PCa Commentary | Volume 198 – February 2025

Posted by Edward Weber | February 2025

“Pluvicto” (177Lutetiun-PSMA-617) Therapy for Prostate Cancer — What’s Coming Up in the Future for Pluvicto? Updated Results, Patient Selection Guidance, Early Use and 177Lu in Combination.

Pluvicto was approved in March 2022 for therapy in men with heavily pretreated castration resistant metastatic prostate cancer, and since then, it has become a frequently prescribed life-prolonging treatment. Sartor et al., NEJM 2021, reported that the median imaging-based progression-free survival for 177Lu PSMA was 8.7 months vs. 3.4 for ADT alone, and the median overall survival was 15.3 months vs.11.3 for ADT. Quality of life was similar. Pluvicto is administered via a short IV infusion every 6 weeks for 4-6 cycles.

The search for biomarkers to predict response to 177Lu

“Real-world” outcomes were further defined by Kafka et.al., Eur Urol Oncol, June 2024, in a study searching for predictive biomarkers of response to guide patient selection. Results:

“A prostate-specific antigen (PSA) decrease of > 30% was observed in 41.7%, 63.5% and 77.8% of patients after the first, second and third treatment cycle, respectively” with 33.7% showing a PET-based response after the third cycle. Any PSA rise after the first cycle doubled the risk of progression. Achieving a PSA decrease of < 30% after the first two cycles and a PSA doubling time < 6 months “is an early marker of lack of response that can be easily implemented in clinical practice.”

An analysis by Hartrampf et al., Prostate. 2022, aimed at determining the likelihood of response after the first 8-week cycle of Lu PSMA to guide an early switch to an alternate therapy. The two studies reviewed ~65% of men who showed any PSA response, and those men had a median overall survival of 18-19 months vs. 7-9 months for men with no PSA response. The conclusion: “Early biochemical response is tightly linked to prolonged survival, irrespectively of the magnitude of PSA decline,” and in those patients, treatment should be continued. An analysis by Armstrong et al. (Eur Assn Urol. 2024) found that “the magnitude of PSA decline was associated with improvement” as measured at 12 weeks: Those men with > 50-90% or >90% decline from baseline experienced 70% and 87% reduced risk of death compared to the 29% of men with increasing PSA levels.

Currently, many men with heavily treated mCRPC will have already been treated with Taxotere chemotherapy before addressing the issue of the next treatment. In this context, the study by Hoffman et al. (Lancet. Jan. 2024) is relevant. Their trial compared Lu PSMA treatment to the platinum-based chemotherapy cabazitaxel. In the initial trial phase, Lu PSMA bettered the chemotherapy in response rate, 66% vs 37%, with a 37% better progression-free survival. However, in the final results of the “cross-over” portion of the trial, the overall survival of the two study groups was similar, 19 months, suggesting that in the advanced stage of disease progression, Lu PSMA treatment followed by cabazitaxel could be useful.

“PET scans predict patient response to Pluvicto”

As reported in Radiology. 8/2024 by Kuo and Morris et al., the average collective tumor uptake of all lesions on a Pylarify PET is the best predictor of the benefit from Pluvicto, as based on an evaluation of data from the VISION trial. This value is termed the “SUVmean” (Standard Uptake Value) and requires special software for calculation: The higher the SUVmean value above the average of 7.6, the better the response, progression-free and overall survival, although men with lessor SUVs may respond, but less so. The SUVmean value, if available, could play a role in patient selection.

Moving Pluvicto “up front” in prostate cancer management

An overview of this issue was presented by Jia and Spratt in the Lancet, Oct. 2024: “A step closer to the use of [177Lu]Lu-PSMA-617 in metastatic hormone-sensitive prostate cancer.” They cited several reasons for its earlier use: Later in the treatment cycle in advanced disease, PC becomes heterogeneous “with 15-20% of metastatic castration-resistant cancers losing [PSMA] expression completely,” and the cancer may become radioresistant [to the intracellular radiation from 177Lu] as compared to hormone-sensitive prostate cancer. Also cited was the possibility of requiring fewer cycles of radioligand therapy as used in the UpFront trial.

An example of forward positioning of 177 Lu is the “UpFrontPSMA” trial, which compared 2 six-week cycles of 177Lu followed by 6 every 3-week cycles of docetaxel to docetaxel alone in 122 patients with de novo high-volume metastatic hormone-sensitive prostate cancer (i.e., metastatic at diagnosis). All received continuous ADT. The patients had high-volume PSMA-positive disease and negative fluorine 18F FDG PET-CTs (to rule out neuroendocrine and PSMA negative lesions). Results: At 48 weeks, an undetectable PSA developed in 41% in the combo cohort vs. 16% in the chemotherapy-alone group. At 2.5 years, follow-up PSA progression-free survival was 31+ months for the combo vs. 20 months docetaxel alone. (Currently, this category of patient might be treated with “triple” therapy of chemotherapy, ADT, and darolutamide.)

Two cycles of Pluvicto would have the additional advantage of fewer adverse effects compared to the conventional 6 cycles. The combined treatment is associated in general with fatigue ~30%, anemia ~25%, dry mouth ~ 50%, and potential kidney injury.

Two interesting protocols testing “up-front” 177 LU

1. Pluvicto in association with metastasis directed therapy (MDT): “The purpose of this study is to evaluate the efficacy and safety of lutetium (177LU) … in participants with oligometastatic prostate cancer progressing after definitive therapy to their primary tumor,”  “The goal of the protocol is to delay the need for ADT/castration and delay recurrence (NCT05939414).”  After radiation to all sites of metastatic disease, the randomization is between 177Lu and observation.
2. Combining Pluvicto with prostatectomy and removal of testicles in men with de novo metastatic hormone sensitive PC + ADT— a pilot study.

Bottom Line:

New Information: Predicting response to [177Lu] PSMA-617 (Pluvicto) therapy. And “UpFrontPSMA,” a protocol evaluating Pluvicto in early metastatic disease comparing Pluvicto, docetaxel/ADT to docetaxel/ADT alone.

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