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Michael J. Morris, MD In an interview with OncLive ® , Michael J. Morris, MD, broke down efficacy and safety data from the phase 3 PSMAfore trial (NCT04689828) that supported the expanded approval of lutetium Lu 177 vipivotide tetraxetan (Pluvicto) for select patients with prostate-specific membrane antigen (PSMA)–positive metastatic castration-resistant prostate cancer (mCRPC).
1 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. This decision was based on data from PSMAfore. Morris detailed the design and enrollment criteria for PSMAfore; highlighted the key efficacy data that supported the approval; and detailed the importance of quality-of-life (QOL) outcomes from the study.
Morris is a medical oncologist and clinical director of Genitourinary Medical Oncology at Memorial Sloan Kettering Cancer Center in New York, New York. In another interview with OncLive , Morris outlined the significance of the label expansion and its implications for disease management prior to chemotherapy. Morris : We know that in the community [setting], there is quite a bit of use of second-line ARPIs.
Many patients and clinicians decide—usually as part of a complex, multi-parameter decision-making—whether the patient would go on to a second-line ARPI vs chemotherapy. This [strategy] has generated a huge amount of discussion and perhaps controversy in the field, because it's clear that chemotherapy is the more active of the 2 [treatments], and an ARPI as a second-line therapy is relatively inactive. However, many patients or clinicians will say the patient’s disease is moving slowly enough or that their patient is frail enough.
The patient also might not want chemotherapy. The means of [disease] progression may lead [clinicians] to say that chemotherapy is not appropriate. For example, you have a patient who has 1 or 2 new lesions on a bone scan as the manifestation of the disease progression.
That doesn't necessarily mean that the next move is going on docetaxel. There are many different factors that might be incorporated into this decision as to whether chemotherapy is appropriate [in the post–up-front ARPI setting]. [PSMAfore enrolled] a patient population for whom chemotherapy was felt not to be appropriate and where the [treatment] decision-making would be to put [a patient] on a second-line ARPI, and the choice of that therapy was the control arm.
The purpose of PSMAfore wasn't to test any specific ARPI vs lutetium Lu 177 vipivotide tetraxetan; rather, we wanted to test the drug class [in the second line]. For the investigational arm, [patients received] lutetium Lu 177 vipivotide tetraxetan given [once] every six weeks for 6 total doses. The primary end point was radiographic progression-free survival [rPFS].
What's important to factor into the design is that a crossover was allowed from the control arm to the experimental arm after radiographic progression. Most patients who radiographically progressed took advantage of that opportunity and crossed over; for that reason, the trial is just as much about lutetium Lu 177 vipivotide tetraxetan vs an ARPI as it is lutetium Lu 177 vipivotide tetraxetan deferred until radiographic progression [on a second-line ARPI]. In many ways, [the trial tested] an early vs deferred strategy, and rPFS was truly measuring what's happening on the initial treatment as opposed to overall survival [OS].
Most patients did receive lutetium Lu 177 vipivotide tetraxetan in this trial on either arm, and OS was a secondary end point. Patients needed to have [previously] received some testosterone-lowering agent and an ARPI. For most patients, that would be an ARPI in the castration-sensitive setting; however, there was no requirement [in PSMAfore] that patients receive their ARPI for castration-sensitive disease.
In many parts of parts of the world, an ARPI was not used during the period of accrual, and if the patient got docetaxel for their up-front therapy, that would be exclusionary because these needed to be chemotherapy-naive patients. There are patients who got just ADT and then an ARPI for first-line mCRPC, and that was acceptable for this study. I wouldn't say in today's day and age that I would consider that to be best practice, but [enrollment criteria] didn't dictate [a requirement] for when the patient received an ARPI.
They just needed disease progression after an initial ARPI. [Patients also needed to undergo] a PSMA PET scan before they go on to treatment to ensure that they're eligible to receive lutetium Lu 177 vipivotide tetraxetan. We use the same criteria as the [phase 3] VISION trial [(NCT03511664) that supported the initial FDA approval of lutetium Lu 177 vipivotide tetraxetan in 2022].
That's a pretty permissive rule set for declaring eligibility for PSMA-directed therapy with lutetium Lu 177 vipivotide tetraxetan. Otherwise, if they were candidates to receive a PARP inhibitor, they needed to receive that up-front. The usual organ functionality criteria that apply to most protocols also applied here.
There were very few screen failures on the basis of PSMA PET scans, and that didn't turn out to be a major hurdle in terms of [enrolling patients] onto the study. In terms of the primary end point, the hazard ratio [for rPFS] was in favor of the lutetium Lu 177 vipivotide tetraxetan arm at [0.41], and the [median] rPFS was approximately double in the [experimental] arm [9.
3 months] as opposed to the control arm [5.6 months]. The quality-of-life [QOL] data [are important].
When you look at the tolerability of the 2 regimens, lutetium Lu 177 vipivotide tetraxetan was far better than the tolerability of a second-line ARPI. There were far fewer dose reductions of lutetium Lu 177 vipivotide tetraxetan than there were of second-line ARPIs. Patient-reported outcomes far favored the use of lutetium Lu 177 vipivotide tetraxetan vs a second-line ARPI, meaning that QOL was preserved as a result of this durable disease control.
If you were a patient who had mCRPC on this trial, you are generally a happier, more satisfied person with cancer by receiving lutetium Lu 177 vipivotide tetraxetan than you were receiving a second-line ARPI. There was not a big difference in overall survival [OS], and from a design perspective, [we see] that happens in many respects because of this crossover design. It could be that there are other reasons why we didn't see an OS benefit between the 2 arms, but the crossover is a significant confounder that we need to consider.
It’s important to recognize that in the VISION trial population, the [rate of] grade 3/4 hematologic toxicities was—depending on what cell line you were looking at—between 8% and 13%, and that [rate] was about half of that in [PSMAfore]. If you look at the dose-reduction rate for the lutetium Lu 177 vipivotide tetraxetan arm, it was 3.5% [for the experimental arm] vs 15.
1% in the second-line ARPI arm. 2 You're still looking out for the same [potential adverse effects] in terms of treatment, such as thrombocytopenia. It's rarer to see significant anemia or thrombocytopenia in this population; however, xerostomia is still an issue because the drug is taken up by the salivary glands.
Most of [these AEs] are low grade and reversible, but they still need to be discussed with patients..
