Oral Presentation 33rd ASM of the Australian & New Zealand Bone & Mineral Society 2023

The Tyr Phenomenon: A Hypocalcaemic Response in High-Volume Treatment Responders to 177Lu-PSMA Therapy (#14)

Shejil Kumar 1 , Megan Crumbaker 2 , Roderick Clifton-Bligh 1 3 , Adrian Lee 4 5 , Louise Emmett 2 6 7
  1. Endocrinology Department, Royal North Shore Hospital, Sydney
  2. Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, New South Wales, Australia
  3. Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
  4. Department of Medical Oncology, Royal North Shore Hospital, Sydney, New South Wales, Australia
  5. Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
  6. St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia
  7. Garvan Institute of Medical Research, Sydney, New South Wales, Australia

Background: 177Lutetium-prostate-specific membrane antigen (177Lu-PSMA) is an effective treatment for metastatic castration-resistant prostate cancer (mCRPC) which is generally well-tolerated. Clinically significant hypocalcaemia has not been reported during 177Lu-PSMA treatment.

Methods: A clinical dataset of men with progressive mCRPC (n = 127) receiving a minimum of two doses of 177Lu-PSMA-I&T at 6-week intervals was evaluated to estimate the incidence, severity and clinical associations with hypocalcaemia. A median of 8 GBq was administered at each dose with blood collected at baseline and 3-week intervals including corrected calcium, alkaline phosphatase (ALP) and prostate specific antigen (PSA) concentrations.

Results: Forty-one of the 127 men (32%) experienced a reduction in serum calcium and 6/127 (5%) developed laboratory-defined hypocalcaemia within 12-weeks of commencing 177Lu-PSMA. Baseline SPECT total tumour volume was significantly higher in those who developed hypocalcaemia (median 3,249 cm3 [interquartile range 1,856-3,852] vs 465 [interquartile range 135-1,172]; p = 0.002). The mean PSA response was 78% ± 24% in those who developed hypocalcaemia and some developed marked osteosclerosis. Two patients experienced severe hypocalcaemia (1.54 mmol/L, 1.68 mmol/L) with appropriately elevated parathyroid hormone (PTH) concentrations despite prior cessation of denosumab and required treatment with ≥50mg daily prednisone. Hypocalcaemia was associated with elevated ALP (2,049 U/L, normal-range 35-110) and P1NP (744 ug/L, normal-range 15-115) concentrations in one patient.

Conclusion: Clinically significant hypocalcaemia and osteosclerosis are rare but important side effects of 177Lu-PSMA in men with high-volume osseous metastatic disease and significant treatment response. Given markedly elevated bone formation markers and response to high-dose glucocorticoids in the most severe case, we hypothesise Lu-PSMA triggered an exaggerated osteoblastic response resulting in depletion of circulating calcium stores and subsequent hypocalcaemia. Prospective evaluation of 177Lu-PSMA-induced hypocalcaemia and histopathological examination of the tumour microenvironment is required to better understand the underlying mechanisms, optimal treatment, and consequences of any associated osteosclerotic response.

 

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