Extended therapy with [177Lu]Lu-PSMA-617 in responding patients with high-volume metastatic castration-resistant prostate cancer

Abstract

Purpose The currently used scheme for radioligand therapy (RLT) of patients with metastatic castration-resistant prostate cancer (mCRPC) consists of 4–6 cycles of 6.0–7.4 GBq [177Lu]Lu-PSMA-617 each. This standard treatment scheme has proved safe and effective resulting in objective response in most patients with no significant toxicity. Many patients, however, show high-volume residual tumor burden after the sixth cycle and may benefit from treatment continuation. Extended treatment with additional cycles has been withheld due to concerns on potential increased toxicity. Methods Twenty-six patients with high-volume residual tumor burden (according to CHAARTED) after standard RLT with [177Lu]Lu-PSMA-617 and no alternative treatment option received additional RLT cycles reaching a median of 10 (range 7–16) cycles with a mean activity of 7.4 ± 0.9 GBq per cycle. Response assessment with [68Ga]Ga-PSMA-11 PET/CT was done every 2–3 cycles or if disease progression was clinically suspected or based on change in PSA value (according to the PCWG3 criteria). Toxicity was measured using routine blood work up including blood counts, liver and renal function, and was graded according to CTCAE v5.0 criteria. Survival outcome was calculated based on the Kaplan-Meier method. Results Further PSA decline of 33 ± 28% during the extended treatment was observed in 21/26 (81%) patients, whereas 5/26 (19%) patients showed a PSA increase; correspondingly in 11/21 patients with an initial response (PR or SD) to extended cycles, treatment was discontinued due to progressive disease, whereas six (23%) patients achieved low-volume residual disease. Two (8%) patients died without showing progression, and two (8%) patients are still under therapy. The median progression-free survival was 19 (95% CI: 15–23) months, and the overall survival was 29 (95% CI: 18–40) months. Grade ≥ 3 hematological toxicities occurred in 4/26 (15%) patients during treatment extension, and nephrotoxicity (grade ≥ 3) was observed in 1/26 (4%) patient during the follow-up. Conclusion Extended radioligand therapy is a feasible treatment option in patients with high-volume residual tumor after the completion of standard treatment with six cycles of [177Lu]Lu-PSMA-617. Improved survival and the acceptable safety profile warrant further investigation of the concept of additional cycles in selected patients.

PSMA Radioligand Therapy in Prostate Cancer

“…Most patients presented extra decline in PSA (81%) and positive image-based response with 11/21 (52.3% presenting partial response [PR] or stable disease [SD]) with acceptable grade ≥3 toxicity in 15% of patients. 38 Gaudreault et al 39 evaluated 6 patients that were excluded from the LuPSMA trial with a total of 89 PSMA-negative/FDG-positive targets identified. Median gross tumor volume (GTV) of 4.3 cm 3 , and median SUV max of 4.8 were found in 18 F-FDG PET/CT.…”

“…Mader et al 38 demonstrated retrospectively in 26 mCRPC patients that an extension of treatment applying additional cycles after the usually recommended 6 cycles of PSMA-RLT could be a safe option in patients with a high volume of disease. Most patients presented extra decline in PSA (81%) and positive image-based response with 11/21 (52.3% presenting partial response [PR] or stable disease [SD]) with acceptable grade ≥3 toxicity in 15% of patients 38 …”

Highlighting recent progress in the treatment of men with advanced prostate cancer

“…81% of patients had some further PSA response to treatment past six cycles with median PFS of 19 months (95% CI 15–23 months) and median OS of 29 months (95% CI 18–40). Only 15% of patients had ≥ Grade 3 hematologic toxicity [22]. In a separate prospective phase II analysis, thirty-five men with chemotherapy-naïve mCRPC were randomized to [ 177 Lu] lutetium-PSMA-617 versus docetaxel.…”

How Can Radiopharmaceutical Therapies Reach Their Full Potential? Improving Dose Reporting and Phase I Clinical Trial Design

“…6,13 On the basis of published RPT data showing that patients who received extended treatment courses exceeding these normal organ dose constraints still have limited toxicity, there is a specific concern in the field that the majority of patients treated with RPTs are undertreated. 4,[14][15][16][17][18][19][20][21][22] The inability to escalate beyond the above constraints in clinical trials leads to many phase I RPT trials stopping escalation before any DLT is observed, as opposed to other phase I trials with escalation guided primarily by clinical toxicity (Fig 1). This precludes treatment optimization with many RPT agents.…”

“…In terms of the overall controversy noted above regarding AD constraints for bone marrow (2 Gy) and kidney (23 Gy), there is already evidence that these limits can often be safely exceeded in clinical practice in patients receiving multiple courses or extended cycles of RPT. 4,14,15,22 This suggests that current treatment regimens also merit reevaluation to assess whether larger initial administered activities per cycle are tolerable. In particular, in the bone marrow, acute toxicity is readily observable during the phase I DLT observation period (typically 3-8 weeks after administration).…”