommended phase 2 dose for ²²⁵Ac-PSMA-617. The study included 3 cohorts: group A included patients who had prior chemotherapy and ARPI exposure, but no prior ¹⁷⁷Lu-PSMA-617 exposure; group B included chemotherapy/ARPI/¹⁷⁷Lu-PSMA-617–naive patients (so, those who were basically just exposed to prior ADT); and group C included patients who were previously treated with ¹⁷⁷Lu-PSMA-617, regardless of their chemotherapy and ARPI exposure. Patients received different doses (4, 6, 8, or 10 MBq) intravenously every 8 weeks. What was nice is that we saw antitumor activity across all cohorts. There are data on ²²⁵Ac-PSMA-617 activity in patients with prior ¹⁷⁷Lu-PSMA-617 exposure, as addressed in cohort C, which demonstrated a prostate-specific antigen response of 52.5%. This was lower compared with the RLT- and chemotherapy-naive patients in group B (85.2%) but still pretty respectable.

Overall, when it comes to personalizing treatment for patients with mCRPC, there are a lot of options. There is chemotherapy as well as ¹⁷⁷Lu-PSMA-617, and, in a subset of individuals with HRR alterations, PARP inhibitor therapy is an option. Presently, we are using clinical parameters to help guide treatment decisions. However, to help ensure that we sequence and strategize therapies appropriately, it is important to understand what is going on with the patient with regard to their clinical, genetic, and imaging phenotypes. Our hope is that this evolves into a more personalized approach that leverages factors such as PSMA positron emission tomography findings and molecular features to help make sure that patients with mCRPC are receiving the best treatment at the right time.