(UroToday.com) The 2023 American Society of Clinical Oncology (ASCO) annual meeting held in Chicago, IL between June 2nd and June 6th was host to a prostate, testicular, and penile cancers oral abstract session. Dr. Shahneen Sandhu presented the results of LuPARP, a phase 1 trial of 177Lu-PSMA-617 plus olaparib in mCRPC patients.
177Lu-PSMA-617 is currently FDA approved in docetaxel and androgen receptor signaling inhibitor (ARSI)-pretreated metastatic castrate-resistant prostate cancer (mCRPC) patients on the basis of results from the VISION and TheraP trials.1,2 Addition of 177Lu-PSMA-617 to standard of care therapy in the VISION trial has been shown to improve overall survival (OS) compared to standard of care therapy alone (HR: 0.62, 95% CI: 0.52 – 0.74, p<0.001). In the TheraP trial, use of 177Lu-PSMA-617 was shown to be associated with superior progression-free survival (PFS) rates compared to cabazitaxel in the 3rd line setting (HR: 0.63, 95% CI: 0.46 – 0.86, p=0.0028). Olaparib is a potent poly (ADP-ribose) polymerase (PARP) inhibitor and has demonstrated activity in mCRPC patients in various settings.
177Lu-PSMA-617 delivers significant Beta radiation to PSMA-expressing tumors. 177Lu-PSMA-617 primarily causes single strand DNA breaks, which are typically repaired by PARP-dependent pathways. Blocking PARP could result in the conversion of DNA single strand breaks to lethal double strand breaks via replication fork collapse. Enhanced anti-tumor activity was demonstrated in the combination of PARP inhibitors and radiotherapy, including 177Lu-DOTATATE.5,6 In the LuPARP trial, the investigators hypothesized that olaparib will promote radiosensitization of 177Lu-PSMA-617, resulting in intensification of DNA damage, and thus improved efficacy.
The LuPARP phase 1 trial schema was as follows:
This trial included 48 patients with mCRPC. All eligible patients had received a prior ARSI (enzalutamide, abiraterone, or apalutamide) and docetaxel. All patients had normal organ function and an excellent ECOG performance status of 0-1. All patients underwent a 68Ga-PSMA-11 plus an FDG-PET/CT with the following inclusion criteria:
- PSMA SUVmax >15 at any site
- SUVmax >10 at other sites
- No FDG discordance
This study followed a 3+3 dose escalation design. In cohorts 1-6, the dose of olaparib was sequentially increased from 50 mg to 300 mg on days 2-15 (day 0: day of LuPSMA administration). In cohorts 7 to 9, the timing of olaparib administration (days -4 to 14 and -4 to 18), along with the dose of olaparib, were sequentially varied. Results of this analysis would inform the recommended phase 2 dose (RP2D). In this phase 1 trial, the primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and RP2D. Secondary endpoints included efficacy outcomes: rPFS, PSA-response rate, PSA progression-free survival (PSA-PFS), objective response rate (ORR), and OS, as well as safety.
The DLT criteria were summarized as below:
In this phase 1 trial, 177Lu-PSMA-617 was administered at a dose of 7.4 GBq 6 weekly for 6 cycles. Olaparib was concurrently administered at a dose of 50 to 300 mg twice daily on days 2 to 15, -4 to 14, or -4 to 18 of each 6-week cycle. PSMA PET/CT was performed at baseline and then 12 weekly for 48 weeks, followed by every 24 weeks thereafter. Blood biomarkers were collected serially every 12 weeks and at disease progression. Tumor biopsies were based on archival tumor tissue and were collected at baseline, weeks 2-4 and at disease progression.
With regards to treatment-related adverse events (AEs), no DLTs were reported across the dose levels. There were no grade 4 AEs. One treatment-related serious AE occurred (febrile neutropenia). Dose delay due to hematological toxicity occurred in 3 (9%) patients (cohorts 2, 5, and 6). Dose reduction was required in 4 patients (12%), 3 due to hematological toxicity and 1 due to xerostomia.
In the overall cohort (i.e., Cohorts 1 to 9), the PSA50 and PSA90 response rates were 66% and 44%, respectively. The ORR by RECIST v1.1 criteria was 78%. How do these results compare to those from TheraP and VISION? As summarized in the table below, the PSA50 responses from this trial were identical to those from TheraP (66%) and higher than that in VISION (46%).The PSA90 response of 44% in LuPARP was slightly higher than that in TheraP (38%).
Early results from Cohorts 7-9 were promising with PSA50 and PSA90 responses of 75% and 58%, respectively. We do note however that this is a Phase 1 trial, and this study is neither designed, nor powered, to assess efficacy outcomes.
There appears to be evidence of significant cellular heterogeneity in PSMA expression as demonstrated below:
The investigators observed high rates of total and PSMA+ CTCs in this cohort of PSMA-expressing mCRPC. Total and PSMA+ CTCs declined with combined olaparib and 177Lu-PSMA-617 treatment. Early declines in total and PSMA+ CTCs including 12-week CTC clearance paralleled PSA responses. Notably, total and PSMA+ CTCs rose again in the setting of disease progression.
Dr. Sandhu concluded that:
- 177Lu-PSMA-617 in combination with olaparib has promising activity
- The PSA50 response rate is 66% across the dose levels
- The PSA90 response was 44%, and most notable at higher olaparib dose levels
- The objective response rate is 78%
- Three patients had a treatment break due to a deep response
- 177Lu-PSMA-617 in combination with olaparib is well-tolerated
- There were no dose limiting toxicities
- 4 patients had one dose reduction, 3 patients had a treatment delay for management of toxicity, and no patients discontinued the drug for toxicity
- The recommended phase 2 dose is 7.4 Gb of 177Lu-PSMA-617 in conjunction with olaparib 300 mg twice daily on days -4 to 18 of each 6-weekly cycle
- Translational work to better understand the impact of 177Lu-PSMA-7617 and olaparib on the tumor microenvironment is ongoing
Presented by: Shahneen Sandhu, MBBS, FRACP, Associate Professor, Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 2 – Tues, June 6, 2023.
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