(UroToday.com) The 2023 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium held in San Francisco, CA between February 16th and 18th was host to a prostate cancer rapid abstract session. Dr. Scott Tagawa presented the results of a randomized, double-blind phase II study of ketoconazole, hydrocortisone, and anti-PSMA antibody J591 radiolabeled with 177Lu or 111In in patients with high-risk non-metastatic castrate-resistant prostate cancer (nmCRPC).
Dr. Tagawa began by noting that biochemical relapse may occur in up to a third of patients after primary local therapy. Salvage pelvic radiation therapy may help address intra-pelvic residual disease; however, it does not treat metastases outside of the pelvis. Patients with initially hormone-sensitive disease may progress to a state of castration-resistance without having visible disease on conventional imaging (i.e. nmCRPC).
The prostate-specific membrane antigen (PSMA) gene is located on the short arm of chromosome 11 in a region that is not commonly deleted in prostate cancer, thus making it highly prevalent in all forms of prostate cancer, including some castrate resistant forms. As such, PSMA has become a common target for targeted therapy. J591 is a de-immunized monoclonal antibody against the extracellular domain of PSMA and allows for accurate targeting and minor efficacy without an associated payload. The J591 monoclonal antibody may be linked to 177Lu, which is a predominantly β-emitting radionuclide with some γ-emission for imaging. Conversely, 111In is a predominantly γ-emitter with some auger emission for therapy. In this study, the authors hypothesized that an anti-PSMA “salvage radioimmunotherapy” may delay time to metastasis on conventional imaging (i.e. development of mCRPC).
This was a phase II randomized trial of high-risk nmCRPC patients (PSA doubling time <8 months or PSA>20; serum testosterone <50 ng/ml, negative conventional imaging with CT/bone scan). All patients initially received a 4-week run-in with ketoconazole (400 mg TID) and hydrocortisone (20 mg AM, 10 mg PM) and subsequently underwent a 2:1 randomization, stratified by the investigational site and primary therapy, to either 177Lu-J591 or 111In-J591. Ketoconazole and hydrocortisone were continued per the treating physician’s discretion with patients undergoing interval CT/MRI and bone scan every 6 months and subsequently every 3 months following PSA progression. The primary study endpoint was 18-month metastasis-free survival (MFS). With a target sample size of 55 patients, this study had 80% power with an alpha of 10% to detect an absolute difference of 80% versus 50% in 18 months MFS.
This trial included 55 patients, with a median age of 68 years (range: 52 – 88). The primary local therapies were a radical prostatectomy and primary radiation therapy for 75% and 22%, respectively. 22% of patients received prior local salvage therapy. The median baseline serum PSA was 8.0 ng/ml (range: 1- 78). The median PSA doubling time was 3.0 months (range: 0.87 – 7.85 months). Baseline characteristics were well-balanced across the two treatment arms.
With regards to the primary endpoint in the ITT population (9 not evaluable), the 18-month MFS was:
- 177Lu-J591: 50%
- 111In-J591: 24% (p=0.0066; significance pre-set at an alpha of 10%)
Secondary analysis similarly demonstrated a superior biochemical progression-free survival in the 177Lu arm (18.7 versus 8.9 months), with superior per protocol MFS (23.8 versus 20.8 months).
With regards to biochemical response, confirmed PSA50 and PSA90 responses were observed as follows:
- PSA50
- 177Lu-J591: 82%
- 111In-J591: 71%
- PSA90
- 177Lu-J591: 50%
- 111In-J591: 35%
With regards to adverse events, grade 3 or worse heme-related AEs were more common with 177Lu (neutropenia: 57% versus 11%, with 1 febrile neutropenia; thrombocytopenia: 77% versus 11% with 25% versus 6% platelet transfusions). Notably, there were fewer grade 3 or worse AEs with 177Lu:
- Abdominal pain: 0% versus 11%
- ALT increase: 3.3% versus 22%
- Diarrhea 0% versus 22%
Dr. Tagawa concluded as follows:
- In this study performed in the pre-PSMA PET era utilizing ketoconazole + hydrocortisone and radiolabeled mAb J591:
- Fewer patients with high-risk nmCRPC developed metastases by 18 months with 177Lu versus 11In
- Positive study based upon randomization phase II proof of concept design with 80% power and preset alpha of 10%
- Secondary endpoints directionally support activity of 177Lu-J591
- Most patients had PSA50 response in both arms
- There was more frequent heme toxicity with the β/γ emitter 177Lu compared to the γ/auger 111In, albeit with less frequent non-heme toxicity
- Fewer patients with high-risk nmCRPC developed metastases by 18 months with 177Lu versus 11In
Presented by: Scott T. Tagawa, MD, MS, FACP, Professor of Medicine and Urology, Weill Cornell Medicine, New York, NY
Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, Thurs, Feb 16 – Sat, Feb 18, 2023.
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Delaying Time to Metastasis in Patients With High-Risk, M0 CRPC With Radiolabeled J591 Plus Ketoconazole and Hydrocortisone - Scott Tagawa