PSMA - Lutetium Treatment

Lutetium-177 linked to PSMA: an update

One of the more important emerging forms of radiotherapy for metastatic castrate-resistant prostate cancer (mCRPC) is the radioactive element lutetium-177 (¹⁷⁷Lu) chemically bonded to a ligand — an antibody or a small molecule that attaches to the prostate-specific membrane antigen (PSMA). We’ll call this class of medications [¹⁷⁷Lu]PSMA.

PSMA is expressed on the surface of 95 percent of all metastatic prostate cancer cells; see this link for a fuller explanation. Many of the studies on [¹⁷⁷Lu]PSMA have been conducted in Germany. Recently, we reported on a small study from Bad Berka, Germany, with some early encouraging results. There have been a few more trial reports since then.

All of the more recently published studies used a ligand called PSMA-617, a small molecule that attaches to PSMA, rather than a PSMA antibody. It was hoped that this ligand would be more specific to prostate cancer cells, with less affinity for salivary glands and kidneys where it can cause side effects and false positives.

Kratchowil et al. at the University of Heidelberg reported on 30 patients treated with one to three cycles of [¹⁷⁷Lu]PSMA-617.

• PSA decreased in 21/30 patients (70 percent).
  • PSA decreased by > 50 percent in 13/30 patients (43 percent)
  • 8/11 patients (73 percent) who had three cycles of therapy had PSA declines >50 percent that were sustained for over 24 weeks; the number and size of their metastases decreased as well.
• Hematotoxicity (from bone marrow suppression) was mild.
• Xerostomia (dry mouth), nausea and fatigue were transient and occurred in < 10 percent.
• Excess radioactivity was cleared from the kidneys within 48 hours.

Rahbar et al. at the University Hospital Münster (again in Germany) reported on 74 patients treated with a single dose of [¹⁷⁷Lu]PSMA-617.

• PSA decreased in 47/74 patients (64 percent).
  • PSA decreased by > 50 percent in 23/74 patients (31 percent)
• PSA was stable (−50 percent to +25 percent) in 35/74 patients (47 percent)
• PSA increased by > 25 percent in 17/74 patients (23 percent)
• No significant loss of red blood cells, white blood cells, or kidney function
• Mild decline in platelets, but within normal range

Rahbar et al. also report outcomes on 28 patients after one vs. two treatments.

• PSA decreased in 59 percent of patients after one treatment and in 75 percent after two treatments.
  • PSA decreased by > 50 percent in 32 percent of patients after one treatment and in 50 percent after two treatments.
• Median survival was 29 weeks, compared to 20 weeks based on historical expectations.
• No clinically significant or lasting toxicity occurred.

Radiotherapy with ¹⁷⁷Lu, though encouraging, is still in its early days. There is much work to be done in identifying the optimal ligand, optimal dose, optimal number of treatments, optimal patient/disease characteristics, and adjuvant therapies. We encourage participation in clinical trials in the US (see NCT00859781) and in Germany.

Editorial note: This commentary was written for The “New” Prostate Cancer InfoLink by Allen Edel.