Initial results of the randomized phase II TheraP trial show that therapy directed to prostate-specific membrane antigen (PSMA) with lutetium-177–labeled PSMA-617 (LuPSMA) significantly improved prostate-specific antigen (PSA) response compared with cabazitaxel in men with metastatic castration-resistant prostate cancer that had progressed on docetaxel.1 LuPSMA had an improved toxicity profile compared with cabazitaxel.
Michael S. Hofman, FRACP, MBBS
“This is the first randomized trial to compare LuPSMA with a standard of care in men with docetaxel-progressing metastatic castration-resistant prostate cancer,” stated lead author Michael S. Hofman, FRACP, MBBS, of Peter MacCallum Cancer Centre, Melbourne. “Cabazitaxel, the comparator, is a relevant comparator that has been shown to improve overall survival in men who have disease progression on docetaxel,” he added.
TheraP Overview
At the ASCO20 Virtual Scientific Program, Dr. Hofman presented initial results of TheraP for the primary endpoint of PSA response and secondary endpoint of safety. Other key secondary endpoints, such as radiographic progression-free survival, overall survival, and patient-reported quality of life, will be presented in the future.
“My clinical interpretation of these results is that LuPSMA represents a novel class of radiopharmaceutical with high activity and relatively low toxicity in [metastatic castration-resistant prostate cancer] progressing on docetaxel. These results are consistent with prior single-center phase II data, and LuPSMA may represent a favorable treatment option compared with cabazitaxel in a selected population with high PSMA expression,” Dr. Hofman stated.
“Improvement in overall survival [with LuPSMA] is not yet defined. We eagerly await results of the upcoming phase III VISION trial, which will tell us more,” he continued. VISION is comparing standard of care with or without LuPSMA for patients with metastatic castration-resistant prostate cancer who have disease progression on docetaxel and enzalutamide or abiraterone acetate.
“Study results thus far warrant further exploration of LuPSMA earlier in the course of disease and in combinations,” Dr. Hofman said.
David R. Wise, MD, PhD
“Results of TheraP are a positive step in the development of LuPSMA for post–androgen receptor inhibitor, post-docetaxel, [metastatic castration-resistant prostate cancer],” noted David R. Wise, MD, PhD, of Perlmutter Cancer Center at NYU Langone Health, New York. TheraP was one of three prostate cancer abstracts that Dr. Wise discussed during the Genitourinary Cancer Highlights Session at the ASCO20 meeting. “We await the results of VISION,” he added.
Background
Metastatic castration-resistant prostate cancer is a lethal disease. Several life-prolonging treatments are available, including docetaxel, sipuleucel-T, cabazitaxel, abiraterone acetate, enzalutamide, radium-223, and olaparib, but the vast majority of patients still succumb to the disease. Novel treatments are needed, and one fertile avenue of research is PSMA-directed therapy.
PSMA is a unique antigen expressed on the surface of prostate cancer cells. LuPSMA is a radiolabeled small molecule that binds with high affinity to PSMA and delivers therapeutic beta-emitting radiation to tumor sites.
Lu-177–PSMA-617 is the furthest along in development of PSMA-targeted agents being studied. Several nonrandomized trials have shown encouraging efficacy and safety of LuPSMA in metastatic castration-resistant prostate cancer. One phase II trial, of which Dr. Hofman was lead author, found that LuPSMA reduced the PSA level by 50% or more in 64% of men, with low toxicity.2,3
Study Details
TheraP is the first randomized trial to compare LuPSMA in men with docetaxel-progressing metastatic castration-resistant prostate cancer defined by rising PSA and PSA > 20 ng/mL. The study was conducted at 11 sites in Australia. Participants were screened with a PSMA-directed positron-emission tomography (PET) scan and fluorodeoxyglucose (FDG)–PET/computed tomography (CT).
A total of 200 patients were randomly assigned 1:1 to LuPSMA for 6-week cycles for up to 6 cycles or cabazitaxel 20 mg/m2 every 3 weeks for up to 10 cycles. If an exceptional response was observed in the LuPSMA arm, treatment was paused and restarted upon progression.
Patients were stratified by disease burden, prior enzalutamide or abiraterone acetate therapy , and study site. Of the 200 randomly assigned patients, 98 were treated in the LuPSMA arm and 85 were treated in the cabazitaxel arm.
The primary analysis was an intention-to-treat analysis, and sensitivity analysis per protocol was performed as well. The primary endpoint was PSA response, defined as ≥ 50% reduction in PSA from baseline. Secondary endpoints, including PSA progression-free survival, overall survival, and quality of life, will be reported in the future.
At baseline, treatment arms were well balanced. About 91% had received prior enzalutamide or abiraterone acetate, 78% had a high disease burden (> 20 metastatic sites on PSMA-PET), and 92% were Eastern Cooperative Oncology Group performance status 0 or 1. Median PSA was 110 ng/mL in the LuPSMA arm and 94 in the cabazitaxel arm. More than 50% of patients had Gleason scores of 8 or higher at diagnosis, and about 30% had Gleason 7 disease. As of data cutoff on March 31, 2020, the median follow-up was 13.3 months, Dr. Hofman reported.
For the primary endpoint, the intention-to-treat analysis showed that LuPSMA led to a significantly greater percentage of patients with a PSA decline ≥ 50%: 66% in the LuPSMA arm vs 37% in the cabazitaxel arm, representing a 29% absolute greater PSA response in the experimental arm compared to cabazitaxel (P < .0001). The sensitivity analysis adjusting for the many more patients that dropped out before treatment in the cabazitaxel cohort showed a 23% difference in PSA response rate favoring LuPSMA (P = .0016).
A preliminary analysis of PSA progression–free survival found that LuPSMA delayed disease progression by 31% compared with cabazitaxel. Progression-free survival data are not yet mature.
Safety
grade 3 or 4 neutropenia was more common with cabazitaxel: 8% vs 40%, respectively. Febrile neutropenia occurred in 8% of men with cabazitaxel compared to none with LuPSMA. Cabazitaxel was associated with more diarrhea, change in taste, and neuropathy than LuPSMA, whereas more thrombocytopenia, dry mouth, and dry eye occurred in LuPSMA-treated patients.
Grade 3 or 4 adverse events were more frequent with cabazitaxel: 54% compared with 35% in those receiving LuPSMA. There was one treatment discontinuation due to toxicity in the LuPSMA arm and three in the cabazitaxel arm.
Strengths vs Limitations
Dr. Hofman enumerated several strengths of the TheraP study:
- It is the first randomized controlled study of LuPSMA.
- It included an active and clinically relevant control arm.
- It used FDG-PET and PSMA–PET/CT to select patients.
- It showed a large difference in the primary endpoint.
He also cited limitations, including the need for longer follow-up and the results of other key secondary endpoints. The study was not blinded, and a higher percentage of patients withdrew in the cabazitaxel arm prior to treatment: 1% vs 16%, respectively.
“In men with progressive disease following docetaxel, LuPSMA was more active than cabazitaxel with relatively fewer grade 3 and 4 adverse events and PSA progression–free survival favoring LuPSMA in this preliminary analysis. LuPSMA represents a potential new class of effective therapy for men with [metastatic castration-resistant prostate cancer],” Dr. Hofman stated.
DISCLOSURE: Dr. Hofman has served in a consulting or advisory role for Endocyte and Janssen; has received institutional research funding from Endocyte; and has been reimbursed for travel expenses from Genzyme, Ipsen, and Janssen. Dr. Wise has been employed by Best Doctors; has received honoraria from OncLive; has served in a consulting role for AlphaSights, Foundation Medicine, GLG Pharma, Guidepoint Global, Leap Therapeutics, Pfizer, and Silverlight; and has been reimbursed for travel expenses from Pfizer.
REFERENCES
1. Hofman MS, Emmett L, Sandhu SK, et al: TheraP: A randomized phase III trial of 177Lu-PSMA-617 theranostic versus cabazitaxel in metastatic castration-resistant prostate cancer progressing after docetaxel: Initial results. ASCO20 Virtual Scientific Program. Abstract 5500.
2. Hofman MS, Violet J, Hicks RJ, et al: [177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): A single-center, single-arm, phase 2 study. Lancet Oncol 19:825-833, 2018.
3. Violet J, Sandhu S, Iravani A, et al: Long-term follow-up and outcomes of re-treatment in an expanded 50 patient single-center phase II prospective trial of Lutetium-177 (177Lu)-PSMA-617 theranostics in metastatic castrate-resistant prostate cancer. J Nucl Med. November 15, 2019 (early release online).
