A recent study published in the Journal of Nuclear Medicine highlights the extensive intrapatient intermetastatic heterogeneity (IIH) in metastatic castration-resistant prostate cancer (mCRPC) using a triple-tracer PET imaging strategy. The multi-center prospective study, involving 98 mCRPC patients, found that IIH was present in a significant majority, impacting overall survival and radiopharmaceutical therapy eligibility.
Prevalence and Impact of IIH
The study revealed that 82.7% of mCRPC patients exhibited IIH, defined by discordant features across multiple metastases on 18F-FDG and 68Ga-PSMA PET/CT scans. Furthermore, 45.9% of patients had at least one 18F-FDG-positive/68Ga-PSMA-negative lesion, potentially indicating neuroendocrine differentiation. A subset of these patients underwent additional 68Ga-DOTATATE PET/CT, with 16.2% showing at least one 68Ga-DOTATATE-positive lesion. The presence of IIH was associated with a significantly shorter median overall survival of 9.5 months, compared to patients without IIH (log-rank P = 0.03; hazard ratio, 2.7; 95% CI, 1.1–6.8).
Triple-Tracer Imaging Phenotypes
The triple-tracer approach identified 12 distinct combinations of lesion imaging phenotypes. In the subgroup of patients who underwent 68Ga-DOTATATE PET/CT (n=37), the prevalence of IIH was 83.8%. The median overall survival was significantly shorter in patients with at least one 68Ga-DOTATATE-positive lesion (3.0 months) compared to those without (6.4 months) (log-rank P = 0.0004; HR, 5.1; 95% CI, 1.9–13.7).
Implications for Radiopharmaceutical Therapy
Based on pre-specified PET criteria, 53.1% of the participants were deemed eligible for PSMA radiopharmaceutical therapy (RPT). However, none were eligible for DOTATATE RPT. This highlights the potential of PSMA-targeted therapy for a significant portion of mCRPC patients, while also underscoring the need for alternative strategies for those with neuroendocrine features.
Methodology and Patient Population
The study enrolled adult males with pathologically proven adenocarcinoma of the prostate and at least three active metastases on conventional imaging, showing biochemical or radiographic progression under continuous androgen deprivation. Patients underwent 18F-FDG and 68Ga-PSMA-617 PET/CT scans within 10 days. 68Ga-DOTATATE PET/CT was performed if an 18F-FDG-positive/68Ga-PSMA-negative lesion was detected. The primary endpoint was the prevalence of IIH, defined as having at least two lesions with different imaging phenotypes. Secondary endpoints included the proportion of patients with suspected CRPC neuroendocrine differentiation and eligibility for PSMA or DOTATATE RPT.
Expert Commentary
According to the researchers, the findings underscore the importance of characterizing the molecular and prognostic significance of each imaging phenotype to better select patients for intensified management and guide biopsy sites for precision medicine. The high prevalence of IIH suggests that treatment intensification combinations may be more beneficial than single-agent regimens for these patients.
Study Limitations
The authors acknowledge that the dichotomization of tracer uptake as positive or negative may have contributed to the high apparent prevalence of IIH. Additionally, the decision to perform 68Ga-DOTATATE PET/CT in only a subset of patients limited the ability to compare triple-tracer imaging across the entire cohort.
