Radioligand Therapy Continues to Show Promise for Metastatic CRPC

Radioligand therapy (RLT) with actinium-225 targeting prostate-specific membrane antigen (²²⁵Ac-PSMA) had a “substantial antitumor effect” in heavily pretreated metastatic castration-resistant prostate cancer (mCRPC), a large, retrospective, multicenter study showed.

Data on 488 men showed an overall survival (OS) of 15.5 months and median progression-free survival (PFS) of 7.9 months. A third of the patients had progression on prior lutetium-177 (¹⁷⁷Lu)-PSMA treatment.

A majority of patients developed xerostomia after the first cycle of treatment and all patients who received seven cycles of therapy, but rates of grade ≥3 bone marrow and renal toxicity were low, reported Mike M. Sathekge, MD, of the University of Pretoria in South Africa, and co-authors in Lancet Oncology.

“The results of this international multicenter study provide the strongest evidence to date supporting the antitumor activity and safety of ²²⁵Ac-PSMA RLT for mCRPC treatment,” the authors wrote in a summary of the findings. “The antitumor effect of ²²⁵Ac-PSMA RLT in mCRPC is influenced by several factors, including previous treatment with taxane-based chemotherapies and the pattern of mCRPC metastases. These factors should be considered in selecting patients for ²²⁵Ac-PSMA RLT, especially considering the current limitations in ²²⁵Ac supply and the prevalence of xerostomia induced by this therapy.”

Radioligand therapy for mCRPC is an active area of clinical research, involving multiple radioisotopes, said A. Oliver Sartor, MD, of the Mayo Clinic in Rochester, Minnesota. Just last fall, he reported that lutetium-177-PSMA (Pluvicto) more than doubled PFS in mCRPC as compared with an androgen receptor signaling inhibitor.

The retrospective study of ²²⁵Ac-PSMA adds to a growing body of literature in the field and has the advantage of drawing data from multiple clinical sites.

“It’s really nice to see this big multicenter study,” Sartor told MedPage Today. “They’re looking at retrospective data but looking across a whole series of sites. To be able to bring that together, it’s a really important observation, moving away from mostly single-institution studies we’ve had for a while… . Actinium is one of the isotopes that we’re very familiar with, and I think this is the single best study that we have seen to date.”

“What they found is really a confirmation of what we have done before, but we now have more confidence,” he added. “The response for these individuals is actually quite strong. If you look at the waterfall plot for PSA [prostate-specific antigen] responses, 57% of patients had a PSA decline of 50% or more. That’s a good number in these patients, who were pretty heavily pretreated.”

Despite the high rate of xerostomia, the treatment appeared fairly tolerable, Sartor continued. Anemia, thrombocytopenia, and leukopenia are always a reason for concern, but the rates of severe cytopenias and severe renal toxicity were fairly low.

Radioligand therapy has added to an expanding list of therapeutic options that have already improved survival in mCRPC, Sathekge and co-authors noted in their introduction to the study. As PSMA is overexpressed in mCRPC, it offers an attractive target for imaging and treatment of the disease.

Both alpha and beta emitters have been evaluated for mCRPC treatment. ²²⁵Ac emits multiple alpha particles that are “much more energetic,” as compared with the beta particles emitted by ¹⁷⁷Lu. By inducing double-stranded DNA damage with fewer DNA hits, ²²⁵Ac offers a potential to improve tumor-cell killing, the authors continued.

The effectiveness of ²²⁵Ac-PSMA has been shown in several settings, including extensive skeletal metastases of mCRPC, in combination with ¹⁷⁷Lu-PSMA, and in the post-¹⁷⁷Lu-PSMA setting. Though informative, most previous studies have involved few patients and/or conducted at a single center.

Sathekge and colleagues reported findings from the retrospective study involving seven centers in Australia, India, Germany, and South Africa. The primary objectives were OS and PFS, which were determined at a central location and based on information provided by the treating center.

Patients included in the analysis had received multiple prior therapies for mCRPC, including docetaxel (66%), cabazitaxel (Jevtana, 21%), abiraterone (Zytiga, 39%), enzalutamide (Xtandi, 39%), and radium-223 dichloride (4%). The patients had a mean age of 68, mean baseline PSA of 169.5 ng/mL, and median follow up was 9.0 months.

OS was significantly longer in patients who had a PSA decline ≥50% (24.2 vs 9.3 months, P<0.0001). Median OS was significantly lower in patients with prior taxane treatment (13.7 vs 24.2 months, P=0.016), previous exposure to an androgen receptor signaling inhibitor (12.7 vs 19.9 months, P=0.0015), previous ¹⁷⁷Lu-PSMA (10.5 vs 18.8 months, P=0.0002), liver metastases (7.7 vs 17.6 months, P<0.0001), peritoneal metastasis (4.8 vs 15.7 months, P<0.0001), and baseline anemia (10.6 vs 19.3 months, P<0.0001). The pattern was similar for PFS, except that baseline ECOG performance status ≥2 was associated with worse PFS (6.6 vs 8.6 months, P=0.0019).

Xerostomia occurred in 68% of evaluable patients after the first cycle of ²²⁵Ac-PSMA. Grade ≥3 anemia occurred in 13% of patients, leukopenia in 4%, thrombocytopenia in 7%, and renal toxicity in 5%. The data showed no serious adverse events or treatment-related deaths.

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