SNMMI 2021: Beta Emitting PSMA Molecular Radiotherapy in mCRPC

(UroToday.com) The Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2021 annual meeting included a metastatic castrate-resistant prostate cancer (mCRPC) session and a presentation by Dr. Robert Flavell discussing beta-emitting PSMA molecular radiotherapy in mCRPC. Dr. Flavell notes that there is much excitement around PSMA radioligand therapy, which is a theranostic treatment strategy that leverages the success of PSMA PET imaging. There are numerous clinical trials underway, which are mainly but not exclusively revolving around 177Lu-based agents.

Dr. Flavell highlighted that a variety of beta-PSMA therapy agents are under development, predominantly based on 177Lu PSMA-617. Ultimately, PSMA-PET is essential for selecting beta-PSMA therapy, and there is strong clinical data supporting the use of 177Lu PSMA-617 emerging, which will likely fuel approval in the near future. PSMA is a theranostic prostate cancer target that is highly expressed on prostate cancer, and maybe targeted with antibodies or small molecules, predominantly against the extracellular domain:

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With regards to PSMA as a theranostic prostate cancer target, small molecular therapies are primarily focused on a urea-based scaffold. However, changes in imaging and therapeutic payload can have a substantial impact on affinity and delivery. A variety of antibody-based agents are under development.

Dr. Flavell then discussed in more detail 177Lu, which is mainly a beta emitter with a half-life of 6.7 days. Beta particles have a path length of 1.5 mm in tissue, which produces a lesser quantity of 113 and 208 keV gamma rays that can be used for planar imaging and SPECT. Lower energy and quantity of gamma rays simplifies the radiation safety requirement when compared to 131I. Ultimately, 177Lu PSMA-617 is arguably the most widely studied therapy, with good response rates seen across many studies (PSA50’s of typically 20-60%). The most common side effect of 177Lu PSMA-617 is bone marrow suppression.

Dr. Flavell then discussed two transformative trials that have incorporated 177Lu PSMA-617. The first of these, which is now published in The Lancet,1 is the TheraP trial. This ANZUP/PCFA sponsored trial began in 2016 and is a phase III randomized controlled trial of a direct targeted radioligand. TheraP enrolled patients with mCRPC who had previously received docetaxel and were eligible to receive cabazitaxel. Patients were required to have progressive disease with a rising PSA with an absolute PSA of 20 ng/mL or higher. All patients underwent both Ga-68-PSMA-PET/CT and F-18-FDG-PET/CT prior to randomization. To be eligible for inclusion, patients must have had a high avidity lesion on PSMA PET/CT (SUV max >20 at any site) with measurable disease with SUV max of 10 or greater. Further, there could be no sites of disease which were FDG positive but PSMA negative.

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Among 200 men at 11 sites in Australia who were eligible, randomization was performed in a 1:1 fashion to 177Lu-PSMA-617 or cabazitaxel. Randomization was stratified according to disease burden, prior use of enzalutamide or abiraterone, and study site. The primary study outcome was PSA response and these data were initially reported at ASCO 2020. PSA response was operationalized looking at a response of at least 50% from baseline. Compared to those receiving cabazitaxel (37%, 95% CI 27 to 46%), responses were significantly higher among those who received Lu-PSMA (66%, 95% CI 56 to 75%) with an absolute difference of 29% (95% CI 16 to 42%, p<0.0001).

More recent data were presented at ASCO-GU 2021 examining secondary endpoints including PSA/radiologic PFS (PCWG3), pain response (≥2 point reduction on McGill-Melzack Present Pain Intensity scale, objective response rate (RECIST 1.1), adverse events (CTCAE), PROs (EORTC QLQ-C30) and overall survival. As of a data cut-off of July 20, 2020, the median follow-up was 18.4 months. PFS was significantly longer in those assigned Lu-PSMA rather than cabazitaxel (rates at 1 year 19% [95% CI 12-27%] versus 3% [1-9%], HR 0.63, 95% CI 0.46-0.86; p = 0.003) based on 173 events. A similar benefit was seen whether PFS was examined radiographically (rPFS, HR 0.64, 95% CI 0.46-0.88; p = 0.007; 160 events) or based on PSA (PSA-PFS, HR 0.60 95% CI 0.44-0.83; p = 0.002; 172 events). Among men with measurable disease (n=78), objective response rates were significantly greater in the Lu-PSMA arm (49% vs 24%, RR 2.1, 95% CI 1.1-4.1; p = 0.019). Similarly, among those with pain at baseline (n=90), pain responses occurred in 60% in the Lu-PSMA arm versus 43% for cabazitaxel (RR 1.42, 95% CI 0.84-4.48; p = 0.10). Overall, patient-reported global health status was similar between arms (Lu-PSMA 64 [95% CI 61-67] versus cabazitaxel 60 [95% CI 57-64]), though significantly better function was noted for patients receiving Lu-PSMA with respect to fatigue, social functioning, insomnia, and diarrhea domains. No PRO domains were superior for cabazitaxel. The authors further assessed deterioration-free survival, defined as the time to a 10 point or greater decline in EORTC QLQ-C30 global health-related quality of life. Again, this favored the Lu-PSMA treated group.

The second trial discussed by Dr. Flavell, which was recently presented at ASCO 2021, was the phase 3 VISION trial. The VISION trial is an international, randomized, open-label phase 3 study evaluating 177Lu-PSMA-617 in men with PSMA-positive mCRPC who had previously received treatment with next-generation androgen receptor signaling inhibition (abiraterone, enzalutamide, etc) and one or two prior lines of taxane chemotherapy. Additionally, patients must have had an ECOG performance status of 0-2 and a life expectancy of at least 6 months. Importantly, patients must have had PSMA-positive disease on the basis of a central review of 68Ga-PSMA-11 staging scans. PSMA positivity was defined as uptake greater in metastatic lesions than in the liver. Further, they could have no PSMA-negative metastatic lesions.

Following enrollment, patients were randomized in a 2:1 fashion to receive either 177Lu-PSMA-617 (7.4 GBq every 6 weeks x 6 cycles) plus standard of care or standard of care alone. Standard of care treatments were at the discretion of the treating investigator, however cytotoxic chemotherapy, immunotherapy, and radium-223 were explicitly excluded. Most patients received alternative androgen-directed therapies while others received palliative radiotherapy and glucocorticoids. As follows is the schema for the VISION trial:

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The authors assessed two alternate primary endpoints: radiographic progression-free survival using PCWG3 criteria by independent central review and OS. In addition to these two primary endpoints, they also assessed key secondary endpoints of objective response rate (ORR; RECIST v1.1), disease control rate (DCR), and time to first symptomatic skeletal event (SSE) as well as other secondary endpoints including safety and tolerability, biomarkers including PSA, and health-related quality of life and pain

Among 1,179 screened patients, the VISION trial enrolled 831 patients, including 551 patients that were allocated to 177Lu-PSMA-617 plus standard of care and 280 allocated to standard of care only. Over a median study follow-up of 20.9 months (as of a data cut-off of 27 January 2021), treatment with 177Lu-PSMA-617 plus standard of care significantly improved OS by a median of 4.0 months (median OS, 15.3 versus 11.3 months; HR, 0.62 [95% CI 0.52, 0.74]; p < 0.001, one-sided), compared to standard of care alone, in the overall cohort of all randomized patients (n=831).

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Treatment with 177Lu-PSMA-617 plus standard of care significantly improved rPFS by a median 5.3 months (median rPFS, 8.7 versus 3.4 months; HR, 0.40 [99.2% CI: 0.29, 0.57]; p < 0.001, one-sided).

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While a higher rate of high-grade (grade 3-5) treatment-emergent adverse events was observed with 177Lu-PSMA-617 (28.4% versus 3.9%), overall therapy was well tolerated. However, it bears note that there were 5 deaths attributable to 177Lu-PSMA-617 treatment. In terms of specific adverse events, treatment with 177Lu-PSMA-617 plus standard of care was associated with increased rates of bone marrow suppression, xerostomia, and nausea and vomiting.

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Dr. Flavell concluded his presentation of beta-emitting PSMA molecular radiotherapy for mCRPC with the following take-home points:

  • There is strong evidence from multiple small studies together with TheraP and VISION trials that will likely fuel FDA approval of 177Lu-PSMA-617 in the coming year
  • Several questions remain, including assessing the role of (i) dosimetry versus fixed dosing (200 mCi) and (ii) combination therapies, such as immunotherapy, radiation sensitizers, and hormonal therapy
Presented by: Robert Flavell, MD, Ph.D., University of California – San Francisco, San Francisco, CA

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the Society of Nuclear Medicine & Molecular Imaging - 2021 Virtual Meeting, June 11-15, 2021

References: 

  1. Hofman MS, Emmett L, Sandhu S, et al. [(177)Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet 2021; 397(10276):797-804.
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