Three new modalities for treatment of advanced prostate cancer are in development that will significantly impact management and extend overall survival:

  •  immunotherapy with checkpoint blockade;
  •  poly ADP-ribosepolymerase (PARP) inhibitors; and
  •  anti-PSMA radioligand therapy (RLT)

This Commentary will update the outcomes of 177-Lutetium RLT and discuss future developments.

Brief Background: The prostate specific membrane antigen (PSMA) is a transmembrane receptor expressed on ~95% of prostate cancer cells and functions to provide energy for cancer growth. It can be targeted by either a small molecule, urea, or antibody, J597, joined with a radioisotope, i.e., 177-Lutetium. Once internalized, the radioisotope emits beta particles (electrons) over a 2 mm distance causing lethal double-stranded DNA damage to the cell and nearby cells over its 6.7 day half-life.

Early Trials: 177-Lu RLT Is Safe, Effective and Well Tolerated with Fewer Adverse Effects Than 2nd-Line Docetaxel Chemotherapy.

** Hoffman et al. reported on 50 patients with heavily pretreated mCRPC using 177Lu-PSMA-617, 80% having failed docetaxel/abiraterone/enzalutamide. A greater than 50% decline was seen in 64%; overall survival, 18 months; objective response, 82%. Complete response was seen in 29% and partial response in 53%. Pain was improved in 37% of patients.

** A “Systematic Review and Meta-Analysis,” Yadav et al., American Journal of Radiology,
Aug. 2019 carefully assessed the outcome of 681 heavily pretreated patients, 90% with bone metastases, and reported a >50% PSA decline in 46%; median overall survival, 13.7 months. An approximately similar group treated with carbazataxel showed a >50% PSA decline in 39%.

Conclusion: “Therefore in comparing PSA responses from other systemic therapies, all meta analyses of 177Lu-PSMA RLT, including the current study, consistently showed comparable results with minimal toxicity compared with chemotherapy.”

The Vision Trial and Beyond: UroToday interview at ASCO 2019 with Dr. Oliver Sartor, Principal Investigator for the Trial: “177Lu-PSMA-617 in the Treatment of Patients with Progressive PSMA-Positive Metastatic Castrate-Resistant Prostate Cancer.”

This clinical trial (NCT03511664), sponsored by Endocyte, has completed enrollment of 750 men with early data available only regarding toxicity. Randomization: Best supportive care (BSC) vs BSC plus 177Lu-PSMA-617. Treatment cycle was q 6 weeks with an option for two more cycles for good responders. Endpoints: arm-to-arm comparison of radiographic progression-free survival; time to first skeletal event; PSA progression-free survival; safety and tolerability and others.

Take-away Points:
** These patients were heavily pretreated, having progressed on Zytiga, Extandi, and, some after chemotherapy. Dr. Sartor pointed out that men with advanced metastatic disease with high PSAs are not optimal [but not to be excluded] for 177Lu therapy since, late in the disease, tumor heterogeneity may develop with mutations, such as transdifferentiation to 177Lu unresponsiveness, which dilute RLT effectiveness. He advises earlier application of 177Lu therapy… possibly eventually prior to chemotherapy.

** “If you want to know the truth toxicity wise, we’ve not seen very much. The exception being salivary gland targeting yielding mouth dryness.” “… actually the cytopenias [bone marrow suppression] that are seen during the course of therapy have been pretty minimal.”

** ADT up-regulates PSMA expression. The continuation of ADT during mCRPC treatment increases the PSMA target. Dr. Sartor noted a European trial in hormone-sensitive men comparing ADT to LU RLT alone in which the early RLT results “look good, perhaps even equivalent of ADT.”

Based on its Effectiveness and Safety FDA Approval is Likely for Men with Advanced Metastatic Cancer as Treated in the Vision Trial: Application of the Vision Protocol into Clinical Practice … and the Future.

** 177-Lutetium’s 6.7-day half-life is of sufficient duration for therapeutic use. Unlike the need for a nearby cyclotron for the Choline and Acetate PET/CT tracers, and also no need for an in house generator, 177-Lutetium can be manufactured at a nearby facility and shipped to a nuclear medicine department for a short intravenous administration. This is the current manner of obtaining Technetium-99M for conventional bone scanning. The Ga68-PSMA joined with the small molecule 617 is furthest in development, but a 18F-fluorinated version promises greater sensitivity. Many other tracers are in the research stage, such as with the antibody J579.

** Patient selection: Patients with low avidity of the PSMA target are less likely to respond to RLT.
Patients having a mutated BRCA 1 or 2 or mutations in others in the current 13 member BRCA- like family show increased response. In one study of mCRPC patients receiving PSMA RLT the group with BRCA2 mutations showed an overall survival of 49 months versus 17 months for the non-mutated patients (Panagiotis et al., Am Assn Cancer Res Annual Meeting 2019).

** Reported in UroToday, Feb 12, 2020; “Early initiation of Lu177 PSMA Radioligand Therapy Prolongs Survival in Metastatic PCa,” Kulkarni et al., Theronostic Center for Molecular Radiology and Precision Oncology, Germany:

The 274 patients had advanced heavily pretreated mCRPC receiving 11 cycles per patient.
Any PSA decline was seen in 71% and 55% showed a PSA decline of >50%. Partial response was seen in 25% of men, 6 having a complete response. Stable disease was seen in 42%; 32% progressed. Mean follow-up: 61 months.

The overall survival for all participants in the study was 30.9 months: When divided into subgroups treated with vs without prior chemotherapy, they concluded: – “so the chemotherapy-naive patients live significantly longer, [38 months], almost double as compared to chemotherapy treated patients. Eleven patients refused ADT and received first-line RLT: the median survival was not reached at 61 months follow-up in this group. Conclusion: “… early initiation of lutetium-PSMA radioligand therapy is effective in metastatic prostate cancer, offering significant survival benefit.”

** Protocols in Progress for Combinations of Agents:
177Lu-PSMA-617 vs Cabazataxel;
177Lu-PSMA-617 combined with Ketruda (pembrolizumab);
177Lu-PSMA-617 combined with Lazaparib (olaparib); and
trials using fractionated doses of 177LU or 225 Actinium.

RLT offers a very promising and entirely different regimen for treating prostate cancer as opposed to standard therapy with the current androgen receptor blocking agents. RLT is narrowly targeted and already found to be safe and effective, specifically addressing the nearly ubiquitous PSMA antigen. As its development progresses it likely will be moved earlier in prostate cancer management.