(UroToday.com) The 2023 ESMO annual meeting included a session on prostate cancer, featuring a presentation by Dr. Louise Emmett discussing ENZA-p (ANZUP 1901), a phase 2 trial of enzalutamide and 177Lu-PSMA-617 in poor-risk mCRPC. Enzalutamide (PREVAIL trial, median OS 32 months)1 and Lutetium-177-PSMA-617 (LuPSMA; VISION trial, median OS 15 months)2 both improve OS in mCRPC. Preclinical and clinical data suggest synergy for LuPSMA with androgen receptor pathway inhibitors in mCRPC. Specifically, the clonal adjustment theory suggests that enzalutamide increases androgen resistance, allowing LuPSMA to have increased activity:
At the 2023 ESMO annual meeting, Dr. Emmett and colleagues evaluated the activity and safety of combining enzalutamide with adaptive-dosing of LuPSMA vs enzalutamide alone as first-line treatment for mCRPC.
Participants in ENZA-p had mCRPC not previously treated with chemotherapy or androgen receptor pathway inhibitors (prior abiraterone and/or docetaxel for hormone-sensitive disease were allowed), 68Ga-PSMA-positive disease on PET, and at least 2 risk factors associated with early progression on enzalutamide:
- LDH >= upper limit of normal
- ALP >= upper limit of normal
- Albumin <35 g/L
- De novo metastatic disease at diagnosis
- <3 years since initial diagnosis
- >5 bone metastases
- Visceral metastases
- PSA doubling time <84 days
- Prior abiraterone
The PSMA PET screening criteria included SUVmax >= 15 at one site and >= 10 at all other measurable sites, with mismatch on diagnostic CT not an exclusion criteria. Patients were randomized (1:1) to either enzalutamide 160 mg daily (enzalutamide-alone) or enzalutamide 160 mg daily plus adaptive dosing LuPSMA 7.5 GBq on days 15 and 57, with 2 further doses of LuPSMA given if there was persistent PSMA-positive disease on interim 68Ga-PSMA PET (day 92) (enzalutamide + LuPSMA). Stratification was by study site, volume of disease, early docetaxel for hormone sensitive disease, and prior treatment with abiraterone. The trial design for ENZA-p is as follows:
The primary endpoint was PSA-progression free survival. Secondary endpoints include radiological PFS (rPFS), PSA50%, and PSA90% response rates (PSA50 RR, PSA90 RR), adverse events, and OS. There were 160 participants followed until 150 PSA-PFS events occurred to provide 80% power, with a 2-sided significance level of 5%, assuming a true hazard ratio of 0.625 and a median PSA-PFS of 5 months with enzalutamide alone. Two patients were added secondary to dropouts. The interim analysis was planned at ~75% of 150 events (113), which was pre-specified before examining unblinded data. This was triggered on May 18, 2023, by reporting the 113th event. Given that four additional events occurred before May 18, 2023, 117 PSA-PFS events were included in this interim analysis.
After 220 men were screened, ENZA-p randomized 162 patients from August 2020 to July 2022: 79 to enzalutamide and 83 to enzalutamide + LuPSMA (two withdrew prior to treatment). Imaging screen failure rate was 18% (40/220). The median age was 71 (range 45-96), prior docetaxel was used in 54% of men, and prior abiraterone in 13%. The complete baseline characteristics are as follows:
At the interim analysis, protocol treatment was ongoing in 48 patients, including 16 in the enzalutamide arm and 32 in the enzalutamide + LuPSMA arm. In the enzalutamide + LuPSMA arm, 81% of patients received four doses of LuPSMA. Over a median follow up of 20 months (IQR 18-21), PSA-PFS was longer with enzalutamide + LuPSMA vs enzalutamide-alone (median 13 vs 7.8 months; HR 0.43, 95% CI 0.29-0.63, p<0.001):
Radiographic PFS also favored the enzalutamide + LuPSMA arm (HR 0.67, 95% CI 0.44-1.01):
PSA50RR and PSA90RR were higher with enzalutamide + LuPSMA vs enzalutamide-alone: 93% (77/83) vs 68% (54/79) (p<0.001) and 78% (65/83) vs 37% (29/79) (p<0.001), respectively:
Symptomatic adverse events were reported in 33% (27/81) of patients assigned enzalutamide + LuPSMA vs 35% (28/79) enzalutamide-alone. As follows is a tornado plot summarizing the adverse events of interest:
Dr. Emmett concluded her presentation discussing ENZA-p (ANZUP 1901), a phase 2 trial of enzalutamide and 177Lu-PSMA-617 in poor-risk mCRPC with the following take-home points:
- This is the first trial combining an ARSI with LuPSMA
- There is strong evidence of enhanced anticancer activity on the primary endpoint of PSA-PFS (HR 0.43)
- The control group has an active, life-prolonging treatment (enzalutamide)
- This is the first trial of adaptive-dosed LuPSMA based on an interim PSMA PET, with the potential to reduce toxicity by only administering if there is persistent PSMA-avid disease. 2-4 doses of LuPSMA were administered with further doses given (2-6) to improve PFS
- There is a planned follow-up for progression free and overall survival in July 2024
- Extensive embedded translational imaging/liquid biopsies are being collected for biomarker analysis
Presented by: Louise Emmett, MBChB, FRACP, MD, St Vincent’s Hospital Sydney, Darlinghurst, Australia
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 European Society of Medical Oncology (ESMO) Annual Meeting, Madrid, Spain, Fri, Oct 20 – Tues, Oct 24, 2023.
References:
- Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014;371(5):424-433.
- Sartor O, de Bono J, Chi KN et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021 Sep 16;385(12):1091-1103.