PSMA, VISION, and the Will Rogers phenomenon

The FDA recently approved a second drug for prostate-specific membrane antigen (PSMA)-targeted positive emission tomography (PET) imaging of PSMA-positive lesions in men with prostate cancer. With the FDA approval of piflufolastat F 18 (Pylarify), men with prostate cancer suspected of harboring metastases who are potentially curable with local therapy will be indicated to undergo PSMA-targeted PET imaging that will aid in decision-making.¹ This is also indicated for patients with suspected recurrence of prostate cancer based on PSA levels after primary treatment.

Piflufolastat F 18 is expected to be distributed from multiple sites in the United States. The first FDA PSMA-targeted PET imaging drug, Ga 68 PSMA-11, was approved on December 1, 2020, for the same indications.² Ga 68 PSMA-11, based on available information, is only available locally at 2 sites in California. These tools will inevitably reveal (or exclude) early metastasis, and that is good news.

I could not help but take this opportunity to reflect on the historical nature of this. Interestingly, there is a tie to an Oklahoman. The “Will Rogers phenomenon” is a term used to describe an “epidemiological paradox” named after a comment the humorist made about migration during the Great Depression. Rogers is credited with stating, “When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states.”

So what does this have to do with PET imaging? In 1985, Dr Alvan Feinstein proposed the term “Will Rogers phenomenon” to describe the “stage migration” he observed in patients with lung cancer undergoing a new imaging test, the CT scan.³ Suddenly, small-volume metastases could be seen (or excluded). In addition, by detecting metastases that had been silent and unidentified, this “new technological data” resulted in a stage migration. Many patients who previously would have been classified in a “good” stage were assigned to a “bad” stage. Because the prognosis of those who migrated, although worse than that of other members of the good-stage group, was better than that of other members of the bad-stage group, survival rates rose in each group without any change in individual outcomes.

These new imaging tools, like the PSMA PET scans, allow for detection of cancer metastases before they became evident clinically. So now the clinical application will begin. However, the therapeutic interventions that have been approved for metastatic and castration-resistant prostate cancer were based on conventional imaging. Now, for the first time in urologic cancer care, we are presented with a novel tumor-directed therapy based on enhanced imaging.

The VISION trial (NCT03511664) compared standard of care to standard of care plus lutetium-177–PSMA-617 (Lu-PSMA) in men with CRPC who had received at least 1 next-generation androgen receptor signaling inhibitor and up to 2 chemotherapy regimens.⁴ This trial demonstrated improvement in its 2 primary end points, overall survival and radiographic progression-free survival, with the addition of Lu-PSMA. Therefore, the combination of enhanced detection of early metastasis coupled with tumor-directed therapy linked to that imaging should improve the outcome of patients with this advanced disease. The Will Rogers phenomenon continues to be impactful, and when combined with a precision treatment, the outcomes of this disease state will be “doubly improved” for generations to come.

Cookson, professor and chair of urology at the University of Oklahoma College of Medicine, Oklahoma City, is coeditor in chief for Urology Times®.

References

1. FDA approves second PSMA-targeted PET imaging drug for men with prostate cancer. FDA. May 27, 2021. Accessed June 28, 2021. https://bit.ly/3A8UEZq

2. Drug trials snapshot: Ga 68 PSMA-11. FDA. December 9, 2020. Accessed June 28, 2021. https://bit.ly/2Te2O2b

3. Feinstein AR, Sosin DM, Wells CK. The Will Rogers phenomenon. Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. N Engl J Med. 1985;312(25):1604-1608. doi:10.1056/NEJM198506203122504

4. Sartor O, de Bono J, Chi KN, et al; VISION Investigators. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. Published online June 23, 2021. doi:10.1056/NEJMoa2107322