Following the March 2025 decision by the FDA to expand the indication of lutetium Lu 177 vipivotide tetraxetan (Pluvicto) to include adult patients with prostate-specific membrane antigen (PSMA)–positive metastatic castration-resistant prostate cancer (mCRPC) who have received an androgen receptor pathway inhibitor (ARPI) for whom a delay of taxane-based chemotherapy is appropriate, key factors such as the nature of disease progression and patient preferences and treatment goals must be carefully weighed to properly identify ideal candidates for this approach, according to Daniel J. George, MD.1
Radioligand Therapy vs Chemotherapy in mCRPC
- In March 2025, the FDA expanded the indication of lutetium Lu 177 vipivotide tetraxetan to include adult patients with PSMA-positive mCRPC who have received an ARPI and for whom a delay of taxane-based chemotherapy is appropriate.
- Factors to consider when selecting between lutetium Lu 177 vipivotide tetraxetan and chemotherapy in this setting include the nature of disease progression, patient- and disease-related factors, and patient preference.
- Ongoing studies could help define a role for radioligand therapy in earlier prostate cancer settings.
The regulatory decision was based on data from the phase 3 PSMAfore trial (NCT04689828), which showed that patients who received the radioligand therapy achieved a significant radiographic progression-free survival compared with those who transitioned to another ARPI (HR, 0.41; 95% CI, 0.29-0.56; P < .0001). The expanded indication followed the initial March 2022 FDA approval of the agent for the treatment of adult patients with PSMA-positive mCRPC who previously received an ARPI and taxane-based chemotherapy.2
In an interview with OncLive®, George, the Eleanor Easley Distinguished Professor in the School of Medicine, Medicine, Medical Oncology, a professor of Medicine, Medicine, Medical Oncology; and a professor in urology at Duke Health in Durham, North Carolina, discussed which patients he considers for treatment with lutetium Lu 177 vipivotide tetraxetan, the future of radioligand therapy in prostate cancer, and other novel treatment approaches being investigated for patients who experience disease progression on an ARPI-based regimen.
OncLive: What is your approach for treating patients with mCRPC who experience disease progression following an ARPI-based regimen?
George: When patients have metastatic hormone-sensitive prostate cancer [(mHSPC) and are receiving] an ARPI, the prognosis can be quite good in some cases, particularly in those with good prostate-specific antigen [PSA] responses. As the disease progresses into castration-resistant metastatic disease on an ARPI, the clock is ticking.
These are patients who need to be aware, even if they feel well and asymptomatic, that their life expectancy is in that 2-to-3-year range, and it’s not indefinite. The changes are going to come quicker; the need to take on potentially more adverse effects with cytotoxic therapy is going to be greater, and [we need] to recognize that the expectations of therapy are going to be more modest in this setting. With all that said, it’s a spectrum. We have patients who have slow PSA rising and minimal metastatic disease burden on ARPI, for whom we’re going to be comfortable doing a clinical trial of an investigational, unproven agent. We’re going to be comfortable using sipuleucel-T [Provenge] and other types of less immediately cytotoxic therapies.
[Many] patients will have more rapidly progressive disease, higher volume disease, and risk of complications and symptoms. For those patients, using cytotoxic therapy, whether that’s taxane-based therapy or a radioligand therapy, [such as] lutetium Lu 177 vipivotide tetraxetan, is the first major treatment decision.
What are some of the factors you consider when deciding to give chemotherapy or deferring it in favor of radioligand therapy to a patient with mCRPC who is eligible for both treatments?
When I’m addressing a patient at that critical juncture of post-ARPI with disease progression, I’m looking at a couple of things. How is that disease progression? Is it clinical? Is it radiographic? Is it PSA only? Is it a combination of all 3? I’m looking at their tumor volume as well, and at whether the patient is a chemotherapy candidate.
In the real world, a lot of ou r patients are just not good chemotherapy candidates. [Even] if they are, it’s going to come at a physical cost. They [are often] frail and [have] other [comorbidities] that are going to clinically worsen from that chemotherapy. These are the factors that I [use to determine] whether they’re good up-front chemotherapy candidates. If they are willing, starting chemotherapy is a good choice because we know that lutetium Lu 177 vipivotide tetraxetan has an [overall] survival [OS] benefit post-chemotherapy.
We also know that [lutetium Lu 177 vipivotide tetraxetan] has a significant benefit prechemotherapy, and for many of our patients who are not chemotherapy candidates. I use chemotherapy fitness as my first judge, and then it’s patient preference. At the end of the day, they get a voice and this a shared decision. A lot of patients want to put chemotherapy off until they really need to do it, and I’m perfectly comfortable with that. Starting with lutetium Lu 177 vipivotide tetraxetan in the majority of patients is absolutely a reasonable course.
What is your approach to PSMA testing when you are considering using lutetium Lu 177 vipivotide tetraxetan?
[To me, when a patient] has emerging castrate resistance in their disease, that’s the best time to get a PSMA-PET scan. First, it’s our best staging. It’s our most sensitive test for assessing the full extent of the disease, and it gives me peace of mind that there isn’t visceral disease hiding in there. If it is lymph node–only disease, I can feel confident there isn’t [disease] in the bone. Importantly, if there’s oligometastatic disease, if these patients have 1 or 2 areas that are growing but really the rest of the disease is still ARPI responsive, I’ll consider some of these are patients for tumor-directed radiotherapies.
It’s also a theranostic for lutetium Lu 177 vipivotide tetraxetan and I use it as such. It’s important also to be able to gauge at this point in time how ubiquitous and intense that PSMA uptake is. I’m also talking with my nuclear medicine physicians about the scan and their interpretation.
Where do you see the story of radioligand therapy going next within the prostate cancer treatment paradigm?
Lutetium Lu 177 vipivotide tetraxetan has shown us is that there is a role for this therapy throughout the disease continuum, from hormone-sensitive disease all the way through chemotherapy-refractory castration-resistant disease. Not unlike how ARPIs were developed, the goalposts have changed as we move into these other disease spaces.
I’m less worried about being able to see the OS end points as we move earlier and earlier [into new disease settings], because there are so many other things that affect the outcomes in these patients. I’m more interested in the ability to get to minimal residual disease [MRD]. If we think about what our goals are for patients with early mHSPC, historically we’ve [designed] the registrational trials to look at rPFS and OS, but if you talk about our patients, those aren’t necessarily their goals. They want to get to MRD and to get off therapy.
In the future, if radioligand therapies are part of the mix of treatments, whether they be up-front combinations or induction followed by consolidation or maintenance therapy, they may allow us to get patients off treatment—maybe not all patients, but some patients in the metastatic, hormone-sensitive setting. That’s going to be an important aspect of this.
Our goal as patient advocates is ultimately to come up with a combination or sequence of therapies that get us to MRD in the greatest number of patients and ultimately get patients off treatment. If that’s a cure, that’s wonderful, but even a break from therapy for these patients is welcome in order to restore some of their functionality and overall health.
Are there any novel agents being developed for patients with mCRPC that are of particular interest to you?
It’s probably one of the most exciting times in prostate cancer drug development right now. We have more mechanisms to target now than ever before, and what started out as just basically the AR pathway has now expanded to PSMA-targeted approaches—not just radioligands, but potentially antibody-drug conjugates and bispecific antibodies.
Beyond PSMA, we’re seeing evidence for [targeting] KLK2 and STEAP2 [alterations]. We’re getting more targets in prostate cancer, and we’re getting mechanisms to start targeting. Other targets that are drivers of more aggressive forms of prostate cancer, and more androgen-independent forms of prostate cancer are coming into clinic. This is an incredibly important aspect, because before we were limited to what we could target in prostate cancer. We’d get these next-generation sequences and our big list of mutations, and things would be non-actionable.
You’re going to see now more and more actionable targets in that profiling is going to become more and more critical in how we’re treat these patients. That’s going to make the testing and diagnostics all the more important. And I hope you know that today, we can already justify doing that on a systematic level for everybody with advanced prostate cancer, knowing that these therapies are coming.
References
- FDA expands Pluvicto’s metastatic castration-resistant prostate cancer indication. FDA. March 28, 2025. Accessed November 10, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-pluvictos-metastatic-castration-resistant-prostate-cancer-indication
- FDA approves Pluvicto for metastatic castration-resistant prostate cancer. FDA. March 23, 2022. Accessed November 10, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pluvicto-metastatic-castration-resistant-prostate-cancer?utm_medium=email&utm_source=govdelivery
