May 8, 2018  A study published today in Lancet Oncology reported highly promising results from a phase 2 clinical trial testing a new treatment, 177Lu-PSMA-617, which targets radiation directly to prostate cancer.

“We show in a prospective study that in men with metastatic castration-resistant prostate cancer who have progressed after standard treatments with PSMA-avid disease, LuPSMA (177Lu-PSMA-617) resulted in high responses, a low toxicity profile, and improves quality-of-life parameters especially in men with pain,” concluded the study authors.

177Lu-PSMA-617 is a member of a new class of drugs that act like nuclear warheads attached to tumor-homing missiles, delivering radiation directly to tumor cells to obliterate them.   These targeted radiation treatments consist of a radioactive isotope attached to a molecule that specifically targets tumor cells.  In this case, the radioactive isotope is 177-lutetium (177Lu), an unstable form of the element lutetium, which shoots off high-energy beta particles when it decays.  Beta particles kill cells by bombarding and breaking their DNA.  PSMA-617 is a small molecule that specifically binds to PSMA (prostate specific membrane antigen), a protein that is present at high levels on 90-95% of prostate cancers, including most metastatic castration-resistant prostate cancers (mCRPC).  PSMA is absent or present at very low levels on most other tissues in the body, a property that is important in limiting side effects of targeted therapies.

This new type of “PSMA-targeted radionuclide” therapy is being tested for prostate cancer in many different forms (different isotopes attached to different PSMA-targeting molecules), and has received a significant amount of interest from the medical community due to exciting but anecdotal case reports.  Clinical trials are needed to prove safety and efficacy, as well as to figure out the best way to use these treatments in patients.

PCF-funded investigator Dr. Shahneen Sandhu, of the Peter MacCallum Cancer Centre in Australia, led a prospective, single-arm (no placebo or comparison group) phase 2 trial to test 177Lu-PSMA-617 in 30 men with mCRPC whose tumors express PSMA.  All but two of the men had previously received and progressed after standard treatments (chemotherapy, abiraterone acetate, and/or enzalutamide).  Patients received between one to four cycles of 177Lu-PSMA-617.  PSA levels dropped by over 50% in 17 of the 30 (57%) patients treated, and by over 30% in 21 (70%) patients.  Tumors stopped growing or shrank in many patients, including complete or partial tumor shrinkage in 14 of 17 (82%) patients who had metastatic tumors in lymph nodes and other non-bone sites on CT (computed tomography) scans.

The treatment was well tolerated.  The most common side effects included low-grade dry mouth (87% of patients) and low to high grade decreases in white blood cell (37% grade 1-2; 37% grade 3) and platelet counts (27% grade 1-2; 10% grade 3), anemia (13% grade 1-2; 13% grade 3), and pain (17% grade 1-2; 3% grade 3).  Some patients also experienced low-grade dry eyes (17%), fatigue (50%), nausea (50%), vomiting (33%), anorexia (23%), and weight loss (10%).

Despite side effects, patients experienced clinically meaningful pain alleviation and improvements in cognitive function, insomnia, and overall quality of life.

Based on the promising results from this trial, Sandhu and team have opened a randomized clinical trial in Australia comparing 177Lu-PSMA-617 with docetaxel in mCRPC.  In recognition of the promise of PSMA-targeted radionuclide therapies, in 2017 the Prostate Cancer Foundation (PCF) funded three $1 Million research awards to teams that are conducting clinical trials, to better understand how to optimally use these treatments.  PCF also recently convened an international working group meeting to discuss the basic science and clinical research needed to validate and optimize the use of these treatments in patients.  A randomized phase 3 clinical trial  comparing 177Lu-PSMA-617 plus best supportive/best standard of care versus best supportive/best standard of care alone, is also being initiated.

 

Dr. Andrea Miyahira has a PhD in cancer immunology, and is Director of Research at the Prostate Cancer Foundation.