Selectivity of patients, dosing play a role in the future evaluation of PSMA combinations in mCRPC

With the ongoing evaluation of prostate-specific membrane antigen-targeted radionuclide therapy (PSMA-TRT), physicians may be able to exploit the selectivity of PSMA expression to deliver high doses of radioactive particles to tumors, while relatively sparing normal organs, in patients with metastatic castration-resistant prostate cancer, according to Scott T. Tagawa, MD, MS, FACP.

“I think PSMA has been clearly validated in the clinic. We can target with both antibodies as well as small molecules. I would say that fairly clearly for trials and for a population, that imaging plays a role in selection,” Tagawa, professor of medicine and urology, and attending physician at NewYork-Presbyterian – Weill Cornell Medical Center in New York City, said during a presentation at the Society of Urologic Oncology 23rd Annual Meeting.¹ “[It is] much more difficult with individual patients sitting in front of you so, it's more of a risk-benefit type thing, depending on how many options are out there.”

On its own, radiation is a mainstay in prostate cancer treatment—in both curative and palliative therapy. However, PSMA-TRT shows potential as it includes various components, with PSMA-targeting vehicles comprised of different properties related to size and radioactive particles, including alpha and beta emitters, that affect efficacy and toxicity in part because of related properties, Tagawa explained.

In particular, he pointed out 3 PSMA-TRTs in current phase 3 clinical trials: ¹⁷⁷Lu-PSMA-617, ¹⁷⁷Lu-PSMA I&T, and ¹⁷⁷Lu-J591. To support their use and further evaluation of PSMA-TRTs, however, prospective, randomized studies are needed.

Two such studies have been conducted: the international, open-label, phase 3 VISION trial (NCT03511664),² and the multicenter, unblinded, randomized phase 2 TheraP trial (NCT03392428),³ both evaluating ¹⁷⁷Lu-PSMA-617.

“The VISION trial was positive for both of the alternative primary end points and overall survival, with rapid progression-free survival,” Tagawa said. “And the TheraP study in a select patient population, head-to-head against cabazitaxel [Jevtana], was positive in virtually all end points, mostly PSA based, but not necessarily worse for overall survival.”

With this, he questioned where the field goes from here. “So in terms of the existing beta-radiolabeled products, I think we can do more to optimize the dosing schedule. We are looking to optimize patient selection with the population. So one way is to move it earlier. I think that the VISION population has the highest hazard of having PSMA-negative disease and radio-resistant tumors,” Tagawa said, adding that randomized trials of combination therapies and of more potent agents should also be done.

For example, PSMA-TRT combinations, such as the ongoing studies of ¹⁷⁷Lu-J591 plus docetaxel and ¹⁷⁷Lu-PSMA-617 plus idronoxil, can affect the alteration of the target, radiosensitization, and the uptake and/or retention of the small molecules.

To conclude, Tagawa noted that PSMA—a clinically-validated, consistent cell-to-surface target—remains relevant, but can be improved upon, as the antibodies and peptides that target PSMA-positive cells can be radiolabeled and have different kinetics and biodistribution.

“With more potent agents, can we actually cure patients? I'm not so sure about that…because of heterogeneity,” Tagawa concluded. “So we'll see. But I think with combinations, maybe someday we're going to be able to get there.”

References

1. Tagawa S. Theranostics: The VISION Trial and Beyond. Presented at: Society of Urologic Oncology 23rd Annual Meeting; November 30-December 2; San Diego, California.

2. Sartor O, de Bono J, Chi KN, et al. Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021;385:1091-1103. doi:10.1056/NEJMoa2107322.

3. Hofman MS, Emmett L, Sandhu S, et al. [177Lu]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). doi:10.1016/S0140-6736(21)00237-3.