Expanded FDA Approval Broadens the Role of Lutetium Lu 177 Vipivotide Tetraxetan in PSMA+ mCRPC

Michael J. Morris, MD

The FDA’s recent expanded approval of lutetium Lu 177 vipivotide tetraxetan (Pluvicto) in patients with metastatic castration-resistant prostate cancer (mCRPC) represents a notable shift in treatment sequencing and provides an additional option for select patients prior to chemotherapy, according to Michael J. Morris, MD.

On March 28, 2025, the FDA expanded the indication for lutetium Lu 177 vipivotide tetraxetan to include adult patients with PSMA-positive mCRPC who have been treated with androgen receptor pathway inhibitor (ARPI) therapy and are considered appropriate to delay taxane-based chemotherapy.

The regulatory decision was supported by data from the phase 3 PSMAfore trial (NCT04689828). Findings demonstrated that in patients with PSMA-positive mCRPC who received prior treatment with an ARPI and were considered appropriate for delayed taxane-based chemotherapy, lutetium Lu 177 vipivotide tetraxetan (n = 234) generated a median radiographic progression-free survival (rPFS) of 9.3 months (95% CI, 7-not estimable) vs 5.6 months (95% CI, 4-6) a second-line ARPI (n = 234; HR, 0.41; 95% CI, 0.29-0.56; P < .0001).

“Quality of life [QOL] and pain control were [also] better maintained—it wasn't just a pure radiographic end point. Lutetium Lu 177 vipivotide tetraxetan was superior in controlling disease and in maintaining QOL and pain control [over] a second-line ARPI,” Morris explained.

In an interview with OncLive®, Morris discussed the clinical implications of the expanded approval of lutetium Lu 177 vipivotide tetraxetan, how the agent fits into the pre-chemotherapy setting in the management of mCRPC, and factors for selecting therapies for patients who may be eligible for lutetium Lu 177 vipivotide tetraxetan under the updated indication.

Morris is a medical oncologist and clinical director of Genitourinary Medical Oncology at Memorial Sloan Kettering Cancer Center in New York, New York.

OncLive: What is the significance of this expanded approval of Lutetium Lu 177 vipivotide tetraxetan?

Morris: In the past, lutetium Lu 177 vipivotide tetraxetan was only approved in a very late clinical context for [patients with] castration-resistant patient [disease] who was [previously treated with] ADT and an ARPI, and chemotherapy [following an ARPI]. [With the previous indication for lutetium Lu 177 vipivotide tetraxetan], we were talking about patients toward the end of life. The reality is that in that context, [these] patients [had] probably been [heavily] pretreated, their disease is pretty extensive, and their normal organ functionality is somewhat compromised.

[The updated] approval expands the use [of lutetium Lu 177 vipivotide tetraxetan] from that very late context to the pre-chemotherapy setting—in today’s day and age, that means for first-line mCRPC. If we think about what we [use] as the standard of care for most patients with mCRPC, most of those patients should have already received and progressed through ADT [and an ARPI]. Patients who have received and progressed through those [prior treatments] can now go on directly to lutetium Lu 177 vipivotide tetraxetan.

[The expanded approval] is a different clinical context in many respects. It sounds nominal to say that it has moved from a post-chemotherapy context to a pre-chemotherapy context, but that is quite a different patient population. [Patients in the pre-chemotherapy setting have a survival] difference that's measured in years, in terms of their potential for longevity, [and] the approval is more clinically relevant than the label might suggest.

[However, regarding potential targeted therapy indicated for this patient population, It’s important to note that] the PSMAfore trial did not [enroll] patients who were homologous recombination deficiency [HRD] positive, [defined as the presence of] a BRCA1/2 mutation or another DNA repair deficiency. [Patients with HRD-positive disease] needed to receive a PARP inhibitor up-front before they went on to the PSMAfore study. That is a reasonable continuation in terms of standard practice. If there's an actionable mutation, patients should have that acted on, and I would consider that to be a targeted therapy. We still would say a patient [with HRD-positive disease] should get a PARP inhibitor up-front, and then you can consider [using] a PSMA-directed therapy like lutetium Lu 177 vipivotide tetraxetan or chemotherapy.

The PSMAfore trial did not address the appropriate role for chemotherapy. There was no chemotherapy involved in this study, so [the data] do not give us a sense as to whether it is the same as, inferior to, or superior to chemotherapy [in this mCRPC setting].

The trial eligibility criteria specifically said the patients could not be chemotherapy candidates, either because the patient refused or the doctor and patient agreed that the patient couldn't tolerate chemotherapy. Therefore, that's a separate decision as to whether a patient should get lutetium Lu 177 vipivotide tetraxetan or docetaxel [in this setting].

What advice would you offer clinicians seeking to integrate lutetium Lu 177 vipivotide tetraxetan into practice and into earlier lines of therapy?

My advice is to treat each patient as an individual. Some decisions need to be made in terms of when a patient progresses on their first-line ARPI as to what therapy they should get next.

All patients should undergo genomic sequencing to ensure that they aren't candidates for a PARP inhibitor. If they do have an actionable mutation, a small percentage of those might be eligible for a checkpoint inhibitor, but that [represents] a true minority of patients. For most [patients with] prostate cancer, there won't be an [actionable] mutation, and a second-line ARPI should no longer be in the discussion.

What steps should be taken to determine a treatment for a patient who may be eligible for lutetium Lu 177 vipivotide tetraxetan?

First, get a PSMA scan and see if a patient is a candidate for lutetium Lu 177 vipivotide tetraxetan; if they are, then [you need to determine if a] patient is fit for chemotherapy. Do you think that they are a good patient for this [radioligand] therapy?

[You also should consider] tumors characteristics. Does it have, for example, neuroendocrine differentiation? Does it have P53 or RB1 mutations? All of those go into this treatment decision-making. Is this patient better off getting chemotherapy or lutetium Lu 177 vipivotide?

Finally, does the patient want chemotherapy? Do they have the performance status and the normal organ functionality to sustain chemotherapy? What are the patient's values and ideals in terms of going forward?

We don't have head-to-head data on lutetium Lu 177 vipivotidevs chemotherapy in this context. However, chemotherapy trials historically have an shown QOL detriments associated with chemotherapy, and [lutetium Lu 177 vipivotide tetraxetan] does not have that same QOL profile in terms of its adverse effects.

I would be remiss in saying that there are some patients with very advanced disease for whom other clinical trials might be appropriate, and for whom there are other considerations. Certainly, in the very advanced patient population, palliative care should be entertained.

There are arguments about using [lutetium Lu 177 vipivotide] early vs using it late, but in the end, you take each patient as an individual. [You need to consider] the patient’s disease, characteristics, previous treatments, response [to prior therapy], and genomic and other biomarker [factors]. Talk to the patient in terms of AE profiles and what he wants in terms of QOL vs longevity. Make a shared decision [with the patient] as to how to approach the next therapy.

Reference

FDA expands Pluvicto’s metastatic castration-resistant prostate cancer indication. FDA. March 28, 2025. Accessed April 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-pluvictos-metastatic-castration-resistant-prostate-cancer-indication