PCa Commentary #110: Lutetium-177, a promising radioisotope for the treatment of prostate cancer.

Lutetium-177 (177Lu), a radioisotope, can be linked with either a monoclonal antibody (J591) or alternatively a small molecule inhibitor (PSMA-617) both of which target the prostate specific membrane antigen (PSMA), a marker expressed on 95% of prostate cancer cells.  Both agents are under active study. When employed at therapeutic strength and targeted to the PSMA molecule, 177Lu becomes a “theranostic,” meaning that the low level gamma signaling of Lu177 identifies the PSMA target to the PET scanner while at the same time the beta emission treats the cancer.

The prior PCa Commentary, Volume #109, http://www.pctrf.org/pca-commentary-109 [control+click link to follow] discussed the targeting mechanism and the diagnostic potential of the emerging 68Ga-PSMA PET/CT. That article concluded with a brief example of two remarkable responses to the combination of the radioisotope Actinium 225 with PSMA targeting. This Commentary is a brief heads-up describing the radioisotope, 177-Lutetium, already much studied in Europe, which also holds great promise for the treatment of prostate cancer.

What is Lutetium-177 ?

Lutetium-177 is one of the 32 synthetic radioisotopes of the element Lutetium-175, a rare earth metal, and was chosen as a radiotherapeutic because of its appropriate half-life of 6.64 days, during which it decays to produce a gamma ray and low-energy beta particles (essentially electrons) with a cytotoxic range of about 125 cells (0.25 mm). The name Lutetium is derived from the Latin Lutetia, the Roman name for Paris, where it was discovered in 1907.  A nearby cyclotron is not required and the 6+ day half-life allows sufficient time for transportation from a manufacturing site to the nuclear medicine department for intravenous administration.

There are differences in the behavior of the monoclonal antibody (mAb) and the inhibitor relating their biodistribution. “The mAb’s have a long circulation time so will continue to deliver 177Lu (or whatever is attached) for many days, whereas the ligands [i.e. inhibitors] are gone from the circulation in hours. Also, because of their size, the mAbs do not target salivary glands, kidneys, and other such areas of low-level PSMA expression, but do have high circulation in the bone marrow (so lead to myelosuppression)”, personal communication, Dr. Scott Tarawa.

When either the antibody or the inhibitor is mated to the extracellular portion of PSMA the combination is quickly internalized to where the radioisotope effects its damage. The half-life allows sufficient time to carry out DNA injury from within the cell. The rapid internalization limits collateral damage to nearby normal tissue. Lutetium-177 therapy should be particularly effective on micro-metastases because of easier penetrance compared to large tumor masses, a feature that would seem to argue for its use early in the course of the disease.

What Do We know So Far About 177Lu Radioisotope Therapy ?

Considerable research on 177Lu therapy has been performed in the past few years in Europe and in the US particularly at Cornell Medical College by Dr. Scott Tagawa and colleagues. The early studies have been targeted to evaluate safety and short-term efficacy. In general, mild to moderate reversible hematologic toxicity has been reported. A dry mouth syndrome (xerostomia) can occur because of a low concentration of benign PSMA targets in the parotid glands. Clear evidence for short-term efficacy has been demonstrated.

Five European studies were reviewed. All the men had mCRPC. A PSA decline of >50% was a common measure of evaluation. These were not clinical trials with the requisite documentation of patient inclusion criteria and follow-up for toxicity, but collectively they document substantial PSA response and acceptable toxicity.

Early Studies of 177Lu in the United States:

Dr. Scott Tagawa and colleagues at Cornell Medical College, Memorial Sloan-Kettering, and Duke have conducted detailed research as to the toxicity profile of the agent, the best regimen for administration, selection of optimal patients to receive treatment, and consideration of combination therapy with chemotherapy. In their 2013 study, “Phase II Study of Lutetium-177-Labled Anti-Prostate Specific Membrane Antigen Monoclonal Antibody j591 for Metastatic Castration-Resistent Prostate Cancer,” Clin Cancer Research, they reported reversible hematologic toxicity in 47 patients from a single dose administration. At the highest dose (70mCi/m2) two cohorts showed median survivals of 16.3 and 27.3 months. PSA declines were seen in 46.9% of men at this dose level. Grade 4, i.e. clinically significant, platelet and neutrophil suppression, was seen in 46.8% and 25.5%. “Those with poor PSMA imaging were less likely to respond.”

The abstract #121 presented by this group of researchers at the 2013 GU Cancer Symposium added additional details. “12 of 15 pts had baseline and follow-up CTC [circulating tumor cells] counts at 4-6 weeks: 66.7% had >50% decline and 25% were unchanged …”  Although 93.3% had accurate targeting (imaging) of known sites of disease, as seen in initial analysis, a trend for fewer >30% PSA declines was seen with less intense PSMA imaging.”

In the conclusion of the 2013 article the authors stated: “Future directions in progress with anti-PSMA-RIT [radioimmunotherapy] include (i) studies to improve patient selection using imaging and CTC and immunohistochemical PSMA expression analysts; (ii) improving therapeutic margin with dose-fractionation; [and] (iii) using taxane chemotherapy radiosensitization and tumor debulking.”

Much of this work has already been accomplished. In abstract 194, ASCO supp 2015, Tarawa and colleagues reported results of 3 cycles of a two-dose fractionation of 177Lu-J591 combined with taxotere chemotherapy. A PSA decline of >50% was seen in 73.3% and a >30% in 80.0% of the patients.

[From personal communication with Dr. Tagawa]:  “A randomized phase III registration trial in men with metastatic CRPC is planned.” The Cornell lead study group currently has studies with 177Lu-j591 and 177Lu-PSMA-617 in non-metastatic CRPC with the hope of curing some men with micrometastatic disease. Studies are contemplated to employ 177Lu-j591 in the setting of biochemically recurrent prostate cancer.

Additional studies will open up in Texas and UCSF in 2017. A phase II trial of 177-PSMA-617 for men with advanced CRPC is expected to open at UCLA in the first half of 2017.

BOTTOM LINE:  The story of 177Lu in the treatment of prostate cancer is just at its beginning, with more work to come in refining the regimens. Early work, however, shows great promise that this radiotherapeutic agent will become an effective and safe member of our increasing armamentarium against prostate cancer.

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