Efficacy and safety of rechallenge with [¹⁷⁷Lu]Lu-PSMA-I&T radioligand therapy in metastatic castration resistant prostate cancer

The purpose of this study was to evaluate the safety and outcome of rechallenge [¹⁷⁷Lu]Lu-PSMA-I&T in newly progressed mCRPC patients after response to initial [¹⁷⁷Lu]Lu-PSMA radioligand therapy (PRLT).

We retrospectively included 18 patients who underwent rechallenge with [¹⁷⁷Lu]Lu-PSMA-I&T. All patients presented with (i) newly progressed disease after response to initial PRLT; (ii) a [⁶⁸Ga]Ga-PSMA-11 PET/CT confirming the presence of PSMA-positive metastases; iii) ECOG performance status 0–1. Adverse events were graded according to CTCAE v5.0. Response was assessed by PSA and classified according to PCWG3 recommendations. For patients who underwent restaging with [⁶⁸Ga]Ga-PSMA-11 PET/CT, imaging response was categorised according to adapted PERCIST v1.0. In patients with discordant [⁶⁸Ga]Ga-PSMA-11 PET/CT and PSA, other available imaging modalities were evaluated to confirm disease status. Overall survival (OS) was calculated from the first cycle of initial PRLT and rechallenge PRLT, respectively, until last patient contact or death.

Patients were initially treated with a median of 5 cycles (range 4–7) and were rechallenged after a median of 9 months (range 3–13). Each patient received a median of 4 (range 2–7) rechallenge cycles (median cumulative activity 26.1 GBq). None of the patients experienced life-threatening G4 adverse events during either treatment period. Grade 3 adverse events included one case of anaemia, one case of thrombocytopenia, and one case of renal failure. In 8/18 patients long-term toxicities were evaluated. Serious toxicities (≥ Grade 3) occurred in 3/8 patients (n = 1 G4 thrombocytopenia, n = 1 G4 renal failure and n = 1 pancytopenia and G4 renal failure). Best PSA50%-response was observed in 44% of patients and PSA-disease control was confirmed in 56% of patients at the last cycle. Of the 12/18 patients restaged by imaging, 6/12 (50%) patients had disease control (partial response/stable disease), 1/12 had a mixed response, and 5/12 had progression. After a median follow-up time of 25 months (range 14–44), 10 patients had died, 7 were still alive, and one patient was lost at follow-up. The median OS was 29 months (95%CI, 14.3–43.7 months) for the initial treatment and 11 months (95%CI, 8.1–13.8 months) for the first rechallenge course.

More than half of patients benefit from rechallenge PRLT. Our analysis suggests that rechallenge may prolong survival in selected patients, with an acceptable safety profile.