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Randomized Prospective Phase III Trial of 68Ga-PSMA-11 PET/CT Molecular Imaging for Prostate Cancer Salvage Radiotherapy Planning [PSMA-SRT] - Beyond the Abstract

Curative treatments for localized PCa include radical prostatectomy or radiotherapy2. After the failure of local therapy, recurrence is detected by rising serum PSA levels. Biochemical recurrence (BCR) occurs in 20 to 80% of patients within 10 years after radical prostatectomy. Locally recurrent disease after radical prostatectomy may be cured by salvage radiation therapy (SRT). The effectiveness of any local therapy depends on accurate imaging to rule out areas of disease that would remain untreated. The lack of sensitivity of standard-of-care imaging for recurrent PCa combined with a sensitive and specific biomarker of early disease recurrence (serum PSA level) generates a unique challenge for local treatment of PCa BCR: cancer is present, but we do not know where it is. There is thus an unmet clinical need to improve target delineation in patients with potentially curable PCa with early BCR.

68Ga-PSMA-11 (PSMA) PET/CT molecular imaging is highly sensitive and may offer anatomic localization of PCa biochemical recurrence. Therefore PSMA PET/CT has the potential to guide and improve SRT planning. Radiation fields can be expanded to encompass areas of disease not seen by current first-line imaging and not normally targeted by consensus radiation fields. Evidence of metastatic disease indicates that local therapy alone would not offer a cure, SRT may be considered futile and abandoned. Our recent multicenter post-hoc analysis of 270 patients with early BCR after prostatectomy showed that PSMA PET/CT would have had a major impact in 19% of patients. 

J Calais
It remains unclear if incorporation of PSMA PET/CT imaging into the planning of SRT could improve its likelihood of success. There is no randomized prospective trial designed to determine whether PSMA PET/CT can improve outcome at 5 years in patients with PCa early BCR following radical prostatectomy. 

This study justifies a randomized phase III imaging trial of SRT with or without PSMA PET/CT investigating its potential benefit on clinical outcome2.

The purpose of this trial is to evaluate the success rate of SRT for recurrence of PCa after prostatectomy with and without planning based on PSMA PET/CT. This is a Phase 3 Randomized Prospective Clinical Trial conducted at UCLA Ahmanson Translational Theranostics Division.

We will randomize 193 patients with post-prostatectomy BCR to undergo standard SRT (control arm) as routinely planned or to undergo a PSMA PET/CT scan before SRT (interventional arm). Patients can receive SRT in the institution of their choice. Only the PSMA PET/CT is performed at UCLA. The PSMA PET/CT scan is free for the patient (offered by UCLA Ahmanson Translational Theranostics Division). If randomized to standard arm, the patient does not come to UCLA and cannot undergo a PSMA PET/CT at UCLA. Patients may undergo any standard-of-care imaging in both arms (including AXUMIN) at the institution of their choice.

We will follow the patients remotely for 5 years after SRT. The primary endpoint is the success rate of SRT measured as the rate of biochemical progression-free survival (BPFS) after initiation of SRT. If the PSMA PET/CT scan show disease outside the pelvis and the treating radiation oncologist decides to not perform SRT patient will not be included in the analysis of the primary endpoint but will still be followed.

Potential pitfalls in study design include i) drop-out of patients randomized to the control arm as patients may be able to undergo PSMA PET/CT scans in other institutions; ii) potential FDA approval of PSMA PET imaging probes (Gallium-68-PSMA-11 or Fluor-18-DCFPyL) in the near future which would, in essence, lead to termination of new enrollment. As PSMA PET/CT imaging may become standard-of-care, randomizing patients to the control arm would no longer be feasible. Therefore, the time period for patient recruitment may be limited (1 to 2 years starting from September 2018). Even if the required number of patients to reach statistical power (n = 193) is not met, patients already enrolled in the trial will still be followed for 5 years as this would remain highly valuable and unique data.

This is the first prospective randomized phase 3 trial designed to determine whether a molecular imaging modality, PSMA PET/CT, can improve outcomes after SRT. Like testing the addition of systemic therapies to SRT, testing the addition of PSMA PET/CT to SRT may improve disease control. However, unlike additional systemic therapies, PSMA PET/CT has few if any side effects, minimal risks, and enables better patient selection and disease state identification.

Written by: Jeremie Calais, MD, MSc, Assistant Professor at the Ahmanson Translational Imaging Division of the Department of Molecular and Medical Pharmacology, UCLA Nuclear Medicine Department, Los Angeles, CA

References:
1. Calais J et al. Potential Impact of 68Ga-PSMA-11 PET/CT on the Planning of Definitive Radiation Therapy for Prostate Cancer. J Nucl Med. 2018 Nov; 59(11):1714-1721.
2.Calais J et al. 68Ga-PSMA-11 PET/CT Mapping of Prostate Cancer Biochemical Recurrence After Radical Prostatectomy in 270 Patients with a PSA Level of Less Than 1.0 ng/mL: Impact on Salvage Radiotherapy Planning. J Nucl Med. 2018 Feb;59 (2):230-237. Epub 2017 Nov 9.
3. Calais J et al. Randomized prospective phase III trial of 68Ga-PSMA-11 PET/CT molecular imaging for prostate cancer salvage radiotherapy planning [PSMA-SRT].  BMC Cancer 2019  Jan;19(18) . 


Randomized prospective phase III trial of 68Ga-PSMA-11 PET/CT molecular imaging for prostate cancer salvage radiotherapy planning [PSMA-SRT].  Link to this FREE OPEN ACCESS article.