Towards Improving the Efficacy of PSMA-Targeting Radionuclide Therapy for Late-Stage Prostate Cancer-Combination Strategies.

PURPOSE OF REVIEW: [177Lu]Lu-PSMA-617 is a radiopharmaceutical that emits beta-minus radiation and targets prostate-specific membrane antigen (PSMA)-positive prostate cancer. Despite its clinical success, there are still patients not showing sufficient response rates. This review compiles latest studies aiming at therapy improvement in [177Lu]Lu-PSMA-617-naïve and -resistant patients by alternative or combination treatments. RECENT FINDINGS: A variety of agents to combine with [177Lu]Lu-PSMA-617 are currently under investigation including alpha radiation-emitting pharmaceuticals, radiosensitizers, taxane chemotherapeutics, androgen receptor pathway inhibitors, immune checkpoint inhibitors, and external beam radiation. Actinium-225 (225Ac)-labeled PSMA-targeting inhibitors are the most studied pharmaceuticals for combination therapy or as an alternative for treatment after progression under [177Lu]Lu-PSMA-617 therapy. Alpha emitters seem to have a potential of achieving a response to PSMA-targeting radionuclide therapy in both initial non-responders or responders to [177Lu]Lu-PSMA-617 later developing treatment resistance. Emerging evidence for immunostimulatory effects of radiopharmaceuticals and first prospective studies support the combination of [177Lu]Lu-PSMA-617 and immune checkpoint inhibition for late-stage prostate cancer.

Exploring the role of combined external beam radiotherapy and targeted radioligand therapy with [177Lu]Lu-PSMA-617 for prostate cancer - from bench to bedside.

Management of prostate cancer (PC) might be improved by combining external beam radiotherapy (EBRT) and prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) with lutetium-177 (177Lu)-labeled PSMA inhibitors. We hypothesized a higher efficacy of the combination due to augmentation of the radiation dose to the tumor and interactions of EBRT with PSMA expression potentially increasing radiopharmaceutical uptake. Therefore, this study analyzed the influence of radiation on PSMA expression levels in vitro. The results were translated to evaluate the efficacy of the combination of photon EBRT and [177Lu]Lu-PSMA-617 in a murine PC xenograft model. Finally, a clinical case report on a combined elective field EBRT with RLT dose escalation illustrates a proof-of-concept. Methods: PSMA gene and protein expression were assessed in human PSMA-overexpressing LNCaP cells after irradiation using reverse transcription quantitative polymerase chain reaction (RT-qPCR), flow cytometry and On-Cell Western assays. In the in vivo therapy study, LNCaP tumor-bearing BALB/c nu/nu mice were irradiated once with 2 Gy X-ray EBRT and injected with 40 MBq [177Lu]Lu-PSMA-617 after 4 h or received single or no treatment (n = 10 each). Tumor-absorbed doses by [177Lu]Lu-PSMA-617 were calculated according to the Medical Internal Radiation Dosimetry (MIRD) formalism after deriving time-activity curves using a gamma probe. An exemplified patient case is demonstrated where fractionated EBRT (54 Gy to prostate; 45 Gy to pelvic lymphatics) and three cycles of [177Lu]Lu-PSMA-617 (3.4-6.0 GBq per cycle) were sequentially combined under concurrent androgen deprivation for treating locally advanced PC. Results: At 4 h following irradiation with 2-8 Gy, LNCaP cells displayed a PSMA protein upregulation by around 18% relative to non-irradiated cells, and a stronger upregulation on mRNA level (up to 2.6-fold). This effect was reversed by 24 h when PSMA protein levels were downregulated by up to 22%. Mice treated with the combination therapy showed significantly improved outcomes regarding tumor control and median survival (p < 0.0001) as compared to single or no treatment. Relative to monotherapy with PSMA-RLT or EBRT, the tumor doubling time was prolonged 1.7- or 2.7-fold and the median survival was extended by 24% or 60% with the combination, respectively. Additionally, tumors treated with EBRT exhibited a 14% higher uptake of the radiopharmaceutical as evident from the calculated tumor-absorbed dose, albeit with high variability in the data. Concerning the patient case, the tri-modality treatment was well tolerated and the patient responded with a long-lasting complete biochemical remission for five years following end of PSMA-RLT. The patient then developed a biochemical relapse with oligo-recurrent disease on follow-up imaging. Conclusion: The present preclinical and clinical data demonstrate that the combination of EBRT with dose escalation by PSMA-RLT improves tumor control and potentially prolongs survival. This may pave the way for further clinical investigations of this approach to explore the curative potential of the combination therapy.