PSMA-Targeted PET Tracer Shows Increased Diagnostic Performance in Prostate Cancer

Michael J. Morris, MD

The prostate specific membrane antigen (PSMA)-targeted PET radiopharmaceutical ¹⁸F-DCFPyL-PET/CT identified localized disease that went undetected with standard imaging in men with biochemically recurrent prostate cancer, according to results from the phase 3 CONDOR trial, explained Michael J. Morris, MD, who added that the modality also impacted subsequent treatment decisions.

To be eligible for enrollment, men had to have biochemically relapsed prostate cancer defined by a prostate-specific antigen (PSA) level of at least 0.2 ng/mL if they had undergone radical prostatectomy or at least 2 ng/mL if they had radiation therapy or cryotherapy, as well as negative or equivocal standard-of-care imaging.

In total, 208 men received the ¹⁸F-DCFPyL tracer. The correct localization rate (CLR) of true positives among 3 independent readers ranged from 84.8% (95% CI, 77.8%-91.9%) to 85.6% (95% CI, 78.8%-92.3%) to 87.0% (95% CI, 80.4-93.6%), superseding the predefined 20% CLR for success.

Moreover, 63.9% of patients had a change in their intended treatment course after receiving the ¹⁸F-DCFPyL tracer.

“These data show that the positive predictive value of PyL is very good. Secondly, clinicians trust the scan and act on it. They believe that the information that’s furnished by the scan is actionable enough to change the goal of treatment, if not the treatment itself,” said Morris.

The CONDOR trial is the second of 2 prospective, multicenter trials that will be used to support the diagnostic performance of ¹⁸F-DCFPyL-PET/CT for this patient population in regulatory review, added Morris, citing the phase 2/3 OSPREY trial as the second study.

In an interview with OncLive, Morris, medical oncologist, clinical director, Genitourinary Medical Oncology Service, and Prostate Cancer Section Head, Division of Solid Tumor Oncology at Memorial Sloan Kettering Cancer Center, discussed the results of the CONDOR trial and the utility of PSMA-targeted PET imaging in prostate cancer.

OncLive: Could you highlight the promise of PSMA-targeted imaging in prostate cancer?

Morris: PSMA-targeted PET imaging is one of the most promising molecular imaging modalities in prostate cancer. Based on quite a bit of data we have collected from more of an international experience, we know that PSMA PET imaging is superior to standard imaging tools, especially those we are continuing to use in the United States, primarily cross-sectional, atomic imaging, and bone cinematography.

Unfortunately, PSMA imaging hasn’t been approved in the United States. The CONDOR study is one of the clinical trials designed to aggregate the data for regulatory approval of one of the PSMA tracers, ¹⁸F-DCFPyL. This is 1 of 2 studies that was intended to provide the FDA with the evidence needed for FDA approval of this agent for PSMA PET imaging in prostate cancer.

Could you shed light on the design of the trial and the mechanism of action of the tracer?

The imaging agent is a novel urea-based small molecule that targets the external domain of PSMA. It was developed by Martin Pomper, MD, PhD, of Johns Hopkins Medicine, and it’s radiolabeled with F18 as its radioactive source as a PET tracer.

The study is focused exclusively on patients who have biochemically relapsed disease following radical prostatectomy or definitive radiation therapy. That patient population is difficult to [study] because by definition, these patients need to have negative standard imaging. Whatever imaging they undergo to work up their rising PSA after definitive local therapy as part of their local standard of care, whether that’s a CT, MRI, or bone scan, fluciclovine, or some combination of the 2, those scans needed to be noninformative or negative in order to qualify the patient for this study.

If the patient had a prostatectomy, he needed to at least have a PSA of 0.2. If the patient had radiation therapy or cryotherapy needed to have a PSA of at least 2. This is a difficult patient population because there’s nothing to really look at by standard imaging.

The primary end point of the study was the positive predictive value. We looked at the PyL scans that had positive findings and standard scans with negative findings. That’s a tricky design. In collaboration with the FDA, [we decided that] the primary end point of the trial was going to be the CLR, which is equivalent to the positive predictive value or true positives over true positives, plus false positives, with the added requirement of anatomic location matching. We needed to create an anatomic atlas prior to opening the trial.

We used a composite truth standard to define a true positive and a false positive. [We used] a hierarchical structure where the top level of evidence was pathology. If the patient underwent a salvage lymph node dissection or a biopsy of a node or another lesion that was found on the PyL scan, that would be the top level of evidence for positivity. If there was nothing to biopsy or it wasn’t feasible to do [a biopsy], the second standard would be conventional imaging that the patient had not yet received as part of their baseline imaging. That could include fluciclovine or choline, which are FDA approved, or a targeted MRI or CT scan to confirm the PyL findings.

If none of the other 2 [modalities] were appropriate, the patient could have the lesion seen on the PyL irradiated without androgen deprivation therapy (ADT). If the PSA went down by 50%, that too would be considered evidence of positivity.

What did the results show?

The results were extremely positive. We used central review in order to avoid bias for the imaging and composite standard of truth. A statistician, essentially blinded to those 2 groups, read those PyL scans and their standard of truth, and brought those data together. [We considered the results to be successful] if the lower bound of the 95% confidence interval for the correct localization rate was greater than 20%. The 3 independent readers [determined that] the CLR was 85.6%, 87%, and 84.8%. This was well above the 20% benchmark that had been established for positivity.

We also looked at clinical decisions that were made as a result of those scans. Prior to the imaging and following the imaging, the clinician noted how they would manage the patient before and after, and whether the scan changed the management. Sixty-four percent of patients who had the scan had a change in intended management. Importantly, 21% of those changes went from a non-curative systemic therapy to salvage local therapy with curative intent.

About 30% of the patients were slated to have salvage local therapy, but then after the scan, they [were told to] supplement that salvage therapy or replace it all together with systemic therapy.

This is an important study that complements a prior trial called the OSPREY study, which looked at men with high-risk localized disease as well as men with recurrent metastatic or locally recurrent disease. Between these 2 programs, CONDOR and OSPREY, there is enough evidence to submit to the agency for review.

What are the next steps following this trial?

The next step is to submit the data from CONDOR and OSPREY to the agency for review. Certainly, those of us who treat patients with prostate cancer in the United States hope that the review yields an FDA approval. Regulatory approval is separate from reimbursement, so then the Centers for Medicare and Medicaid Services will need to review the reimbursement around PSMA imaging.

There are currently 2 different PSMA imaging studies that are on track for review––Gallium-68 PSMA-11 and F18PyL. From a prostate cancer community perspective, it’s really important that these tools be delivered to patients and physicians, so that they can better understand where their patient’s disease is and make more intelligent decisions, or at least more informed decisions regarding the best treatment for their patients.

When more of these PSMA agents become available, how will we determine which one is best to use?

For the average practitioner, any of these agents are better than what we’re currently using. Which one they choose may depend on issues that are unrelated to the technical aspects of each of the tracers. The decision may come down to what their institutions select.

In terms of availability, F18 already has a relatively large international infrastructure that supports the production of FDG for what is now the most commonly used tracer for head imaging. Many centers won’t have access to gallium-68, which requires a generator to produce.

It may come down to feasibility. In terms of selecting a tracer, in a perfect world, you would need more complete studies comparing one to the other to see which is superior. Right now, those limited studies comparing the 2 suggest but don’t definitively prove that the F18 may have advantages over gallium-68. Regardless of what those subtleties are, either of these [tracers] are so much better than what we currently use in terms of bone scans, CT, and MRI. Either [tracer] would be a real advance over what we use now.

Reference:

Morris MJ, Carroll PR, Saperstein L, et al. Impact of PSMA-targeted imaging with 18F-DCFPyL-PET/CT on clinical management of patients (pts) with biochemically recurrent (bcr) prostate cancer (PCa): results from a phase III, prospective, multicenter study (CONDOR). J Clin Oncol. 2020;38(suppl 15; abstr 5501). doi:10.1200/JCO.2020.38.15_suppl.5501