Staying abreast of ongoing research in the prostate cancer landscape is essential to continue identifying potentially better biomarkers as targets, particularly for the treatment of patients with prostate-specific membrane antigen (PSMA)–positive metastatic hormone-resistant prostate cancer (mHRPC), according to Scott T. Tagawa, MD, MS, FACP, FASCO.
Of note, topline data from the phase 3 PSMAddition trial (NCT04720157) revealed that the study met its primary end point, demonstrating statistically significant and clinically meaningful benefit in radiographic progression-free survival, along with a positive trend in overall survival, in patients with PSMA-positive, metastatic hormone-sensitive prostate cancer (mHSPC) treated with lutetium Lu 177 vipivotide tetraxetan (Pluvicto) plus standard of care (SOC), comprising androgen receptor pathway inhibitor (ARPI) therapy and androgen deprivation therapy (ADT), vs those given SOC therapy alone.1
Furthermore, the role of lutetium Lu 177 vipivotide tetraxetan has continued to shape the PSMA-positive mHRPC treatment paradigm, especially
“It’s not shocking to me and most people that prior chemotherapy exposure is not required for [lutetium Lu 177 vipivotide tetraxetan],” Tagawa said in an interview with OncLive® during Prostate Cancer Awareness Month, observed annually in September. “It’s just the way the trials were done and the way the FDA approves [treatments]. It’s nice to have [both indications] as options.”
In the interview, Tagawa highlighted the importance of continued research in the prostate cancer landscape, current screening tests, and sequencing strategies following ARPI therapies.
Tagawa is a professor of medicine and urology at Weill Cornell Medicine and an attending physician at NewYork-Presbyterian – Weill Cornell Medical Center in New York.
OncLive: Given the incidence of prostate cancer within the general population in the United States and around the world, what is the importance of continued research in this landscape to improve outcomes for patients?
Tagawa: As the most common noncutaneous malignancy, at least in the Western world, is it important [to continue raising awareness of prostate cancer], especially for the ends of the spectrum. There’s a big population [where patients have prostate cancer] discovered by screening who might have low- or very low–risk disease that is probably best served for active surveillance. [It would be great] if there was a biomarker where we can know for sure that [a low-risk malignancy] is not something that is going to affect the patient’s lifetime, using more noninvasive ways to discover that.
Although the vast majority of patients who are diagnosed with prostate cancer never die of prostate cancer, depending on the year, it still is one of the leading causes of death due to cancer among people born with prostates. We also [want to drive further research] because we want to be able to cure those who [currently] might not be considered curable, or to at least extend life so that more people die with, rather than of, prostate cancer, as well as to improve the quality of life [QOL]. Something that could [help] maintain QOL and improve QOL would be a great win.
What are the current screening tests used to diagnose prostate cancer?
The most common screening test we have for prostate cancer is a blood test [to measure the amount of] prostate-specific antigen [(PSA) in the blood], and it’s really a good test. It needs to be interpreted in the right way, and this is more in the primary care realm. When used in the right way, a simple PSA [test] can be quite powerful.
There are additional screening tests available, both as imaging and [with] blood and urine. We’re no longer in an era where it’s ‘wrong to screen.’ We want to have shared decision-making about screening. Even something as mundane as PSA, when interpreted in the right context, which includes age and prostate size, can be quite powerful.
Within the mHRPC and mHSPC spaces, ARPIs have altered the treatment paradigm. Beyond this, when patients progress and require subsequent therapy, what are some of the challenges and considerations for treatment in this setting?
Clearly, ADT and ARPIs work incredibly well, and we hope to improve upon them. However, they’re generally not curative, unless they’re combined with radiation or [another therapy]. A big unmet need is to improve upon their initial use and have options post-ARPI, where traditionally there was chemotherapy and occasional subsets that were not chemotherapy. Chemotherapy is great in that it works for many patients and can improve QOL, but many patients don’t want to [receive] chemotherapy, and we’re not too happy giving chemotherapy some of the time.
[Now, we] have [more treatment] options than we did 5 years ago and 10 years ago when we had some options, because we didn’t have anything 15 years ago. Arguably, all [treatments beyond ARPIs] are what we call biomarker-selected. There are certainly clinical biomarkers that [can indicate] a person needs chemotherapy. Genomics [are used] in terms of PARP inhibitors. Imaging [is used] in terms of either of the targeted radionuclides, radium-223 [Xofigo] in terms of bone scans, and then lutetium Lu 177 vipivotide tetraxetan and others that are coming similar to that with PSMA PET.
All of those non-chemotherapies are somewhat [biomarker] selected, and there are certainly promising drugs that are for selected patient populations or for all comers in the AR pathway that will work beyond the traditional ARPI.
Overall, how have radioligand therapies, like lutetium Lu 177 vipivotide tetraxetan, affected those later-line settings for prostate cancer?
We have a bone-targeted [agent with radium-223], and we have the PSMA-targeted [radionuclide therapy with lutetium Lu 177 vipivotide tetrax]. One of the nice things about both of them, and specifically for the PSMA target, is that it’s another target beyond the AR pathway and microtubules, with a different mechanism of action. Although most patients will develop resistance to AR-targeted therapies, AR and PSMA remain, so it’s a good target for the majority [of patients]. Most tumors have some raised sensitivity, so we can selectively deliver radiation to those PSMA-positive tumors, and we would expect there to be improvements in outcome, and we have [seen these improvements]. Overall survival in one study, a radiographic progressive model in another study, and QOL improvements for both; therefore, it’s nice to have that as an option.
What are the factors to be aware of when determining whether docetaxel is better first before selecting radioligand therapy, or vice versa?
My bias is the target, PSMA. If PSMA is not [expressed] very much, then it doesn’t mean that a PSMA-targeted agent can’t work, but it’s been shown that the PSMA PETs are a very good biomarker, specifically for PSMA small molecules, particularly with [lutetium Lu 177 vipivotide tetraxetan].
[The lack of PSMA expression would represent] deselection from PSMA targeting, or for [treatment with] something else, like chemotherapy. In certain organs, we worry about liver metastases, which are negatively prognostic, no matter what [treatment you select], including chemotherapy. However, we know that data are coming from my former fellow, Himisha Beltran, MD, [of Dana-Farber Cancer Insitute], that [suggest that] even when PSMA is positive in certain organs, like the liver, it tends to be a little bit less [compared with the primary tumor]. The biases in those types of situations might [cause you to lean] more toward chemotherapy; some tumors, however, can have very homogeneously high levels of PSMA. It doesn’t mean that something in the liver can’t respond [with heterogeneous levels of PSMA].
There may be certain characteristics [we can consider]. We can administer these small molecules to someone with renal failure; if they’re on dialysis, we have to make sure [they’re appropriate candidates for lutetium Lu 177 vipivotide tetraxetan], where there’s more data with chemotherapy [in this population]. There are other individual factors, such as someone who’s worried about their family [while receiving radioligand therapy]. We’ve never seen a family member truly have exposure to radiation that has led to a problem, but it is a risk, whereas chemotherapy doesn’t have that risk.
Then, [radioligand therapy is] not fully available [everywhere]. There are many more places today [offering lutetium Lu 177 vipivotide tetraxetan] than there were 6 months ago and years ago, but chemotherapy is available pretty much everywhere, whereas some people have to travel for drugs like lutetium Lu 177 vipivotide tetraxetan.
Are there any other novel classes of drugs that you’re keeping your eye on that have the potential to be used in clinical practice?
I’d say a minor improvement in terms of incremental progress for the field, but [something that] is a major improvement for some patients, is with similar drugs coming in the same space, meaning there are choices. Some of those are very practical choices, [such as,] how many treatments and how often? [Adjusted treatment schedules can be] patient-friendly if they [are shown to] work.
We know that [data from the] PSMAddition trial are positive, as shown in a press release. We don’t know how positive yet; however, it would be nice [to have this option in the mHSPC space].
[Beyond] lutetium Lu 177 vipivotide tetraxetan, what about other things? I’d say the bigger incremental move is from beta to alpha [radioligand therapies]. The linear energy transfer is higher with more potency, which is something that is a little bit more than incremental.
A major improvement would be [to expand] beyond PSMA. Other targets are of interest, with some of them overlapping with this AR-positive group, but it’s OK to have overlapping things because it’s not exactly the same.
A huge unmet need, whether we’re talking about something radioactive or nonradioactive, but for those patients who are AR-low, there are other targets. Using the same type of approach, whether it’s with lutetium Lu 177 vipivotide tetraxetan or something else, might work in that other patient population. [Other targets could include] DLL3, CEACAM5, or others.
My bias is in the world of theranostics, meaning dual picture, where in vivo, we look at all the tumors to see what is there. That’s a great way to select an agent, whether it’s a chemotherapy-type agent that’s targeted, an immune-type agent, or something that’s radioactive. That is something we should incorporate more. Even docetaxel has some emerging biomarkers that help us decide whether it should be AR only or combined with chemotherapy. Should we add docetaxel? That is also a major improvement, even though docetaxel is one of our oldest drugs. If we can figure out how to improve the therapeutic index, then more patients will benefit more so that the efficacy vs the adverse effects is much more in favor of the patient.
Considering it is Prostate Cancer Awareness Month, what is your main takeaway message for colleagues regarding the current state of treatment and future implications of treatment?
There has been, traditionally, both on the patient side and on the physician side, a little bit of nihilism in terms of prostate cancer. There are a lot more options we have today, and many different categories of options that have improved both quantity and QOL. [Even for older patients], everything should be discussed. If someone says no, with informed consent, that’s fine. It doesn’t matter if they’re 50 or 90 years of age; however, we should offer these [options].
It’s not just the treatment; it is the testing for treatments, such as assessing the tumor genome or germline alterations, and remembering that sometimes germline [results] are as important or even more important for their grandchild. We want to approach every single patient with prostate cancer with an open mind and open eyes and discuss everything. Not that everyone must have every single drug, but they should at least have all the testing and therapeutics on the table.
References
- Novartis Pluvicto demonstrates statistically significant and clinically meaningful rPFS benefit in patients with PSMA-positive metastatic hormone-sensitive prostate cancer. News release. Novartis. June 2, 2025. Accessed September 18, 2025. https://www.novartis.com/news/media-releases/novartis-pluvictotm-demonstrates-statistically-significant-and-clinically-meaningful-rpfs-benefit-patients-psma-positive-metastatic-hormone-sensitive-prostate-cancer
- FDA expands Pluvicto’s metastatic castration-resistant prostate cancer indication. FDA. March 28, 2025. Accessed September 18, 2025. FDA. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-pluvictos-metastatic-castration-resistant-prostate-cancer-indication