Adding Radioligand to Enzalutamide Boosts OS in Metastatic CRPC

SAN FRANCISCO — The addition of radionuclide therapy with ¹⁷⁷Lu-PSMA-617 (Pluvicto) to enzalutamide (Xtandi) improved overall survival (OS) in patients with metastatic castration-resistant prostate cancer (CRPC), according to secondary outcome results from a phase II trial.

Patients receiving the combination of ¹⁷⁷Lu-PSMA-617 and the androgen receptor pathway inhibitor (ARPI) lived a median of 8 months longer versus those who received enzalutamide alone (34 vs 26 months; HR 0.55, 95% CI 0.36-0.84, P=0.0053), reported Louise Emmett, MD, of St. Vincent’s Hospital in Sydney.

She noted the survival benefit with the combination was achieved even though 38% of patients in the enzalutamide-alone arm went on to receive the radioligand as subsequent treatment off protocol.

Moreover, “the combination improved both deterioration-free survival and health-related quality of life indicators for pain, fatigue, physical function, and overall health and quality of life,” Emmett said at the American Society of Clinical Oncology Genitourinary Cancers Symposium.

“The really significant overall survival benefits and the improvement in quality of life really raise the question of whether PSMA radioligand therapy in prostate cancer should be administered more broadly in conjunction with an ARPI,” she added. “And I think this paves the way for phase III trials leveraging these complementary therapies across this space.”

Results from the ENZA-p study were published concurrently in Lancet Oncology.

In a discussion following the presentation, Ali Khaki, MD, of the Stanford University School of Medicine in Palo Alto, California, pointed out that data from the TALAPRO-2 study, which was also presented at this year’s symposium, showed that adding talazoparib (Talzenna) to enzalutamide as initial treatment for patients with metastatic CRPC unselected for homologous recombination repair gene status had a survival benefit similar to that seen in ENZA-p.

“Next week in clinic, as well as maybe 6 months, 2 years, 5 years from now, where do you think we end up in how we treat prostate cancer?” he asked. “What would you do for your unselected metastatic CRPC patients — talazoparib with enzalutamide? [Radioligand therapy] with enzalutamide? Or are we still using ARPIs alone?”

“I think we are just starting to examine combinations and we are getting some great results with combinations,” Emmett replied. “I think it’s hard to compare TALAPRO-2 to ENZA-p. They both had strong overall survival benefits … but I don’t see the combinations staying in the metastatic CRPC space. I really ask what we can do in [metastatic hormone-sensitive prostate cancer].”

ENZA-p was performed at 15 hospitals in Australia among men who had not previously been treated with docetaxel or ARPIs for metastatic CRPC, and had gallium-68 PSMA PET/CT-positive disease, an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2, and at least two risk factors for early progression on enzalutamide.

From August 2020 through July 2022, 79 patients were randomly assigned to enzalutamide and 83 to enzalutamide plus ¹⁷⁷Lu-PSMA-617. Patients had a median age of 71 years, and most had high-risk disease, with more than half having >20 PSMA-avid metastases, de novo metastatic disease at diagnosis, or early docetaxel for hormone-sensitive disease.

In addition to OS results, an update of the study’s primary endpoint of prostate-specific antigen (PSA) progression-free survival showed that the improvement with the combination has been maintained.

Regarding the key secondary endpoints, Emmett reported that deterioration-free survival at 12 months favored the combination over enzalutamide for both physical function (median 10.6 vs 3.4 months; HR 0.51, 95% CI 0.36-0.72, P=0.0001) and overall health and quality of life (median 8.7 vs 3.3 months; HR 0.47, 95% CI 0.33-0.67, P<0.0001).

The combination group also had better mean scores for pain (difference 7.3, P=0.012) and fatigue (difference 5.9, P=0.016) until progression versus the enzalutamide-alone group, though the frequency of self-rated xerostomia was lower in the enzalutamide group than in the combination group (57% vs 74%).

Grade 3-5 adverse events occurred in 46% of patients in the combination group compared with 44% in the enzalutamide group.

“What is really pleasing is to see the low level of hematologic toxicity,” Emmett said, pointing out that for the combination group, just 4% of patients had grade 3 anemia, and only 1% had grade 3 platelet thrombocytopenia, with no grade 4 or 5 adverse events.

Emmett noted that the ENZA-p study was limited by the fact that it involved first-line enzalutamide in the early metastatic CRPC pre-chemotherapy setting, “and we know that ARPI has mostly moved to the metastatic hormone-sensitive setting.”

She also acknowledged that the study included a selective population of patients who had risk factors for early treatment failure on enzalutamide, “and this does impact the broad applicability of these findings.”

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