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PSMA PET Guides the Individualized Use of Lutetium-Based Therapies in mCRPC

Supplements and Featured Publications, State of the Science Summit Recaps, Volume 1, Issue 1

Evan Y. Yu, MD, discusses the clinical evolution of radiopharmaceuticals for patients with mCRPC and how PSMA PET may evolve to monitor treatment response.

Evan Y. Yu, MD

Evan Y. Yu, MD

As radiopharmaceuticals gain traction beyond the post-chemotherapy setting for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC), evolving criteria for prostate-specific membrane antigen (PSMA) PET use may help clarify the ideal role for this treatment modality in relation to disease progression, according to Evan Y. Yu, MD.

In an interview with OncLive® following a State of the Science Summit™ on genitourinary cancers, which he co-chaired, Yu discussed the clinical evolution of radiopharmaceuticals for patients with mCRPC, the potential prechemotherapy utility of lutetium Lu 177 vipivotide tetraxetan (Pluvicto; formerly 177Lu-PSMA-617), and how PSMA PET may evolve into a tool for monitoring treatment response and guiding radioligand dosing strategies.

He highlighted the evolving role of PARP inhibitor–based regimens and other targeted therapies for mCRPC in another article.

Yu is the section head of Medical Oncology and a professor in the Clinical Research Division at the Fred Hutchinson Cancer Center in Seattle, Washington. He is also the medical director of Clinical Research Support at Fred Hutchinson/University of Washington (UW)/Seattle Children’s Cancer Consortium, as well as the assistant fellowship director and a professor in the Division of Hematology and Oncology at the UW School of Medicine.

OncLive: What is the current role of lutetium Lu 177 vipivotide tetraxetan for the treatment of patients with mCRPC?

Yu: [Lutetium Lu 177 vipivotide tetraxetan] is FDA approved in the mCRPC setting post-androgen receptor pathway inhibitors [ARPIs] and post-docetaxel chemotherapy. In the past [few] months, [findings from the phase 3] PSMAfore [NCT04689828] and SPLASH [NCT04647526] trials [in patients with mCRPC] have read out. Those are trials using lutetium compounds that target PSMA; lutetium Lu 177 vipivotide tetraxetan [was under investigation in PSMAfore], 177Lu-PNT2002 [was evaluated] in SPLASH.

Both [those trials] showed significant radiographic progression-free survival [rPFS] benefits [with the radiopharmaceuticals] in the prechemotherapy setting, whereas the current FDA approval for lutetium Lu 177 vipivotide tetraxetanis in the post-chemotherapy setting, so we’ve yet to see regulatory approval [for a lutetium compound in the prechemotherapy setting]. However, [these data are] impressive. The overall survival [OS] data are not mature, and there was significant crossover in both these studies; [57% and 84.6%] of patients [in the control arms] crossed over [to the investigational arms in PSMAfore and SPLASH, respectively] after progressing on the control, which was ARPI switch in both [trials].1,2 When patients progressed on ARPI switch, they were allowed to cross over to receive the lutetium PSMA compound in both studies. [That] may make hitting the OS mark difficult. We’re waiting to see what the regulators say about the utility of lutetium compounds against PSMA in the prechemotherapy disease state based on these positive results from both these randomized trials.

How is PSMA PET used in patients with metastatic prostate cancer?

PSMA PET is used in a couple different settings. One is early [in the disease course] with staging and trying to find metastatic disease when the disease is still castration sensitive. However, where we’re using it with known metastatic disease is in mCRPC, where we’re using it to identify patients who could be eligible for PSMA-targeted radioligand therapy. For instance, lutetium Lu 177 vipivotide tetraxetan [is FDA approved] in the post-ARPI and post-docetaxel disease state. In the future, [that treatment] may [be indicated just in the] post-ARPI [setting] for earlier-line mCRPC. [Overall, currently], the only definitive utility of PSMA PET is to identify patients who have PSMA expression and are apt to respond to lutetium radioligand therapies.

What might the future look like regarding the use of PSMA PET in patients with mCRPC?

The future is going to be interesting. There’s hope by regulators, pharmaceutical companies, and oncologists alike that we can use [PSMA PET] to measure treatment response and determine progression. Prostate Cancer Working Group 4 [PCWG4] will [is planning on publishing] an imaging paper and like in the past with conventional imaging—CT and bone scan—there had to be a bit of thought that went into [the] criteria for what they would [classify as] progression.

Subsequently, with the phase 3 abiraterone acetate [Zytiga] studies—COU-AA-301 [NCT00638690] and COU-AA-302 [NCT00887198]—rPFS in the prechemotherapy setting had a strong correlation with OS, and [the COU-AA-302 findings] led to the FDA approval of abiraterone acetate in the prechemotherapy [mCRPC setting]. The hope with PCWG4 is that they will develop PSMA PET criteria, compare it with other conventional imaging criteria, see whether that progression correlates with or is close to surrogacy with OS, and see whether it can be an approvable end point in the future. That’s a potential area [of development].

Measuring PSMA PET response is another potential area because for instance, if a patient is receiving a lutetium PSMA–targeted radioligand therapy and planning to receive 6 doses, if [their disease] disappears on PSMA PET after 2 or 3 doses, should they continue [that therapy]? The idea of dosimetry, using responses and uptake by the PSMA ligand or radio four, then assessing that expression and determining whether we should be dosing and how we should be dosing is complex to [study], but that’s one way of refinement we could use [PSMA PET] for in the future, hopefully.

References

  1. Morris MJ, Castellano D, Herrmann K, et al. 177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial. Lancet. 2024;404(10459):1227-1239. doi:10.1016/S0140-6736(24)01653-2.
  2. Sartor O, Jiang DM, Smoragiewicz M, et al. LBA65 Efficacy of 177Lu-PNT2002 in PSMA-positive mCRPC following progression on an androgen-receptor pathway inhibitor (ARPI) (SPLASH). Ann Oncol. 2024;35(suppl 2):S1254-S1255. doi:10.1016/j.annonc.2024.08.2308

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