225Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: a pilot study

Abstract

Background: A remarkable therapeutic efficacy has been demonstrated with ²²⁵Ac-prostate-specific membrane antigen (PSMA)-617 in heavily pre-treated metastatic castration-resistant prostate cancer (mCRPC) patients. We report our experience with ²²⁵Ac-PSMA-617 therapy in chemotherapy-naïve patients with advanced metastatic prostate carcinoma.

Methods: Seventeen patients with advanced prostate cancer were selected for treatment with ²²⁵Ac-PSMA-617 in 2-month intervals, with initial activity of 8 MBq, then de-escalation to 7 MBq, 6 MBq or 4 MBq in cases of good response. In one patient, activity was escalated to 13 MBq in the third cycle. Fourteen patients had three treatment cycles administered, while in three patients treatment was discontinued after two cycles due to good response. Six out of 17 patients received additional treatments after the third cycle. Prostate-specific antigen (PSA) was measured every 4 weeks for PSA response assessment. ⁶⁸Ga-PSMA-PET/CT was used for functional response assessment before each subsequent treatment cycle. Serial full blood count, renal function test, and liver function were obtained to determine treatment-related side effects.

Results: Good antitumor activity assessed by serum PSA level and ⁶⁸Ga-PSMA-PET/CT was seen in 16/17 patients. In 14/17 patients, PSA decline ≥90% was seen after treatment, including seven patients with undetectable serum PSA following two (2/7) or three cycles (5/7) cycles of ²²⁵Ac-PSMA-617. Fifteen of 17 patients had a > 50% decline in lesions avidity for tracer on ⁶⁸Ga-PSMA-PET/CT including 11 patients with complete resolution (PET-negative and either stable sclerosis on CT for bone or resolution of lymph node metastases) of all metastatic lesions. Grade 1/2 xerostomia was seen in all patients, and none was severe enough to lead to discontinuation of treatment. One patient had with extensive bone marrow metastases and a background anemia developed a grade 3 anemia while another patient with solitary kidney and pre-treatment grade 3 renal failure developed grade 4 renal toxicity following treatment. The group presented with significant palliation of bone pain and reduced toxicity to salivary glands due to de-escalation.

Conclusions: ²²⁵Ac-PSMA-617 RLT of chemotherapy-naïve patients with advanced metastatic prostate carcinoma led to a ≥ 90% decline in serum PSA in 82% of patients including 41% of patients with undetectable serum PSA who remained in remission 12 months after therapy. The remarkable therapeutic efficacy reported in this study could be achieved with reduced toxicity to salivary glands due to de-escalation of administered activities in subsequent treatment cycles. This necessitates further exploration for informing clinical practice and clinical trial design.

Keywords: Actinium-225; Chemotherapy-naïve; PSA response; PSMA; Prostate cancer; Radioligand therapy.

Fig. 1

a Waterfall plot showing PSA response at 8 weeks after one cycle of ²²⁵Ac-PSMA-617 radioligand therapy. b Waterfall plot showing best PSA response to ²²⁵Ac-PSMA-617 radioligand therapy

Fig. 2

A patient with progressive disease while on androgen deprivation therapy achieved a complete response after three cycles of ²²⁵Ac-PSMA-617 (patient number 10, Table 1). He remained symptom-free on 11-month follow-up with his serum PSA remaining below detectable level and the follow-up ⁶⁸Ga-PSMA-11 PET/CT scan remaining negative for disease recurrence

Fig. 3

A treatment-naïve patient who presented with extensive bone metastasis at primary diagnosis achieved a complete remission after three cycles of ²²⁵Ac-PSMA-617 with de-escalating activities of 8/7/6 MBq (patient number 16, Table 1). He also remained symptom-free on 11-month follow-up with his serum PSA remaining below detectable level and the follow-up ⁶⁸Ga-PSMA-11 PET/CT scan remaining negative for disease recurrence

Fig. 4

An example of a patient with progressive disease under therapy with ²²⁵Ac-PSMA-617 after pre-treatment with prostatectomy, external beam radiation and androgen deprivation therapy. The patient decided to switch to chemotherapy and died 4 months after the last cycle of ²²⁵Ac-PSMA-617 (patient number 1, Table 1)

Fig. 5

Bar charts comparing results of leucocyte count and hemoglobin (A), as well as serum creatinine and albumin (B) obtained at baseline and at the completion of ²²⁵Ac-PSMA-617 PRLT. The differences in the pre-treatment and follow-up measurements of leucocyte count (p = 0.292), hemoglobin level (p = 0.485), serum creatinine level (p = 0.683) and serum albumin level (p = 0.633) did not reach statistical significance