Radionuclide Reduces PSA in mCRPC

A phase II trial recently revealed that ¹⁷⁷Lu-PSMA-617 is almost twice as likely to elicit a prostate-specific antigen (PSA) response as chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC). In the TheraP trial, patients treated with the agent also had a higher objective response rate (ORR) and were less likely to experience severe side effects. Findings were presented at the 2021 American Society of Clinical Oncology (ASCO) Genitourinary (GU) Cancers Symposium, held virtually February 11–13, and simultaneously published (The Lancet 2021;397:797–804).

Prostate-specific membrane antigen (PSMA) is a glycoprotein overexpressed on the surface of prostate cancer cells. A small radionuclide, ¹⁷⁷Lu-PSMA-617 consists of PSMA-617, which binds with high affinity to PSMA, and lutetium-177, which releases beta radiation that destroys PSMA-expressing cells. In a single-arm phase II trial, patients treated with ¹⁷⁷Lu-PSMA-617 had a median overall survival (OS) of 13.3 months (Lancet Oncol 2018;19:825–33). TheraP builds on these results by comparing ¹⁷⁷Lu-PSMA-617 to cabazitaxel (Jevtana; Sanofi), the current standard of care.

At ASCO GU, lead author Michael Hofman, MBBS, of the Peter MacCallum Cancer Centre in Melbourne, Australia, reported on 200 men with mCRPC who received either ¹⁷⁷Lu-PSMA-617 or cabazitaxel. All participants had previously received docetaxel and had an increasing PSA level that was at least 20 ng/ml; more than 90% of them had received prior antiandrogen therapy.

Patients in the ¹⁷⁷Lu-PSMA-617 arm had an ORR of 49% and a PSA response—defined as a 50% or greater reduction in PSA—of 66%, compared with 24% and 37% for patients in the cabazitaxel arm. At 12 months, the progression-free survival (PFS) rate was 19% for patients treated with the radiopharmaceutical, compared with 3% for those treated with cabazitaxel. However, both groups had a median PFS of 5.1 months, “demonstrating that the treatment effect was not constant with respect to time,” Hofman said.

¹⁷⁷Lu-PSMA-617 was associated with fewer severe side effects: 33% of patients treated with the agent had grade 3/4 adverse events and 1% discontinued treatment, compared with 53% and 4%, respectively, of patients who received cabazitaxel. Thrombocytopenia and pain were the most common grade 3/4 adverse events caused by ¹⁷⁷Lu-PSMA-617, each occurring in 11% of patients.

“A strength of the study is an active control arm using cabazitaxel, a validated life-prolonging therapy,” Hofman said. He concluded that ¹⁷⁷Lu-PSMA-617 appears to be significantly more active than cabazitaxel, and thus “represents a new class of effective therapy for men with castration-resistant prostate cancer.” TheraP will continue to gather OS data, and ¹⁷⁷Lu-PSMA-617 will undergo additional testing in the upcoming phase III VISION trial.

Anthony D'Amico, MD, PhD, of Brigham and Women's Hospital in Boston, MA, who was not involved in the trial, is “cautiously optimistic” about the results. “I think the science is valid, and I think it's a wonderful targeted treatment,” he said, noting the agent's minimal toxicity.

He added that “there probably is a benefit over cabazitaxel,” but several limitations associated with the relatively small size of a phase II trial make it difficult to assess the magnitude of the difference. Chiefly, patients in the cabazitaxel group had a higher dropout rate than those in the ¹⁷⁷Lu-PSMA-617 group, and they were almost twice as likely to have visceral metastases going into the trial—factors that may have contributed to their poorer outcomes.

Thus, D’Amico said, OS data and results from the phase III trial will be key. “I'd like to see it work. We just need the level one evidence to move it forward.” –Catherine Caruso