Dr George on the Potential Use of Lutetium-177 Earlier in the Treatment Paradigm for mCRPC 

Daniel J. George, MD, medical oncologist, Eleanor Easley Distinguished Professor of Medicine, Duke University School of Medicine, professor of medicine, professor of surgery, Duke Cancer Institute, discusses the emerging potential use of lutetium Lu 177 vipivotide tetraxetan (Pluvicto) and other radioligand therapies earlier in the treatment paradigm and in novel combinations for patients with prostate cancer.

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. The approval was based on findings from the phase 3 VISION trial (NCT03511664).

George explains that using radioligands such as lutetium Lu 177 vipivotide tetraxetan in earlier disease settings could help improve responses when patients have a lower tumor volume and provide an option for patients who may not be candidates for chemotherapy. Patients in earlier settings could also have less heterogeneous disease, George adds.

In terms of potential combination therapies, research is ongoing to evaluate the potential synergy of lutetium Lu 177 vipivotide tetraxetan with other standard agents, such as hormonal therapy, George continues. For example, the phase 3 PSMAddition trial (NCT04720157) is evaluating the radioligand therapy in combination with standard-of-care ARPIs plus androgen deprivation therapy for patients with metastatic hormone-sensitivie prostate cancer.

, investigated lutetium Lu 177 vipivotide tetraxetan in patients with mCRPC, George notes.

Ongoing studies such as PSMAddition examining the earlier use of lutetium Lu 177 vipivotide tetraxetan, especially in chemotherapy-naive patients, may solidify its role as a key therapeutic option in the management of earlier stages of prostate cancer, George continues. Should this study demonstrate generate positive outcomes, it could support the rationale for using radioligands such as lutetium Lu 177 vipivotide tetraxetan in earlier lines of therapies as a part of different combinations, he concludes.

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Daniel J. George, MD, discusses the potential use of lutetium-177 earlier in the treatment paradigm for metastatic castration-resistant prostate cancer.

Dr George on Other Potential Roles for Radioligand Therapy 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.

 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.

 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 

 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.

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?

: 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.

 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 

: 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].

 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.

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

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.

Articles

Daniel J. George, MD, discusses ongoing research with radioligand therapy in prostate cancer and its potential role in novel settings and combinations.

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

Despite the crowded list of treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC), cross-resistance between androgen receptor–pathway inhibitors (ARPIs) and the movement of these agents to earlier lines of therapy have restricted treatment opportunities for this patient population, according to Sandy Srinivas, MD, who added that ongoing research aims to improve outcomes with novel agents, such as AR degraders.

“Although we feel that there is an enormous number of options, for many patients with mCRPC, the number of options we have today are really limited, and that represents a huge unmet need,” Srinivas explained during an interview with OncLive® during Prostate Cancer Awareness Month in September.

In the interview, Srinivas discussed the therapeutic landscape for patients with mCRPC and the challenges associated with current treatment options. She also expanded the role of radioligand therapy in prostate cancer, highlighted novel classes of agents under evaluation, and underscored the importance of clinical trials for advancing care for this patient population.

Srinivas is a medical oncologist, urologic and genitourinary specialist, and a professor of medicine (oncology; urology) at Stanford Medicine, as well as the unit-based medical director of Stanford Hospital, in Palo Alto, California. She also serves as a member of the Prostate Panel at the National Comprehensive Cancer Network (NCCN).

: In mCRPC, what are some of the current challenges in this therapeutic landscape?

: There is an unmet need in mCRPC where we need better drugs to help prolong a patient’s life. If you look at something like the NCCN [Guidelines], it looks like we have an enormous number of options [to treat mCRPC]. However, over the years, many of these drugs have moved into earlier lines of therapy. Therefore, all our AR-targeting drugs, which have been a mainstay for us in mCRPC, have been moved to the frontline and even the localized or hormone-sensitive disease [settings].

We know that there is high cross resistance [with ARPIs], making it a challenge if a patient has had one prior novel hormone therapy when their disease becomes castration resistant. This [makes novel hormone therapy] options limited and nearly non-existent [in the mCRPC setting].

What are the drugs that we do have [for mCRPC]? Essentially, you have chemotherapy agents, such as docetaxel and cabazitaxel, and we have our radioligand targeting drugs, such as lutetium Lu 177 vipivotide tetraxetan [Pluvicto; formerly 177Lu-PSMA-617].

If a patient were to have a homologous recombination repair mutation such as 

, they would be able to access PARP inhibitors. However, that is a small fraction [of patients with mCRPC]. Lastly, if somebody has bone-limited disease, radium-223 [Xofigo] is an option.

What are some patient and disease factors to consider when selecting a treatment regimen for a patient with mCRPC?

There are many factors we take into consideration. [mCRPC] is a disease of [older patients], so frailty, performance status, what home support they have, and how far they live from an institution will help determine if we want to use an intravenous or oral drug. If we want to use chemotherapy, what is the hematologic toxicity profile [of the agent?] What is a patient's underlying bone marrow reserve? All of these are taken into consideration.

When was their last ARPI? Was it given in the hormone-sensitive space or for localized disease? Did the patient [stop treatment with an ARPI] for disease progression or toxicity? Did they complete a full course, where their testosterone levels allow them to see another drug? There are many things to take into consideration, especially as you think about chemotherapy or radioligand therapy.

Although radioligand therapy is exciting for older patients, it does pose some challenges because patients need to be a certain distance from their caregiver, for instance. This is unique for radioligand therapy. All these factors are in our mind when we are thinking about the best treatment for a patient sitting in front of us.

Are there situations where you may consider rechallenge with an ARPI? Are there any data to support that approach?

Almost everybody in the community will rechallenge [with an ARPI] because that's what is available. It's an oral drug, and it's easy. We give it for a month or two to see if the patient responds. Many of us in the field have said that's not the right thing to do because of the significant cross resistance [between different ARPIs]. If you see the real data, for example, if a patient received one of the ARPIs and then get a second one, their likelihood of response is approximately in the 10% to 15% range. Even If they have a response, it's short lived.

Having said that, just because of the lack of other available options, this is the most common [treatment selected]. Many of our clinical trials that we done in the [mCRPC] space look at alternate novel hormonal therapy as a comparator arm, and we have a lot of contemporary data from such trials reinforcing that [the rate of] patients responding in the second-line is very low, and even if they respond, the duration of response is extremely low.

What should community oncologists know about picking lutetium Lu 177 vipivotide tetraxetan

as a potential treatment option for patients?

The FDA approval of lutetium Lu 177 vipivotide tetraxetan

 has been a great advance in the field of mCRPC. It's a drug that's well tolerated compared with chemotherapy, and it's convenient because you can give just one treatment every 6 weeks. It can be given to patients who have diagnostic imaging that shows they are a candidate for this treatment. Patients may have some mild fatigue, mouth dryness, and there may be some impact on bone marrow. However, compared with chemotherapy, it's a better-tolerated treatment.

For many of our patients with prostate cancer who are in their 80s and early 90s, this treatment is something that can be given with very little toxicity. For now, there are centers that are administering this therapy; it is an easy patient referral if imaging comes back [prostate-specific membrane antigen (PSMA)] positive. Fortunately, based on the [phase 3] VISION study [NCT03511664], we know that the screening fail rate is very low. Less than 15% of patients who get the imaging screening [are PSMA negative], so the majority can get the drug.

We are getting better at evaluating who's benefiting from the drug, who should get all 6 cycles [of treatment], who should stop short of 6 cycles, and [how to] recognize early progression. It is important not to put patients through the full 6 cycles if they are not deriving benefit from it.

What ongoing research could help bring novel agents into the mCRPC treatment space?

This is such an area of active interest, and even at the 

, there was exciting data coming out. I think about [ongoing research] in 3 categories.

One, we know that the AR is active; therefore, how can we continue to explore the AR pathway? These drugs are oral and convenient. Knowing the biology, these drugs will remain active for patients with prostate cancer. I'm excited about some of the data that we have seen about AR degraders. These are also oral drugs, and we are seeing patients have a drop in prostate-specific antigen and some meaningful, durable responses with relatively low toxicity. Therefore, I'm interested in seeing how the AR degraders move forward.

Continuing along the AR pathway, there are drugs similar to abiraterone acetate [Zytiga], but they are targeting UPS11, so it's one step higher in the pathway. These drugs are also coming forward. These are oral drugs and seem to have a high level of activity in patients who have had a prior exposure to an ARPI. We are excited to see how that area of research continues.

Second, with the approval of a radioligand therapy, there's been an explosion of drugs that are in development, even within the approved space. Lutetium Lu 177 vipivotide tetraxetan is being studied in the pre-chemotherapy space. At the 2024 ESMO Congress and earlier, we saw data from similar compounds such as 177 Lu-PNT2002 in the phase 3 SPLASH study [NCT04647526], showing that patients do benefit [from radioligand therapy] in the pre-chemotherapy space. That's exciting for our patients who are not candidates for chemotherapy, potentially giving them another option.

Within the radioligand therapy space, there are different agents. Lutetium Lu 177 vipivotide tetraxetan is a beta-emitting agent; there are drugs that are alpha emitters that are being looked at; and there are different sources other than lutetium, such as lead and copper. The whole area is exciting. There are combinations that are being investigated, where these radioligand therapies are being combined with immunotherapy, PARP inhibitors, radium, and ARPIs. There is an explosion of agents and trials in this space.

Having PSMA as a target has been exciting; in addition to radioligand targeting, we now have bispecific antibodies and antibody-drug conjugates [ADCs] directed against PSMA. Within this field, we have seen multiple smaller studies showing some effect, and the same strategies are now being applied to other targets. Similar to PSMA, there is STEEP1 and B7-H3. Each of these targets, in turn, have ADCs and immunotherapy. It is an exciting time for us to be able to have all these clinical trials to allow our patients to participate in them.

How have diagnostics helped reshape the prostate cancer treatment paradigm?

The other area that is exciting is our diagnostics. PSMA imaging has changed the way we stage patients, and with that, we have identified new clinical states, such as oligometastatic sites. How we can delay time to androgen deprivation therapy for many of our patients in order to delay the adverse effects of treatment. I'm excited to see where we go in that space.

Diagnostically, the whole genomic discovery has allowed us to look at personalized medicine to see if we can either escalate care for certain patients or deescalate care for some patients who may be at in different risk category compared with what we have with our clinical factors [alone] up until now. Overall, I am excited to see where that field heads, as well.

With September being Prostate Cancer Awareness Month, what would be your main message for colleagues about the current state of the prostate cancer care?

Genomic testing is important. We still find that there are a lot of patients who don't get genomically tested, whether it be germline or somatic testing. This is important because we do have drugs that they may benefit from. Additionally, clinical trials remain prevalent across care, and we have known that many of these trials have resulted in a prolongation of lives for our patients; that work needs to continue. Thinking about a clinical trial as a first option for our patient is a top priority to move the field forward.

Sandy Srinivas, MD, discusses the therapeutic landscape of mCRPC and the need to develop novel treatment options.

AR Degraders, Other Novel Agents Could Expand Armamentarium in mCRPC

Dr Srinivas on the Role of Lutetium Lu 177 Vipivotide Tetraxetan in mCRPC

Sandy Srinivas, MD, medical oncologist, urologic specialist, genitourinary specialist, professor, Medicine (Oncology) and Urology, Stanford Medicine, discusses the role of the radiopharmaceutical lutetium Lu 177 vipivotide tetraxetan (Pluvicto) in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

 for the treatment of adult patients with prostate-specific membrane antigen (PSMA)–positive mCRPC who have previously received other anticancer therapies, such as androgen receptor pathway inhibition and taxane-based chemotherapy. This approval has been an important advancement in the field of prostate cancer treatment, particularly for patients with mCRPC who have limited therapeutic options, Srinivas begins. The key benefit of lutetium Lu 177 vipivotide tetraxetan is its favorable tolerability profile compared with chemotherapy, she states. The agent also offers a more convenient treatment schedule, with 1 infusion administered every 6 weeks. Accordingly, lutetium Lu 177 vipivotide tetraxetan may be more manageable for older patients who may not tolerate more aggressive therapies, Srinivas notes.

Lutetium Lu 177 vipivotide tetraxetan is administered to patients who show PSMA positivity on diagnostic imaging, making the selection process relatively straightforward, Srinivas continues. With a favorable adverse effect (AE)profile, patients may experience mild fatigue, dry mouth, and some impact on bone marrow, but these AEs are generally less severe than those associated with chemotherapy, she details. This makes lutetium Lu 177 vipivotide tetraxetan a suitable option for patients who require a gentler treatment approach, Srinivas emphasizes.

The phase 3 VISION trial (NCT03511664), which supported the drug's approval, demonstrated that less than 15% of patients who undergo PSMA imaging fail the screening, Srinvas reports. She clarifies that this means the majority of patients tested are eligible for treatment. With ongoing evaluation, clinicians are becoming better at determining who benefits most from the full 6-cycle regimen and who should stop early if disease progression is identified, avoiding unnecessary treatment. Overall, lutetium Lu 177 vipivotide tetraxetan represents a significant addition to the therapeutic arsenal for managing mCRPC with minimal toxicity and substantial clinical benefit, Srinivas concludes.

Sandy Srinivas, MD, discusses the role of lutetium Lu 177 vipivotide tetraxetan for patients with metastatic castration-resistant prostate cancer.

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AR Degraders, Other Novel Agents Could Expand Armamentarium in mCRPC

Dr Srinivas on the Role of Lutetium Lu 177 Vipivotide Tetraxetan in mCRPC