ASTRO 2021: Molecular Imaging and Targeted Radionuclide Therapy with PSMA Radiopharmaceuticals

(UroToday.com) In a special session of the American Society for Radiation Oncology (ASTRO) and Society of Nuclear Medicine and Molecular Imaging (SNMMI) held at the 2021 ASTRO Annual Congress, Dr. Parent presented on the role of molecular imaging and targeted radionuclide therapy using PSMA-based radiopharmaceuticals.

Dr. Parent began with a discussion of the disease overview to contextualize the role of advanced imaging. He emphasized that prostate cancer begins to grow, with an increasingly large tumor volume leading up to initial diagnosis which is followed by curative-intent treatment. However, for many patients, a small volume of untreated disease remains. This forms the basis of eventual biochemical recurrence for which imaging is critical to localize disease and direct treatment with salvage local therapies or hormonal therapy. Following treatment with hormonal therapy, castration resistant disease often develops.

He then highlighted that while prostate specific membrane antigen (PSMA) is a membrane bound metalloprotease that is highly expressed in prostate cancer cells, it is not specific to prostate cancer and expression may be seen in other tumors (eg. glioblastoma). He noted that, while neuroendocrine prostate cancers typically do not have PSMA expression, it’s expression in general correlates well with tumor stage and grade.

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PSMA is a relevant target for both prostate cancer diagnostics and therapeutics. Many small molecular radiopharmaceuticals have been developed around a urea-based scaffold (as highlighted in red in the figure below). This scaffold binds to the PSMA peptide. Changes in linkers and payloads affect biodistribution, receptor affinity, and drug delivery. Further, the linker may affect the internalization of the radiopharmaceutical.

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Considering PSMA-PET imaging, Dr. Parent highlighted that there are intrinsic differences in physiologic uptake between the agents with some demonstrating more profound salivary gland uptake and others having greater urinary tract excretion. He emphasized that for the most part, these subtle differences do not affect clinical utility. He then discussed data on the accuracy of 68Ga-PSMA-11, based on data from patients treated at UM, UCLA, and UCSF for biochemical recurrence who had undergone metastatic lesion biopsy. The SUVmax was seen to correlate with the likelihood of true positive disease localization. With an optimized threshold of 7.5, the sensitivity of 68Ga-PSMA-11 was 69% and specificity was 80%. However, the authors highlighted that there is a significant overlap between the SUVMax of true positive and false positive lesions of PSMA scan, limiting the ability of an SUV threshold to reliably predict prostate cancer.

He then further presented comparative data for 68Ga-PSMA-11 and 18F-fluciclovine. Overall, detection rates were significantly lower when the same patients were imaged with 18F-fluciclovine (26%) compared with 68Ga-PSMA-11 (56%). This was particularly true for patients with low PSA levels, for which 68Ga-PSMA-11 had superior sensitivity. In contrast, at higher PSA levels, he suggested that the two approaches may be fairly comparable.

Dr. Parent then discussed steroid receptor PET imaging. In prostate cancer, the androgenic hormones testosterone and dihydrotestosterone are important for disease development and progression in most patients. Fluorodihydrotestosterone can be labelled to allow for receptor-mediated PET imaging. In older comparisons, this approach outperformed FDG-PET imaging. However, when patients are treated with androgen deprivation therapy, the PET avidity disappears. This approach, therefore, didn’t have significant clinical utility. However, he emphasized that a nearly opposite effect is observed with PSMA-based imaging: androgen receptor signalling and activation leads to decreased PSMA expression. Therefore, use of androgen deprivation therapy results in an increase in PSMA expression, increasing its utility in imaging.

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These findings have important implications for interpreting PSMA imaging in patients during routine clinical care. In the first description of this phenomenon, Dr. Hope noted that PSMA uptake increased more than 7 fold following the initiation of ADT. However, this effect is relatively short lived and it is postulated that short durations of ADT may increase PSMA expression while long-term ADT decreases its expression. In particular, in patients with metastatic castration sensitive prostate cancer, the anti-proliferative effect of ADT may overwhelm any cellular level increases in PSMA expression due to the decreases in the overall burden of disease. There is no true consensus on this clinical implications of these observations. However, he highlighted that short-term ADT in mCRPC may increase tumor detection rates. Further, low PSMA expression following ADT has been associated with disease progression. Finally, he suggested that there may be a role of ADT pauses to increase the sensitivity of PSMA-PET among patients receiving long-term ADT, though it is unclear how long that pause would need to be.

Dr. Parent then transitioned to a discussion of theranostics, premised on the idea of using the same targeting approach to deliver radiotherapeutics as was used for disease imaging. While not yet FDA approved, potential indications for 177Lu-PSMA-617 are patients with mCRPC who have exhausted or are ineligible for alternative treatments who have adequate uptake of PSMA ligands based on pre-therapy imaging. Patients with discordant hypermetabolic (FDG positive) prostate cancer lesions, then to have poor outcomes, and poor response compared to those who received 177Lu-PSMA-617. Even among patients who received 177Lu-PSMA-617, those who had discordance lesions had substantially worse outcomes.

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Some evidence suggests that patients may develop these discordant, hypermetabolic lesions following treatment with 177Lu-PSMA-617. However, unlike patients who have these lesions prior to therapy, this treatment-induced phenotype was not associated with a worse prognosis. Thus, the utility of FDG-PET/CT is likely limited to initial staging before PSMA-based radioligand therapy, and not in ongoing monitoring.

Dr. Parent briefly discussed the TheraP trial, emphasizing that patients were only included if there were no PSMA negative and FDG positive lesions. In contrast, the VISION trial did not require FDG-PET/CT prior to enrollment or treatment. He suggested that the more selective approach in TheraP may contribute to the better outcomes observed. Highlighting a recent editorial from Drs. Srinivas and Iagaru, he emphasized the importance of using PSMA (and FDG) PET prior to treatment with 177Lu-PSMA-617.

He closed by highlighting that there are two FDA approved PSMA-radioligands for PET imaging in prostate cancer. Further, there is a clear role for PSMA-based imaging prior to PSMA-radionuclide therapy with a potential role for FDG-PET to exclude the presence of discordant hypermetabolic lesions. There is a to be determined role for combination therapies in this space.

Presented by: Ephraim E. Parent, MD, radiologist and nuclear medicine physician, Co-chair for the Prostate Cancer Outreach Working Group for the Society of Nuclear Medicine and Molecular Imaging,  Mayo Clinic, Jacksonville, Florida.

Written by: Christopher J.D. Wallis, University of Toronto, Twitter: @WallisCJD during the 2021 American Society for Radiation Oncology (ASTRO) Hybrid Annual Meeting, Sat, Oct 23 – Wed, Oct 27, 2021.

 

 

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