Redefining mHSPC Sequencing: Exploring Impact of PSMAddition

The findings from the phase 3 PSMAddition trial (NCT04720157) are poised to further diversify the treatment landscape for metastatic hormone-sensitive prostate cancer (HSPC). As discussed by Scott Tagawa, MD, MS, FACP, FASCO, at the 19th Annual New York GU Cancers Congress, the trial demonstrated a 28% improvement in radiographic progression-free survival (PFS) when adding lutetium Lu 177 vipivotide tetraxetan (Pluvicto) to the current standard of care—a doublet of androgen deprivation therapy (ADT) and an androgen receptor pathway inhibitor (ARPI).

While ADT plus ARPI remains the primary standard for patients with untreated metastatic disease, Tagawa noted that the potential approval of this radioligand triplet would introduce a powerful new option for PSMA-positive populations. However, the integration of this therapy requires careful sequencing considerations. Current triplets involving docetaxel or PARP inhibitors like niraparib for BRCA2 mutations already exist, and long-term data on how lutetium-177 compared with these established regimens is still emerging, with current follow-up at a median of 2 years. Ultimately, the choice of upfront therapy significantly influences subsequent treatment lines, making it essential to monitor for potential adverse effects and overall survival benefits as the data matures. This evolving paradigm reinforces the need for personalized therapy selection based on molecular profiling and disease volume.

Tagawa is a professor of medicine and urology at Weill Cornell Medicine and an attending physician at NewYork-Presbyterian/Weill Cornell Medical Center.

Transcript:

If I think about those that present with untreated metastatic disease, whether it’s de novo or recurrent, we now have a number of different options, but I’d say the most standard for the average patient is going to be an ADT plus ARPI doublet.

There are several other potential combinations that are there, whether it’s treatment to the primary…or systemic therapy. The 2 current ones I would say, would be docetaxel, even though we haven’t proven that that’s any benefit, adding to ADT plus ARPI, or what is a proven benefit is BRCA2 with niraparib, and that’s an FDA-approved drug. PSMAddition enrolled overlapping patient population. [Patients who were] PSMA-positive, unknown for HRD, but we’ll look at that in some in some of the correlatives––with a lot less in terms of the rigor in calling a PSMA-PET.

The primary end point of radiographic PFS and what’s called the PSMAddition trial is there, most of the other secondary objectives are either slightly in favor of the lutetium-177 or null. The caveat is early follow ups. This is about a median of 2 years in terms of the study. If that were approved today, it would be an option. What we need to tell patients is that we don't know that it's better or worse than docetaxel in a triplet, better or worse than olaparib in a triplet, totally different patients there. Whatever they get, how we’re upfront clearly influences subsequent therapy.

Reference

Kim H, Tagawa ST, Sartor AO, et al. PSMAddition: phase 3 trial of [¹⁷⁷lu]Lu-PSMA-617 plus standard of care (SoC) vs. Soc alone in patients with metastatic hormone-sensitive prostate cancer. Radiat Oncol Biol Phys. 2024;120(suppl 2):e564. doi:10.1016/j.ijrobp.2024.07.1209