Safety and Efficacy of 20 Cycles of [¹⁷⁷Lu]Lu-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer

Current randomized controlled data (1,2) demonstrate the safety and efficacy of 6 cycles of [¹⁷⁷Lu]Lu-PSMA-617 therapy in men with metastatic castration-resistant prostate cancer. In our first phase 2 trial (3), 15 of 30 patients received additional cycles; 11 (73%) had a subsequent prostate-specific antigen (PSA) decline of 50% or more (4). A German multicenter study also supported extended therapy in 111 patients, with a median survival of 31.1 mo from the first administration and no increase in grade 3–4 toxicities (5).

We describe safety and efficacy in a patient who received 20 cycles of [¹⁷⁷Lu]Lu-PSMA-617, receiving a total administered radioactivity of 129 GBq over 5 y. Initially diagnosed at age 59 with de novo bone-only metastatic prostate cancer and a PSA of 96 ug/L, he underwent intermittent androgen deprivation therapy for 13 y before requiring palliative radiotherapy for painful bone metastases. The following year, he was treated with 6 cycles of docetaxel, followed by 18 mo of enzalutamide.

On progression with a PSA of 195 ug/L and a doubling time of 3.0 mo, the patient received 6 cycles of [¹⁷⁷Lu]Lu-PSMA-617, with a PSA nadir of 3.2 ug/L, as part of the TheraP trial. Paired PSMA PET/CT (SUV_max, 73; SUV_mean, 10.7) and ¹⁸F-FDG PET/CT (metabolic tumor volume, 14 cm³) at enrollment had favorable characteristics. A second treatment block of 2 cycles of [¹⁷⁷Lu]Lu-PSMA-617 was given 266 d after cycle 6 (14 mo after cycle 1) on a clinical registry, resulting in a PSA decline of more than 90% (nadir, 14.2 ug/L) and a further treatment break of 229 d. The treatment-free interval remained similar between treatment blocks 2 and 3 at 216 d; however, this interval shortened to 75 and 78 d between blocks 4 and 5 and blocks 5 and 6, respectively (Fig. 1).

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FIGURE 1.

(A) PSA trend over time, with vertical lines indicating cycles of [¹⁷⁷Lu]Lu-PSMA-617. (B) Serial posttherapy SPECT for cycles 1–20. Dashed lines in A indicate time points for posttherapy SPECT imaging shown in B. Video version of figure is available as supplemental file (supplemental materials are available at http://jnm.snmjournals.org).

After cycle 15, he continued to receive symptomatic benefit, but on-treatment biochemical and imaging progression emerged. The hemoglobin and platelet nadirs were 98 g/L and 115 × 10⁹/L, respectively, occurring after cycle 18. Renal function remained normal, with an estimated glomerular filtration rate of 92 mL/min after cycle 20, compared with 117 mL/min at baseline, and an estimated cumulative kidney dose of 55.5 Gy. This exceeds the 23-Gy maximum tolerated dose defined by external-beam radiotherapy, highlighting the limitation of extrapolating external-beam radiotherapy normal-organ constraints to radiopharmaceutical therapy (6). Grade 1 xerostomia occurred from cycle 3 and remained mild and transient, usually lasting a few days after many, but not all, cycles.

After cycle 20, he received 2 cycles of cabazitaxel and had a clinical response but subsequently progressed with new brain metastases and physical decline; he died 2 mo later at age 81, 4.9 y after the initiation of [¹⁷⁷Lu]Lu-PSMA-617. In conclusion, in selected patients, [¹⁷⁷Lu]Lu-PSMA-617 appears to have substantial benefits beyond 6 cycles.

• © 2025 by the Society of Nuclear Medicine and Molecular Imaging.

• Received for publication December 30, 2024.
• Accepted for publication February 18, 2025.