ASTRO 2021: Current and Future Management Paradigms for Metastatic Castrate-Resistant Prostate Cancer

(UroToday.com) The 2021 American Society for Radiation Oncology (ASTRO) Hybrid Annual Meeting included a joint ASTRO/SNMMI session on prostate cancer molecular imaging and radiotheranostics and a presentation by Dr. Ana Kiess discussing the current and future management paradigms for metastatic castration-resistant prostate cancer (mCRPC). Dr. Kiess notes that Radium-223 is a calcium mimic that directly targets hydroxyapatite, as well as an alpha emitter with a very short range of effect. The pivotal phase III trial of Radium-223 in mCRPC (ALSYMPCA) randomly assigned 921 patients, to Radium-223 or matching placebo in a 2:1 ratio.1 Inclusion criteria for this trial included men with symptomatic mCRPC, >= 2 bone metastases, no visceral metastases, nodal disease <= 3 cm, and adequate bone marrow function. The primary endpoint of this trial was overall survival, which showed that radium-223 significantly improved overall survival compared to placebo (14.0 months vs 11.2 months; HR 0.70, 95% CI 0.55-0.88). Radium-223 was also associated with less treatment emergent adverse events than the placebo arm (serious adverse events 47% vs 60%), and associated with improved quality of life outcomes and slower decline in quality of life over time versus placebo: 

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 More recently, 177Lu-PSMA-617 therapy has emerged as a treatment option for mCRPC. Dr. Kiess discussed both the TheraP2 and VISION3 trial in detail. The TheraP trial 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 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, which 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% confidence interval 16 to 42%, p<0.0001).

 Secondary endpoints included 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, 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%] vs 3% [1-9%], HR 0.63, 95% CI 0.46-0.86; p = 0.003) based on 173 events. As 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 vs 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] vs 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, which also favored the Lu-PSMA treated group. 

 The VISION trial is an international, randomized, open-label phase III 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 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. The trial schema for VISION is as follows:

 

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 The trial assessed two alternate primary endpoints: radiographic progression-free survival using PCWG3 criteria by independent central review and overall survival. In addition to these two primary endpoints, they also assessed key secondary endpoints of objective response rate (RECIST v1.1), disease control rate, and time to first symptomatic skeletal event 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 between June 4, 2018 and October 23, 2019, including 551 patients were allocated to 177Lu-PSMA-617 + standard of care and 280 were allocated to standard of care only. In both the radiographic progression free survival analysis set and among all randomized patients, between 45-50% of patients had received more than one androgen receptor pathway inhibitor and 41-48% of patients had received more than one taxane regime. Over a median study follow-up of 20.9 months, treatment with 177Lu-PSMA-617 + standard of care significantly improved overall survival by a median of 4.0 months (median overall survival, 15.3 vs 11.3 months; HR, 0.62, 95% CI 0.52, 0.74), compared to standard of care alone, in the overall cohort of all randomized patients (n=831):

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The second alternate primary endpoint showed that treatment with 177Lu-PSMA-617 + standard of care significantly improved radiographic progression free survival by a median 5.3 months (median radiographic progression free survival, 8.7 vs 3.4 months; HR, 0.40, 99.2% CI 0.29, 0.57):

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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% vs 3.9%), overall therapy was well tolerated. In terms of specific adverse events, treatment with 177Lu-PSMA-617 + standard of care was associated with increased rates of bone marrow suppression, xerostomia, and nausea and vomiting.

There are several important logistical points for using 177Lu-PSMA-617, summarized as follows:

  • You must work closely with a qualified medical physicist
  • You must have a radioactive material license and authorized users
  • You must build a clinical team, have the appropriate equipment, and prepare available space
  • Standard operating procedures and forms are required, including a written directive, medical physics checklist, dose calibration/QA and treatment summary, and patient discharge instructions/wallet card
  • You must have a financial and billing coordinator

Dr. Kiess concluded her presentation of the current and future management for mCRPC with the following conclusions:

  • Radium-223 is a standard of care option for patients with symptomatic mCRPC bone metastases after taxane chemotherapy, without visceral or bulky nodal disease
  • 177Lu-PSMA-617 is not yet FDA approved but shows improved overall survival and limited side effects in patients with mCRPC after taxane chemotherapy
  • Logistics of Radium-223 and 177Lu-PSMA-617 therapy are feasible with a collaborative team and standard operating procedures
  • Future directions include new indications for these agents, selection and dosimetry, and novel agents including PSMA-targeted alpha emitters

 

Presented by: Ana Kiess, MD, PhD, Johns Hopkins University School of Medicine, Baltimore, MD 

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 American Society for Radiation Oncology (ASTRO) Hybrid Annual Meeting, Sat, Oct 23 – Wed, Oct 27, 2021.

 References:

  1. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369(3):213-223.
  2. 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 randomized, open-label, phase 2 trial. Lancet. 2021 Feb 27;397(10276):797-804.
  3. 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.

 

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