FDA-Approved Isotope Therapies Provide 2 Options in the Castration-Resistant Prostate Cancer Armamentarium

Yung Lyou, MD

Findings from ongoing clinical trials, such as the phase 3 PEACE III (NCT02194842) and the PSMAfore studies (NCT04689828), have demonstrated an emergence of promising agents for patients with castration-resistant prostate cancer (CRPC), including radium-223 (Xofigo) and lutetium Lu 177 vipivotide tetraxetan (Pluvicto), respectively.

In March 2025, the FDA expanded the indication for lutetium Lu 177 vipivotide tetraxetan to include patients with prostate-specific membrane antigen (PSMA)–positive metastatic CRPC (mCRPC) who previously received androgen receptor (AR) pathway inhibitor therapy and are cleared to delay taxane-based chemotherapy.1 The regulatory decision was supported by data from PSMAfore. The original FDA approval for the radioligand therapy was granted in March 2022 for the treatment of patients with PSMA-positive mCRPC who were previously treated with other anticancer therapies, including AR pathway inhibition and taxane-based therapy and was supported by findings from the phase 3 VISION trial (NCT03511664).2

Radium-223 was first approved by the FDA in May 2013 for the treatment of patients with CRPC with symptomatic bone metastases and no known visceral metastatic disease.3 The approval was supported by data from the phase 3 ALSYMPCA trial (NCT00699751). PEACE III is currently examining the agent in combination with enzalutamide (Xtandi) vs enzalutamide monotherapy as frontline therapy for patients with mCRPC.4 

"[Data from] PEACE III showed that there’s a superiority when you combine radium-223 plus enzalutamide vs enzalutamide alone in terms of overall survival [OS] and radiographic progression-free survival [rPFS] benefit,” Yung Lyou, MD, hematologist/oncologist and director of the Oncology Clinical Trial Program at the St. Jude Crosson Cancer Institute in Fullerton, California, said in an interview with OncLive®. "I believe that this investigator group has submitted [their findings] for FDA approval and [to] the European regulatory agency, so hopefully, it will be another combination that can be used [in the future] that will give more options to our patients with prostate cancer.”

In the interview following an OncLive State of the Science Summit™ on genitourinary cancers, Lyou discussed available targeted radioligand treatments in prostate cancer, the integration of lutetium Lu 177 vipivotide tetraxetan in clinical practice, treatment selection considerations, the development of novel radioligand therapies, and future research directions for this class of agents.

OncLive: What are the available radioligand isotope agents in prostate cancer?

Lyou: Radium-223 and lutetium Lu 177 vipivotide tetraxetan are the 2 FDA-approved isotopes [which are currently] in use. The idea is that the cancer cell will uptake the radioligand, which includes the radioactive isotope. This will lead to irreversible DNA damage for the cancer cell, and then it will die. The nice thing about these radioligands is that you don’t have to target every single cancer cellular tumor; enough of them just need to be targeted to cause what is called the crossfire threat or the scatter-fail effect to kill cancer cells in the vicinity.

How has the integration of lutetium Lu 177 vipivotide tetraxetan into clinical practice affected care for eligible patients with PSMA-positive mCRPC?

Lutetium Lu 177 vipivotide tetraxetan was [first] FDA approved after [findings from] VISION showed an increased OS in patients who received lutetium Lu 177 vipivotide tetraxetan vs the standard care at the time. These were patients who either got a second antiandrogen agent, such as enzalutamide, or anything else the physician chose. The other standard-of-care agent that most physicians choose is cabazitaxel [Jevtana]. When they were compared, the lutetium Lu 177 vipivotide tetraxetan group had higher OS outcomes. It benefited us by offering an additional choice in our toolbox because we could still use the standard-of-care agents later, but it showed that if we used lutetium Lu 177 vipivotide tetraxetan first it would benefit patients. This therapy targets the PSMA antigen specifically, and it has been used previously for imaging to find cancer cells in the body. It’s much more specific, so the radiation is not delivered to normal tissue as much as some of the other radioligands in the past, and that would inhibit or decrease the number of adverse effects [AEs] that previous radioligands would cause, such as severe myelosuppression or bone fractures.

When lutetium Lu 177 vipivotide tetraxetan is indicated, what are some factors you consider when selecting this treatment?

The clinical trial excluded patients with bone marrow infiltration. Usually, we make sure that the patient doesn’t have any bone marrow infiltration from their prostate cancer. The reason is that if [a patient] has bone marrow infiltration and you give them lutetium Lu 177 vipivotide tetraxetan, it could wipe out their bone marrow and they could develop pancytopenia, which can be irreversible. We want to ensure that our patients are healthy enough to receive lutetium Lu 177 vipivotide tetraxetan, with proper renal function. Usually, most patients should have it within normal range but, to some extent, it is excreted by the kidneys. Therefore, there are a few things that the nuclear medicine physician or radiation oncologist will have to look at to determine if the patient is eligible for lutetium Lu 177 vipivotide tetraxetan.

Is there potential for lutetium Lu 177 vipivotide tetraxetan or other targeted radioligand therapies to play a role in earlier treatment?

Yes, there are many active clinical trials going on right now to evaluate lutetium Lu 177 vipivotide tetraxetan itself and other [radioligand] agents in an earlier setting. These go beyond the mCRPC setting, where patients did not respond well to a taxane, which is the current FDA-approved treatment, but in an earlier setting. For example, PSMAfore assessed whether lutetium Lu 177 vipivotide tetraxetan could benefit patients prior to getting docetaxel after they did not respond well to 1 antiandrogen therapy. There are [also] many other clinical trials using other radioligands and targets.

How do some of the novel targeted radioligand therapies differ from lutetium Lu 177 vipivotide tetraxetan?

[Some novel radioligand therapies] use other particles that may cause fewer AEs. They also use other antigen targets on the cells, so that they can cause fewer AEs and be more specific. Because PSMA is expressed in patients’ salivary glands, many patients will say that they [experience] chronic dry mouth after receiving lutetium Lu 177 vipivotide tetraxetan, which unfortunately can be permanent and can cause an uncomfortable quality of life [QOL]. Hopefully, the other agents will be able to avoid that AE, but overall lutetium Lu 177 vipivotide tetraxetan is fairly well tolerated.

Where do you see research with this class of agents going in the coming years?

Probably in the coming years, I can see combinations of agents being used. For example, PEACE-III was a positive trial comparing, in the mCRPC setting, enzalutamide plus radium-223 vs enzalutamide alone. The combination arm showed an increased OS and increased rPFS. Therefore, I believe the future will be combining other modalities, not necessarily with a radioligand plus an antiandrogen, but perhaps a radioligand with other agents that we have yet to see being developed. Once patients reach the metastatic castration-resistant phase, it’s more difficult to treat and cure [them]. Hopefully, we’ll have more and more tools [in the future] so patients can live longer with a better QOL.

References

1. FDA expands Pluvicto’s metastatic castration-resistant prostate cancer indication. FDA. March 28, 2025. Accessed April 11, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-pluvictos-metastatic-castration-resistant-prostate-cancer-indication
2. FDA approves Pluvicto for metastatic castration-resistant prostate cancer. FDA. March 23, 2022. Accessed April 11, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pluvicto-metastatic-castration-resistant-prostate-cancer
3. Bayer receives U.S. FDA approval for Xofigo® (radium Ra 223 dichloride) injection as a new treatment for castration-resistant prostate cancer with bone metastases. News release. Bayer HealthCare Pharmaceuticals. May 15, 2013. Accessed April 15, 2025. https://www.prnewswire.com/news-releases/bayer-receives-us-fda-approval-for-xofigo-radium-ra-223-dichloride-injection-as-a-new-treatment-for-castration-resistant-prostate-cancer-with-bone-metastases-207545191.html
4. Gillessen S, Choudhury A, Saad F, et al. A randomized multicenter open label phase III trial comparing enzalutamide vs a combination of radium-223 (Ra223) and enzalutamide in asymptomatic or mildly symptomatic patients with bone metastatic castration-resistant prostate cancer (mCRPC): first results of EORTC-GUCG 1333/PEACE-3. Ann Oncol. 2024;35(suppl 2):S1254. doi:10.1016/j.annonc.2024.08.2307