Integration of Lutetium Lu 177 Vipivotide Tetraxetan Highlights Potential of Radioligands in Prostate Cancer

The FDA approval of lutetium Lu 177 vipivotide tetraxetan (Pluvicto) brought radioligand therapy to the prostate cancer treatment paradigm, and further research with this agent and others in this class could establish a broader role for this type of treatment in earlier settings or as parts of combination therapies, according to Daniel J. George, MD.

In March 2022, the FDA approved lutetium Lu 177 vipivotide tetraxetan for the treatment of adult patients with prostate-specific membrane antigen (PSMA)–positive metastatic castration-resistant prostate cancer (mCRPC) who have previously received other anticancer therapies, such as androgen receptor pathway inhibitors (ARPIs) and taxane-based chemotherapy.¹ This approval was supported by data from the phase 3 VISION trial (NCT03511664).

“The quality-of-life effects, the life-prolonging effects, and the tolerability [of lutetium Lu 177 vipivotide tetraxetan] have been a huge bonus to the field,” George said in an interview with OncLive^® during Prostate Cancer Awareness Month, which occurs in September each year. “[The use of lutetium Lu 177 vipivotide tetraxetan] is something that's been translatable from clinical trial into real-world practice.”

In the interview, George highlighted the affect lutetium Lu 177 vipivotide tetraxetan has had on the mCRPC treatment paradigm; expanded on what other roles radioligand therapy could have in the treatment of patients with prostate cancer; and discussed other key updates from across the field.

George serves as the Eleanor Easley Distinguished Professor of Medicine at the Duke University School of Medicine, a professor of medicine, a professor of surgery, and a member of the Duke Cancer Institute in Durham, North Carolina.

OncLive: Since the FDA approval of lutetium Lu 177 vipivotide tetraxetan in 2022, how has this agent affected the treatment paradigm for patients with pretreated, PSMA-positive mCRPC?

George: When you think about where we've gone in prostate cancer in the last 10 years, most of the progress that we've made has been on two fronts. One is in castration-resistant disease; the other is metastatic hormone-sensitive disease. In this castration-resistant space, it's been difficult to improve the median overall survival [OS]; what we have done is add on therapies, one after another, in this disease state to give patients longer OS through sequential lines of therapy.

We have not necessarily expanded first-line therapy; [rather], we have built multiple sequential lines of therapy, and lutetium Lu 177 vipivotide tetraxetan probably represents the best example of that in the last 10 years. [We have been] able to [provide an option for] patients who have been through our best standard hormonal therapies, including ARPIs, or received chemotherapy like docetaxel or cabazitaxel. Historically, we've had no life-prolonging therapies [for these patients]. A lot of drugs have died in that space.

Lutetium Lu 177 vipivotide tetraxetan was a huge winner. It still is today, and we have seen in our real-world experience over the past 2 years since its approval that many of the results we saw in the original VISION study—the FDA registrational study—have translated into real-world practice. That's not always the case, particularly in a refractory population where, in the real world, a lot of these patients may be even sicker than the study patients and harder to treat.

We find lutetium Lu 177 vipivotide tetraxetan is manageable in the real world. A lot of the toxicity profile is not any worse in terms of cytopenias, gastrointestinal toxicities, or fatigue. We've been able to treat the majority of our patients now, especially in the last 18 months or so, with the full 6 cycles of treatment, which lasts 9 months.

This is a patient population that had, on average, an OS of approximately 1 year. Nine months is pushing up against that. We're able to get the majority of our patients through [the full 6 cycles of treatment], and we're seeing patients having substantial treatment breaks after [completing lutetium Lu 177 vipivotide tetraxetan]. This is a disease state where we never got treatment breaks. People went from one treatment to another. They might finish chemotherapy, and within 2 months, their disease was progressing. Not everybody receiving lutetium Lu 177 vipivotide tetraxetan gets a great drug holiday, but even if one-quarter of our patients get a drug holiday of 6 months or more, that's substantial.

What should community oncologists who have a patient with mCRPC who may be a candidate for lutetium Lu 177 vipivotide tetraxetan know about providing this treatment?

Over the last 2 years [since its approval], we've seen a change. The first year, there was limited supply of [lutetium Lu 177 vipivotide tetraxetan], and it was prioritized toward these higher-volume academic centers. Patients in the community weren't getting as much access to this drug; if they were, it was through referrals to these centers.

That's changed in the last year. In our own experience at Duke, our volumes have plateaued; the growth has largely been in community centers that have now come on board and opened access of lutetium Lu 177 vipivotide tetraxetan to a much greater swath of patients than what we saw the first year, and that's just great news for the country. The availability, accessibility, and the experience of physicians using lutetium Lu 177 vipivotide tetraxetan is greater and greater.

[With this experience, there are] a few things to be aware of [when using lutetium Lu 177 vipivotide tetraxetan]. First, the communication between the radiation oncologist or nuclear medicine doctor and the medical oncologist needs to continue. [Medical oncologists] manage a lot of the patient care for those receiving lutetium Lu 177 vipivotide tetraxetan, rather than our nuclear medicine doctors. This is helpful because, although the drug is effective, it doesn’t work in everyone. When it’s not working, we need to change course [with treatment]. Sometimes that involves tough conversations around hospice or going back to chemotherapy. Other times, it involves doing biopsies or further tests to uncover a different histology than we initially thought. It's important that communication stays engaged there.

The second point is that we're learning how to assess response beyond prostate-specific antigen [PSA]. Is there a role for serial PET scans for patients on lutetium Lu 177 vipivotide tetraxetan? It's not part of our guidelines yet and this was not part of the trial. However, in our real-world experience, [serial PET scans] are helpful in deciding. Are there mixed responses? Is there something worth targeting? Is there such a great response that maybe we can do an intermittent drug therapy where we can take a drug hold? Or do we want to continue to treat through that to try to get a maximum treatment response? These are all important but unanswered questions. [There are] a lot of things we're still learning here, but these are things we're learning as a community because the experience is getting broader.

Given lutetium Lu 177 vipivotide tetraxetan is currently approved for use after progression in the mCRPC setting, do you see potential for this agent or other radioligand therapies currently in development to be used earlier in the treatment paradigm?

It's important that we get access to these radioligand therapies earlier the disease for two reasons. The first is that patients may be more likely to respond in an earlier disease setting. Eventually there's going to be higher volume disease, [a chance for more] heterogeneity and different expression, and [potential] resistance to this therapy. Earlier, lower-volume disease gives us that flexibility to potentially see deeper and more durable responses in a higher percentage of patients.

However, importantly, there are a lot of patients who are not candidates for chemotherapy. When we think about the trials and earlier disease state, it's not pre-chemotherapy. It's chemotherapy-naive disease, and maybe half of those patients are destined to not ever get chemotherapy due to other health concerns and whatnot. [It is important to] recognize that label expansions could open up [an agent like lutetium Lu 177 vipivotide tetraxetan] to a population of patients who wouldn't be able to get the drug otherwise.

The other thing is to recognize that we're going to want to understand more [about] how to integrate [radioligand therapies] with other therapies, particularly our hormonal therapies. There's an important study ongoing called [the phase 3] PSMAddition trial (NCT04720157), which is looking at [lutetium Lu 177 vipivotide tetraxetan] in the metastatic hormone-sensitive setting. We will [probably] see other therapies in that hormone-sensitive space, as well. [PSMAddition] is an opportunity in the early frontline setting of hormonal therapy to combine lutetium Lu 177 vipivotide tetraxetan [with standard-of-care treatment]. The jury is out with just how much of an impact that can have. It's difficult to assess these [combinations] when we're going against active comparators like active hormonal therapy, but it's important to recognize that therein lies the opportunity for real synergy.

Every study that we've done so far with lutetium Lu 177 vipivotide tetraxetan, outside of PSMAddition, has been in the resistance setting. VISION was done after patients had progressed on therapy and got lutetium Lu 177 vipivotide tetraxetan alone. The [phase 3] PSMAforestudy [NCT04689828] was done in patients who had progressed on an ARPI and then got lutetium Lu 177 vipivotide tetraxetan monotherapy or ARPI therapy.

PSMAddition is the first phase 3 study to look at lutetium Lu 177 vipivotide tetraxetan in the context of other active therapy [to test for] real synergy. That, to me, is a new breakthrough if we see real advantages there, and it could open the door for other future combinations.

Considering ARPIs have been moving to earlier lines of therapy, what are some other potential strategies for improving treatment options for patients with mCRPC? Could AR degraders or other novel agents play a role in this space?

There's a real opportunity here to continue to build on the AR pathway. There are a couple of things that are important to recognize. First, ARPIs are [in my opinion] the definition of hormonal therapy. The use of androgen deprivation therapy [ADT] alone is insufficient, incomplete pathway inhibition, and we've seen this now in a number of disease states of prostate cancer. There's a substantial clinical benefit to this combination approach with [ARPIs and ADT].

We should be thinking of hormonal therapy as combined therapy, not as monotherapy anymore, unless you want to think about ARPIs alone without ADT. Nonetheless, we need to recognize that ARPIs are now the de facto, standard hormonal therapy.

There are a number of strategies [for targeting the AR pathway beyond APRIs] that look promising. The AR degraders or proteolysis-targeting chimera [PROTAC] approaches that bind to the AR and target it for degradation are looking promising. These studies are going to require certain niches to understand the optimal setting [for these agents]. We don't want to study them in the last stages of chemo-refractory disease, where the AR pathway may not be the sole driver.

We still want to study these where we think that the dominant driver of the disease is AR, meaning earlier in disease, maybe in some of these minimal residual disease states of hormone-sensitive disease, where it's maybe there’s a good but incomplete response, with residual PSA levels, etc., to the early castration-resistant disease settings.

[However], those settings are an opportunity to show the single-agent activity [of AR degraders and PROTACs], and then hopefully we can think of combinations of these, whether it's with ARPIs or other strategies that can combine with these degraders to get a synergistic effect, which could include approaches with PARP inhibitors or other strategies for patients with homologous recombination repair mutations or other biologic effects that that we can target.

Targeting EZH2 and strategies like this also look promising. There's a whole biology around the unraveling and access to AR genes and other enhancers that could be targeted through this approach. It may also be another way of epigenetically controlling the AR at its expression level. This approach is looking promising in phase 2 studies, and we look forward to phase 3 evaluations. Some of these [trials] may require some enrichment strategies to better understand the subpopulations that are most [likely to benefit], whether it's because their disease is AR-driven or because the biology is most susceptible to these approaches.

Those are a lot of nuances that will get worked out, and my hope is that we continue to target and develop strategies around the AR pathway. This AR biology isn't going away. The more we inhibit it, the more we realize how important it is to prostate cancer disease progression.

Given the activity of the AR pathway in prostate cancer across multiple settings, what is your perspective on rechallenging with ARPIs after disease progression or potential intolerance?

The idea of rechallenge is an important one because we're realizing a couple of things about this biology. [The first] is that [the AR pathway] can get turned on, turned off, and turned back on again. There are a lot of epigenetic drivers of this pathway, and recognizing this as not an all-or-nothing approach is important.

Second, [ARPIs] are all different. We've done a lot of real-world database analyses to show that abiraterone acetate [Zytiga] and enzalutamide [Xtandi] are not equal drugs. We see consistently in databases that there are differences in survival with patients treated with enzalutamide consistently living approximately10% longer. We may not consider that dramatic, but when you talk about this across an entire population, that cumulative number of life years is dramatic. To move the needle on a population that has a medically challenging [disease] in a real-world setting is impressive.

We have to recognize that these drugs are not all interchangeable, and abiraterone in particular has a different mechanism of action with biosynthesis inhibition vs the receptor inhibition.

[Additionally], there may be differences in cytostatic vs cytotoxic effects of these ARPIs. This is one of the things we're learning when we do studies like PSMAforeand we see these control arms with some decent times to progression, progression-free survival rates, and even response rates. We start to realize that there probably is a population of patients who can respond.

We did the [phase 2] PANTHER study [NCT03098836] with the combination of two ARPIs: abiraterone and apalutamide [Erleada]. We saw a substantial treatment effect in our cohort of Black patients, who were not [well-represented] in phase 3 studies, and these data suggest that combinations could work in some subpopulations. Maybe we just haven't studied these combination approaches enough.

There are still unanswered questions, even a decade after the development of these [ARPIs], and it's important to recognize that we don't fully understand—at least on an individual basis—those mechanisms of resistance and rechallenge.

Sometimes, [rechallenge] the safest thing to do. Sometimes we have patients who are chemotherapy candidates and whatnot where rechallenges are reasonable. Ideally, we would have biomarkers that would help drive that decision, [The] AR-V7 [biomarker] suggests against [rechallenge], but what would be a positive biomarker to suggest that an ARPI is still worthwhile? From these studies with these combinations, we're starting to figure out some clues as to what those might be in areas like metabolomics and other types of profiles.

Are there any key updates from across the prostate cancer space that you would like to highlight during Prostate Cancer Awareness Month?

I want to bring up an old drug—[Radium-223 (Xofigo)]—and a trial that was recently presented at the 2024 ESMO Congress: the phase 3 PEACE-3 study [NCT02194842], because I think [the data are] profound. Since 2013, we haven't improved the median OS for frontline mCRPC. We’ve tried to combine multiple drugs, like abiraterone and enzalutamide, and we have failed to demonstrate an OS improvement. PEACE-3 did that. The study included patients with mCRPC [receiving] first-line treatment; they did not receive a prior ARPI, and if they did, it was just abiraterone. Therefore, there was a limited number of previously treated patients.

In that population of patients, enzalutamide was an active comparator against enzalutamide plus Radium-223, and [the combination] improved the median OS by [more than] 7 months from 35.0 months [95% CI, 28.8-38.9]—which is [consistent] with what we see in most phase 3 studies—to 42.3 months [95% CI, 36.8-49.1].² That is a clinically substantial benefit. What's remarkable is that the Kaplan Meier curves get wider over time, meaning that as you go out into the population that's responding and benefiting to enzalutamide, you're getting even greater benefit for Radium-223. Even though the treatment [with Radium-223] stopped after 6 months, a couple years later, these benefits were still persisting and getting wider. It suggests that we're changing that metastatic tumor volume in a way that's unique to Radium-223. There's no other drug that does this. This is not something that other radioligands or chemotherapies are able to do the way an alpha particle targeting that osteoplastic interface does. It's a fascinating result and a breakthrough in frontline mCRPC.

Will that translate into the metastatic hormone-sensitive setting? To me, there are basically two key criteria to this benefit. [The first] is there's a bone-dominant phenotype of patients. If they have four or more bone metastases, it's high-volume bone metastasis. [The second is that] they are sensitive to enzalutamide. In the metastatic hormone-sensitive setting patients even more sensitive to enzalutamide; if anything, I would expect even a greater treatment effect in that setting.

References

1. FDA approves Pluvicto for metastatic castration-resistant prostate cancer. News release. FDA; March 23, 2022. Accessed September 30, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pluvicto-metastatic-castration-resistant-prostate-cancer
2. Gillessen S, Choudhury A, Saad F, et al. A randomized multicenter open-label phase III trial comparing enzalutamide vs a combination of Radium-223 and enzalutamide in asymptomatic or mildly symptomatic patients with bone metastatic mCRPC. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA1.