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MADRID -- Radiographic progression-free survival (rPFS) in metastatic castration-resistant prostate cancer (mCRPC) doubled when patients received a radionuclide ligand targeting prostate-specific membrane antigen (PSMA) instead of switching to another androgen receptor pathway inhibitor (ARPI), a randomized trial showed.

In patients with prior progression on an ARPI, median rPFS increased from 5.9 months with another ARPI to 12.02 months with ¹⁷⁷Lu-PSMA-617 (Pluvicto). The benefit was consistent across a spectrum of prespecified subgroups, the notable exception being a small number of patients who received concurrent radiotherapy.

Radiographic response rates more than tripled with the radionuclide ligand and more than twice as many patients had at least a 50% decline in prostate specific antigen (PSA), reported Oliver Sartor, MD, of the Mayo Clinic in Rochester, Minnesota, at the European Society for Medical Oncology (ESMO) congress.

"The lutetium has a manageable safety profile, was very well tolerated, and unequivocally met the primary endpoint of the trial," Sartor concluded.

The trial had some notable limitations that should be considered when evaluating the results, said ESMO invited discussant Christopher Sweeney, MBBS, of the University of Adelaide in Australia. The primary endpoint of rPFS is "modest" as compared with overall survival (OS), and use of a non-life-prolonging therapy (ARPI switch) resulted in a weak control arm. The trial did not define optimal dosing for ¹⁷⁷Lu-PSMA-617 and long-term safety data are needed.

Despite the limitations, the trial documented cancer regression and delayed progression with the radionuclide therapy, and better quality of life (QoL) and pain control.

"However, [¹⁷⁷Lu-PSMA-617] does not replace any existing CRPC option; it is one option," said Sweeney. "I liken this to one piece on a chess board, and we just need to know which chess piece to move first for a patient. PSMAfore does not tell us when best to use lutetium PSMA, but it provides data for use prior to docetaxel in the mCRPC setting, which is great. Many of our patients are not fit for docetaxel but they are fit for lutetium PSMA."

Lutetium-177 is a beta-emitter, which "means that the little beta particles can come out and be able to destroy wherever they are deposited," said Sartor. The radioactive particles gain access to prostate cancer cells the PSMA-617 ligand, which binds to the surface of cancer cells expressing PSMA.

The phase III PSMAfore trial, included patients with progressive mCRPC, progression on one prior second-generation ARPI, and no prior taxane in the metastatic setting and not candidates for a PARP inhibitor. The patients were randomized to ¹⁷⁷Lu-PSMA-617 once every 6 weeks for a maximum of six cycles or to ARPI switch (abiraterone [Zytiga] or enzalutamide [Xtandi]).

The primary endpoint was rPFS by independent review, at which time patients in the control arm had the option to cross over to ¹⁷⁷Lu-PSMA-617. Sartor reported updated information from a planned interim analysis, which included 468 randomized patients.

The results showed that treatment with ¹⁷⁷Lu-PSMA-617 reduced the hazard for rPFS by 57% (95% CI 0.33-0.54, P<0.0001). The overall radiographic response rates were 50.7% (including complete responses in 21.1%) with ¹⁷⁷Lu-PSMA-617 and 14.9% (2.7%) with control therapy. Median duration of response was 13.63 months with ¹⁷⁷Lu-PSMA-617 and 10.05 months with ARPI switch. Additionally, 31.0% and 45.9% of the ¹⁷⁷Lu-PSMA-617 and control group, respectively, had stable disease.

PSA response (≥50 from baseline) occurred in 57.6% of the ¹⁷⁷Lu-PSMA-617 versus 20.4% of the control group. The time to symptomatic skeletal events had yet to be reached in either group, but more than twice as many patients in the control group had events (HR 0.35, 95% CI 0.22-0.57). The time to deterioration of health-related QoL and pain worsening was significantly prolonged with ¹⁷⁷Lu-PSMA-617 (HRs of 0.59 and 0.69, respectively).

An interim OS analysis showed no significant difference between groups, but Sartor noted that 84% of patients in the control arm crossed over to ¹⁷⁷Lu-PSMA-617.

Grade 3/4 treatment-emergent adverse events (TEAEs) occurred more often in the control arm (43.1% vs 33.9%). The most common all-grade TEAEs (≥20%) with ¹⁷⁷Lu-PSMA-617 were dry mouth, asthenia, nausea, anemia, fatigue, constipation, and decreased appetite. The most common ≥3 TEAEs with the radionuclide therapy were anemia (6.2%) and dry mouth (1.3%).

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