Following disease progression on docetaxel, prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy reduced the risk of disease progression or death by 37% vs cabazitaxel in men with metastatic castration-resistant prostate cancer in the phase II TheraP trial reported by Michael S. Hofman, FRACP, MBBS, and colleagues at the 2021 Genitourinary Cancers Symposium (Abstract 6). Lutetium-177–labeled PSMA-617 (LuPSMA)-treated patients had fewer toxicities and improved quality of life compared to those who received cabazitaxel.

Overall survival data are not yet mature. Data were also published in The Lancet to coincide with the presentation at the Symposium.

Michael S. Hofman, FRACP, MBBS

The active comparator in the trial, cabazitaxel, is considered the favored third-line therapy for metastatic castration-resistant prostate cancer following disease progression on androgen receptor–signaling agents (ie, enzalutamide and/or abiraterone) and docetaxel. These new data make LuPSMA an attractive choice if these results are confirmed in phase III trials.

“Lutetium PSMA-617 is a promising alternative to cabazitaxel…. LuPSMA represents a new class of effective therapy for men with castration-resistant prostate cancer,” said lead author Dr. Hofman, of Peter MacCallum Cancer Center.

LuPSMA is targeted to PSMA, an antigen expressed almost universally on metastatic prostate cancer cells but not on normal cells. The drug delivers high levels of beta-particle radiation to PSMA-expressing cells and very low doses to normal cells. Cabazitaxel is a semisynthetic taxane approved for treatment of castration-resistant prostate cancer following docetaxel-based treatment.

TheraP Study Details

The open-label investigator-initiated phase II TheraP trial was initiated in 2018, and randomly assigned 200 men 1:1 to receive LuPSMA intravenously every 6 weeks for up to six cycles (starting dose 8.5GBq, decreasing 0.5 GBq each cycle) vs cabazitaxel (20 mg/m² intravenously for up to 10 cycles).  All men had metastatic castration-resistant prostate cancer and had received previous treatment with docetaxel.

A positive gallium-68 PSMA positron-emission tomography/computed tomography scan was used to select patients for enrollment. A negative scan excluded patients; of 291 patients screened, 91 were excluded. There were 15 dropouts in the cabazitaxel arm during the study vs none in the LuPSMA arm.

Median patient age was 72 years; 91% were previously treated with abiraterone, enzalutamide, or both; and about 95% of patients had an Eastern Cooperative Oncology Group performance status score of 0 to 1.

Results

TheraP met its primary endpoint, with a higher percentage of patients treated with LuPSMA achieving a 50% or greater reduction in prostate-specific antigen levels from baseline compared to cabazitaxel: 66% vs 37%, respectively (P < .0001). LuPSMA treatment doubled the objective response rates compared with cabazitaxel: 49% vs 24%, respectively.

Median radiographic progression-free survival was identical in each arm at 5.1 months, but at 12 months, it was 19% in those treated with LuPSMA vs 3% in the cabazitaxel-treated group.

LuPSMA treatment led to a greater reduction in pain scores after treatment, with 60% of patients reporting improvements vs 43% in the cabazitaxel arm.

Grade 3 and 4 toxicities were reported in 33% of patients in the LuPSMA arm vs 53% of those treated with cabazitaxel.  The most commonly reported grade 3 and 4 events in the LuPSMA arm and cabazitaxel arm, respectively, were neutropenia (4% vs 13%), thrombocytopenia (11% vs 0%), anemia (8% in each arm), diarrhea (1% vs 5%), and fatigue (5% vs 4%).

As measured by the European Organisation for Research and Treatment of Cancer (EORTC) core quality-of-life questionnaire (QLQ-C30), LuPSMA significantly improved the domains of social functioning, fatigue, insomnia, and diarrhea, and numerically improved all other domains. The incidences of skin rash, palmar/plantar soreness, dysgeusia, dizziness, urinary symptoms, and diarrhea were lower in the group treated with LuPSMA compared to cabazitaxel.

The rate of deterioration-free survival (defined as time to > 10-point deterioration on EORTC-QLQ-C30 in global health status, disease progression, or death) was improved at 6 months and 12 months in the LuPSMA-treated group compared with cabazitaxel: 29% vs 13%, respectively. Twelve-month rates were 21% vs 1%.

The study authors concluded, “In men with docetaxel-treated metastatic castration-resistant prostate cancer, LuPSMA is a promising alternative to cabazitaxel with significantly higher activity, fewer grade 3 to 4 adverse events, similar effects on global health status, and improvements in some patient-reported outcome domains.”

Disclosure: For full disclosures of the study authors, visit coi.asco.org or thelancet.com.