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Scott Tagawa, MD, MS, FACP, FASCO, discusses data for lutetium Lu 177 vipivotide tetraxetan in mHSPC from the PSMAddition trial.
The integration of radioligand therapy into the metastatic hormone-sensitive prostate cancer (mHSPC) setting inched closer to reality with the initial readout of data from the phase 3 PSMAddition trial (NCT04720157), according to Scott Tagawa, MD, MS, FACP, FASCO.
Findings from PSMAddition presented at the 2025 ESMO Congress demonstrated that patients with prostate specific-membrane antigen (PSMA)–positive mHSPC treated with lutetium Lu 177 vipivotide tetraxetan (Pluvicto) in combination with an androgen receptor pathway inhibitor (ARPI) and androgen deprivation therapy (ADT; n = 572) achieved a median radiographic progression-free survival (rPFS) that was not reached (NR; 95% CI, not evaluable [NE]-NE) vs NR (95% CI, 29.7-NE) in those treated with an ARPI plus ADT alone (n = 572; HR, 0.72; 95% CI, 0.58-0.90; P = .002).1
In an interview with OncLive®, Tagawa discussed past and present factors that impacted the investigation of lutetium Lu 177 vipivotide tetraxetan in the mHSPC setting. He also reviewed the important efficacy and safety findings from the trial, in addition to the next steps for evaluating lutetium Lu 177 vipivotide tetraxetan in mHSPC.
Tagawa is a professor of medicine and urology at Weill Cornell Medicine and an attending physician at NewYork-Presbyterian – Weill Cornell Medical Center.
Tagawa: It's nice that we have approvals in the later, more heavily pretreated patient population, but we do not think that's optimal. For tumors that are more heavily pretreated, we believe they are more likely to lose PSMA [expression] to some extent, or be PSMA-low, and have more inherent radio-resistance, which we think is the mechanism of action with lutetium products. Moving [lutetium Lu 177 vipivotide tetraxetan] earlier to a disease state that is more universally PSMA expressing and less likely to be radio-resistant made sense.
PSMAddition was a true combination study. We know that at least pre-clinically, when we add hormonal therapy to a prostate cancer cell that has the androgen receptor, there is upregulation of PSMA, and there are also separate data that there may be radio-sensitization. All of that together made sense to move [lutetium Lu 177 vipivotide tetraxetan] forward, and we tend to do this anyway in drug development: start with the biggest unmet need when there is nothing else available, and then try to improve upon what we have [by] moving [drugs] earlier [in the treatment paradigm].
This [trial] took a [standard-of-care (SOC)] backbone, which hopefully almost all patients [with mHSPC] are getting [in real-world practice]. We know it is not 100%, and we want to make it close to 100% because ADT plus ARPI is very effective. [This trial] took that backbone, [and it was given] with or without up to 6 cycles of lutetium Lu 177 vipivotide tetraxetan at the regular dose of 7.4 GBq every 6 weeks, looking to improve rPFS as the primary end point.
[Patients needed to have] metastatic disease on CT, bone scan, or MRI, not just a PSMA PET [scan]. [However], a PSMA PET [scan] was done, and there had to be at least 1 tumor that lit up visually more than the liver. The normal performance status and organ function criteria that we would expect in a phase 3 trial [were included].
Fortunately, [the addition of lutetium Lu 177 vipivotide tetraxetan] led to a positive trial in terms of the primary end point, where vs a very effective SOC therapy, we improved rPFS by 28%. We were trying to hit a minimum of 23.5%, and we hit 28%, which made it a positive trial.
This was an early readout, as it was the first interim analysis for efficacy. At that time point, approximately 60% of the patients in the control arm had confirmed progression [and were allowed to] cross over to lutetium Lu 177 vipivotide tetraxetan as part of the study design—partly for ethical reasons and to ensure the integrity of the study, because it was an open-label study. [The crossover design] may impact more than one of the secondary end points, but more specifically, overall survival [OS]. That secondary end point is very premature, but at the first planned interim analysis, and the hazard ratio [HR] was in favor of the lutetium Lu 177 vipivotide tetraxetan, despite that early crossover. The HR confidence intervals currently cross 1, but we'll see what happens. I don't know that we need to have clear OS benefit because of the crossover, since we know the drug already has OS benefit [in the mCRPC setting].
Additional secondary efficacy end points favored lutetium Lu 177 vipivotide tetraxetan, such as changes in prostate-specific antigen [levels], response [rate], time to symptomatic skeletal events, and other secondary end points, so that was nice to also see.
This was the third phase 3 with [lutetium Lu 177 vipivotide tetraxetan], so there was not much in the way of surprise. What we saw for the common adverse effects [AEs] were what we expect from the 3 components: ADT, ARPI, and lutetium Lu 177 vipivotide tetraxetan. Many of the most common AEs that were more common in the lutetium arm were related, at least in part, to sites of normal PSMA expression, such as salivary glands, lacrimal glands, and small intestine; dry mouth was the most common. Dry eye also happened more commonly with lutetium Lu 177 vipivotide tetraxetan, and then gastrointestinal toxicity because of small intestine uptake included nausea, vomiting, diarrhea, and constipation, which were expected. Fatigue was also more [common], which is not surprising with radiation flowing throughout the body at certain timepoints.
Interestingly, some of the purer hormonal AEs were more common in the non–lutetium Lu 177 vipivotide tetraxetan arm, even though both groups got ADT and an ARPI—maybe it was just more noticeable [in the control arm] in terms of hot flashes and hypertension. There was also more in the way of cytopenias. [Lutetium Lu 177 vipivotide tetraxetan] is a little bit different than chemotherapy, where we don't expect a high amount of neutropenia, but there was some neutropenia, [and] certainly anemia and thrombocytopenia, which we do expect with this particular drug. At least separately, none of them were more than 5% at grade 3/4. High-grade cytopenias were limited to a small proportion [of patients].
We will potentially have 4 different triplets, and I don't think that 100% of patients necessarily are going to need a triplet—100% do not necessarily need a doublet, either. There is going to be some clinical patient selection, as well as some biomarker patient selection. We know [lutetium Lu 177 vipivotide tetraxetan] has a biomarker of PSMA PET, so that will be part of the patient selection. We do know that because the available data points toward improved efficacy that some patients should get [lutetium Lu 177 vipivotide tetraxetan].
Most patients in the [mHSPC] disease state are in the hands of urologists, some are in the hands of oncologists, but neither medical oncologists nor urologists are what we would call authorized users, so we can't administer [radioligand therapies]. We can [administer] ADT and an ARPI, but we need to refer to either radiation oncologists or nuclear medicine physicians, or both, [for lutetium Lu 177 vipivotide tetraxetan]. [The integration of radiation oncologists and nuclear medicine physicians] started to happen a long time ago with Radium-223 [Xofigo] for [patients with] painful bone metastases. That is a more limited patient population than the PSMA-targeted radionuclides, which are much more common in hormone-resistant disease. Moving [lutetium Lu 177 vipivotide tetraxetan] earlier really expands the patient population. We need to make sure that we are able to coordinate and increase the number of senders and authorized users across the country.
The earliest one [being analyzed] right now is quality of life. Broadly speaking, there was no major differences in terms of the patient outcomes, but there might be a tendency to have a little bit of a detriment at least at certain time points in the lutetium Lu 177 vipivotide tetraxetan arm.
Another one that is a little bit behind but will be analyzed hopefully sometime next year are the PET data. Everyone had a PSMA PET [scan] at study entry, and then there was an amendment at progression to also have a PSMA PET [scan]. The baseline PET analysis will be first, and [we] will also look at are their differences in progression [between the 2 arms]. Then, we have archival tissue that was collected, as well as blood biomarkers, so we'll have plasma and buffy coat to assess. All of those will be interesting for the future.
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