ASCO GU 2022: Targeting Prostate-Specific Membrane Antigen: Lutetium and the Next Wave of Novel Radiopharmaceuticals

(UroToday.com) In this presentation, Dr. Shahneen Sandhu presented an update on targeting the prostate-specific membrane antigen (PSMA) in prostate cancer. Her talk focused on Lutetium-177-PSMA-617 (LuPSMA), optimizing patient selection, biomarkers to predict response, and combinations with other systemic therapies.


PSMA is an excellent target for prostate cancer treatment given its high expression in prostate cancer relative to other normal tissues. LuPSMA is a radiopharmaceutical that delivers beta-particle radiation to PSMA-expressing cells. The TheraP study randomized men with metastatic castration-resistant prostate cancer (mCRPC) to receive LuPSMA or cabazitaxel. LuPSMA resulted in a higher proportion of men achieving a greater than 50% decline in PSA (49% versus 24%) and progression-free survival (PFS) at 12 months (19% versus 3%). The subsequent VISION study randomized men with mCRPC who had received a prior androgen receptor pathway inhibitor (ARPI) to standard of care (SOC) therapy versus SOC plus LuPSMA. The addition of LuPSMA resulted in a four-month improvement in overall survival (OS) (hazard ratio = 0.62; P < 0.001).

Dr. Sandhu moved on to discuss considerations for selecting patients likely to benefit from LuPSMA. There is an ongoing debate about the role of imaging prior to administering LuPSMA. PSMA PET and FDG PET scans have both been used for patient selection – the former identifies PSMA-positive lesions whereas the latter identifies metabolically active lesions independent of PSMA expression. Lesions that are FDG-positive and PSMA-negative, as shown in the patient below, indicate sites of prostate cancer that will not be targeted by LuPSMA and thus may identify patients less likely to benefit from this therapy. Of note, FDG PET scans were used for patient selection in the TheraP study, but not the VISION study. Another consideration is utilizing dosimetry to measure an individual patient’s radiation dose. Data support that higher radiation doses are observed in patients who achieve a PSA response, supporting a potential role for dosimetry as a clinical biomarker to predict response and tailor dosing of LuPSMA.

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Dr. Sandhu then reviewed several additional factors that may correlate with response to radiopharmaceutical therapies including the number of receptors on cancer cell surface, heterogeneity of the targeted receptor, radiation dose to cancer cell, power and range of internalized radioactive decay, and radiation sensitivity of the cancer cell. A specific consideration with LuPSMA is how PSMA expression may be modulated by prior or concurrent therapy. Emmett et al evaluated serial PSMA PET scans in men with metastatic prostate cancer starting androgen deprivation therapy (ADT).[1] Interestingly, PSMA expression decreased by 30% nine days after starting ADT in men with metastatic hormone-sensitive prostate cancer (mHSPC) while it increased by 45% nine days after starting treatment in men with mCRPC.

The findings above raise the question of how we can leverage our understanding of prostate cancer biology to optimize LuPSMA activity in the clinic. One approach may be to strategically upregulate PSMA expression. Building upon the finding that ADT upregulates PSMA in men with mCRPC, the ENZA-p study is randomizing men with mCRPC to receive enzalutamide alone or in combination with LuPSMA (NCT04419402). Another approach is to combine LuPSMA with other systemic therapies that may result in synergistic activity. It is well-established that radiotherapy can be enhanced through combination with radio-sensitizing agents. The beta-particle radiation delivered by LuPSMA creates single-stranded DNA breaks. Combination with a PARP inhibitor, which prevent single-stranded DNA breaks from being repaired, is thus a rational approach and supports the ongoing LuPARP study of LuPSMA plus Olaparib (NCT03874884). Another strategy under investigation is combining LuPSMA with immunotherapy. Radiation induces a form of cell death that is immunogenic, activating the cGAS-STING pathway, increasing antigen exposure to the tumor microenvironment, and recruiting dendritic cells and T cells to promote an immune response. Whether addition of immune checkpoint inhibitors will augment LuPSMA activity is the subject of several ongoing clinical trials.

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Dr. Sandhu concluded by highlighting the abundance of trials of LuPSMA in combination with other therapies and LuPSMA in earlier disease settings, reflective of a rapidly evolving therapeutic landscape in prostate cancer. With promising early randomized clinical trial results, Dr. Sandhu hopes to see future studies incorporate dosimetry to tailor drug delivery based on tumor volume and radiation sensitivity, address intra- and inter-patient heterogeneity by using PSMA as an adjunct treatment in synergistic combinations, and understand the biology of PSMA to effectively move treatment to an earlier disease setting.

Presented by: Shahneen Sandhu, MBBS, FRACP, is a consultant medical oncologist and associate professor at the Peter MacCallum Cancer Centre in Victoria, Australia

Written by: Jacob Berchuck, MD, Genitourinary Medical Oncologist at the Dana-Farber Cancer Institute (Twitter: @jberchuck), during the 2022 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, Thursday, Feb 17 – Saturday, Feb 19, 2022


References:

  1. Emmett L, Yin C, Crumbaker M, Hruby G, Kneebone A, Epstein R, Nguyen Q, Hickey A, Ihsheish N, O'Neill G, Horvath L, Chalasani V, Stricker P, Joshua AM. Rapid Modulation of PSMA Expression by Androgen Deprivation: Serial 68Ga-PSMA-11 PET in Men with Hormone-Sensitive and Castrate-Resistant Prostate Cancer Commencing Androgen Blockade. J Nucl Med. 2019 Jul;60(7):950-954.
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