Lutetium Lu 177 Vipivotide Tetraxetan Approval Reshapes the Treatment Landscape for PSMA+ mHSPC

The July 2026 FDA approval of lutetium Lu 177 vipivotide tetraxetan (Pluvicto) plus an androgen receptor pathway inhibitor (ARPI) for the treatment of adult patients with prostate-specific membrane antigen (PSMA)–positive metastatic androgen pathway modulation–naive/sensitive prostate cancer, also known as metastatic hormone-sensitive prostate cancer (mHSPC), represents a significant advancement for both patients and providers, according to Michael J. Morris, MD.

The approval was supported by data from the phase 3 PSMAddition trial (NCT04720157), in which treatment with lutetium Lu 177 vipivotide tetraxetan in combination with standard-of-care ARPI and androgen deprivation therapy (ADT; n = 572) led to a 28% reduction in the risk of progression or death vs standard-of-care therapy alone (n = 572; HR, 0.72; 95% CI, 0.58-0.90).^1,2 Findings from an updated analysis showed that the lutetium Lu 177 vipivotide tetraxetan regimen further reduced the risk of progression or death (HR, 0.67; 95% CI, 0.55-0.82), and showed a positive trend toward improved overall survival (OS) outcomes (HR, 0.80; 95% CI, 0.63-1.01). Data will continue to mature before the final OS analysis. ¹

In an interview with OncLive, Morris, the Prostate Cancer Section head of Genitourinary Oncology and the Steven A. Greenberg Chair in Prostate Cancer Research at Memorial Sloan Kettering Cancer Center in New York, New York, discussed additional data from PSMAddition, the significance of the approval for oncologists practicing in the community, and the future of lutetium Lu 177 vipivotide tetraxetan in prostate cancer management.

OncLive: What was the design of the PSMAddition trial that led to this approval?

Morris: Lutetium Lu 177 vipivotide tetraxetan to date has been approved primarily for patients who have been treated with, and then progressed through, ADT and at least one ARPI. It's mainly been used in what we used to call castration-resistant prostate cancer and now call APMR [androgen pathway modulator–resistant].

The PSMAddition trial [included] patients were androgen pathway modulator–sensitive, what we used to call metastatic castration-sensitive disease, and [they] were [randomly assigned] against the standard of care, which is ADT plus an ARPI. The randomization was either to the triplet of ADT, ARPI, and lutetium Lu 177 vipivotide tetraxetan, or to the control arm of the doublet, ADT and an ARPI.

The study enrolled 1144 randomized patients who were PSMA avid: They needed a PSMA-PET scan to confirm the tumor expresses the target. They either received 6 doses [of lutetium Lu 177 vipivotide tetraxetan] given every 6 weeks per the usual standard, in addition to ADT and ARPI, or they received just the ADT and the ARPI. Essentially, there were 36 weeks during which the two arms differed, during which 1 group received triplet therapy with lutetium and the other received doublet therapy with ADT and an ARPI.

The reason for approval was that the primary end point, radiographic progression-free survival [rPFS], favored the triplet therapy over the doublet therapy with a 33% reduction in the risk of progression or death in favor of the triplet [in the updated analysis]. That's not the totality of the data, though; the data also trended toward an OS benefit, and the longitudinal quality-of-life [QOL] data were quite similar between the triplet and doublet arms.

Were there any additional data to note and/or any subgroup findings?

There were grade 3 or worse adverse effects [AEs] in [50.7]% of [patients in] the experimental arm vs [43.0]% of the control arm, but again, the QOL data, which I presented longitudinally at the 2026 Genitourinary Cancer Symposium, looked quite similar between the 2 arms. [A] common AE was xerostomia, occurring in 46% of patients in the lutetium arm vs [3.7]% in the control arm. This is a well-known lutetium Lu 177 vipivotide tetraxetan–related AE, given PSMA expression and drug uptake in the salivary glands, but these events were grade 1 or 2, and none were serious.

There's also updated OS data now available [from] Novartis, along with updated rPFS data. The updated rPFS HR is now 0.67, which is somewhat more favorable than what's in the label and publication. The most recent OS data show a HR of 0.80, with an upper bound of the confidence interval at 1.01. That point estimate shows a trend toward an OS benefit. The rPFS data keep getting more compelling as more events accrue, and I think this is clearly a positive study in favor of treatment for this hormone-sensitive population.

When most people think of triplet therapy that isn't selected for BRCA or another HRD gene, and isn't selected for a [patient with] PTEN-deficient [disease], they're thinking historically about chemotherapy. However, what we don't know from the chemotherapy data is whether chemotherapy confers a survival or clinical benefit more generally when added to ADT and an ARPI; those docetaxel data were generated in an era when docetaxel was the control arm, and the experimental question was whether an ARPI added benefit to ADT plus docetaxel. This trial addresses contemporary treatment patterns: everyone received ADT and an ARPI, and the question was whether lutetium confers clinical benefit on top of that contemporary standard. The answer is yes.

There may still be patients who should receive chemotherapy. For example, those without PSMA-avid disease should certainly get chemotherapy, and there are patients for whom, based on other histologic features, chemotherapy may be preferable. However, using a contemporary, active control arm, this trial shows that lutetium Lu 177 vipivotide tetraxetan, added to ADT and an ARPI, can confer clinical benefit.

We've seen a couple of label expansions for this agent over the years. What do you think the future holds?

There's an ongoing randomized study looking at this agent one step earlier than PSMAddition in patients with oligometastatic disease who are PSMA-avid, and that trial [the phase 3 PSMA-DC study (NCT05939414)] eliminates ADT altogether. It's a trial of stereotactic body radiation therapy with or without lutetium Lu 177 vipivotide tetraxetan, and it's ongoing.

Looking at the field beyond lutetium Lu 177 vipivotide tetraxetan specifically, there are several randomized phase 3 registration studies evaluating actinium-PSMA–directed therapy across metastatic castration-resistant disease, both in the post–lutetium Lu 177 vipivotide tetraxetan and pre–lutetium Lu 177 vipivotide tetraxetan settings. There are also early studies using alpha emitters with lead-212 that are maturing to the point where we'll have data comparing lead-212 with actinium. And there are new targets emerging as well: ACP3, B7-H3, and STEAP2 are all promising targets.

There are many second-generation PSMA-directed and non-PSMA–directed therapies in various stages of development. Actinium-PSMA agents are furthest along, in phase 3; the non-PSMA–targeted theranostics are [at an] earlier stage; and the lead-212 agents are earlier stage as well. So, generation 2 and generation 3 theranostics are well underway in development, and that's just in prostate cancer.

If you had one takeaway for community oncology colleagues about this approval, what would it be?

First, there are now many options for patients with metastatic HSPC. For patients with a BRCA2 mutation, there's abiraterone acetate [Zytiga] plus niraparib [Zejula], which is already approved. We don't yet know what the approval will look like for [talazoparib (Talzenna) plus enzalutamide (Xtandi)] from the [phase 3] TALAPRO-3 study [NCT04821622], whether it will be a broad indication or something more specific, as was done with niraparib, but that should be an option for [patients with] metastatic HSPC/APMS with an HRD mutation, so stay tuned on that approval. For the PTEN-altered patient, there's ADT and ARPI with capivasertib [Truqap]. For the PSMA-avid patient, there's ADT, ARPI, and lutetium Lu 177 vipivotide tetraxetan. And for those for whom lutetium Lu 177 vipivotide tetraxetan might not be appropriate or whose disease isn’t PSMA-avid, there's ADT, ARPI, and chemotherapy with docetaxel. There are quite a few choices now, and I think it's incumbent on all of us to generate the data on who benefits most from which approach.

Second, for that large group of patients for whom ADT, ARPI, and lutetium Lu 177 vipivotide tetraxetan is a consideration, working hand in hand with nuclear medicine or radiation oncology colleagues and partners is important to building the best multidisciplinary team for the patient.

References

1. FDA approves Pluvicto for PSMA+ metastatic hormone-sensitive prostate cancer (mHSPC), advancing potential new standard of care across metastatic disease. News release. Novartis. July 31, 2026. Accessed August 12, 2026. https://www.novartis.com/news/media-releases/fda-approves-pluvicto-psma-metastatic-hormone-sensitive-prostate-cancer-mhspc-advancing-potential-new-standard-care-across-metastatic-disease
2. FDA approves lutetium Lu 177 vipivotide tetraxetan with androgen receptor pathway inhibitor therapy for metastatic androgen pathway modulation-naïve or -sensitive prostate cancer. FDA. July 31, 2026. Accessed August 12, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lutetium-lu-177-vipivotide-tetraxetan-androgen-receptor-pathway-inhibitor-therapy