At the 2021 virtual annual meeting of the American Society for Clinical Oncology (ASCO), results of the VISION trial testing the addition of Novartis AG's radiopharmaceutical lutetium-177-PSMA-617 ([177Lu]PSMA-617, lutetium (177Lu) vipivotide tetraxetan, lutetium-PSMA) to individualized standard-of-care regimens in metastatic castration-resistant prostate cancer (CRPC) improved both overall survival (OS) and radiographic progression-free survival (rPFS).

"Patients with metastatic cRPC who have already progressed after both androgen receptor pathways inhibitors and chemotherapy had significantly improved overall survival and rPFS if they received lutetium-177-PSMA-617 in addition to safely combinable standards of care relative to those standards alone," plenary presenter Michael Morris told the audience.

Morris is lead investigator of the VISION trial and section head of prostate cancer at Memorial Sloan Kettering Cancer Center.

The median gain in rPFS in the trial was 5.3 months, more than doubling rPFS time, with a hazard ratio of 0.4. At 15.3 vs. 11.3 months, the gain in median OS had a hazard ratio of 0.62.

In principle at least, radiopharmaceutical therapy -- the tissue-specific delivery of radiation-emitting particles -- can combine the best of targeted and nontargeted therapy. Its delivery is specific, but its killing mechanism is not, which forestalls at least some of the reasons that targeted therapies can fail to have their anticipated effects.

Because PSMA expression is relatively specific, Johann de Bono told the audience in a talk on new therapies for the treatment of mCRPC, the drug is likely to be more specific than approved radiopharmaceutical Xofigo (radium Ra 223 dichloride), where one of his concerns "has always been that this agent is really primarily being taken up by osteoblasts." He did, however, warn that "as these tumors evolve, you do start generating PSMA-negative disease."

Cancer cells are good at evading therapy, and resistance mechanisms like target antigen loss remain issues. In her discussion of Morris' presentation, co-investigator Mary Ellen Taplin, professor of medicine at Harvard Medical School, admitted to disappointment over the results. She described the trial as "very positive," but also said that lutetium-PSMA is one more of nearly a dozen agents, developed over the last 30 years, that improve survival by 2-4 months.

"I was hoping for something more," she said.

Possible options for achieving something more include moving lutetium-PSMA into earlier lines of therapy, and combination treatments.

One of the promising possibilities is a combination with PARP inhibitors, which are especially effective in cells with the DNA damage that radiopharmaceuticals cause.

Lynparza (olaparib, Merck & Co./AstraZeneca) is approved for patients with mCRPC who have mutations in one of 15 homologous recombination repair (HRR) genes. The phase III Profound trial that was the basis for Lynparza's approval in mCRPC, also included tests of two companion diagnostics, Myriad's BRACAnalysis CDx, and Foundation's Foundationone CDx, which identifies a broader range of HRR gene alterations in prostate tumor tissue. In mCRPC, both tests are approved as companion diagnostics for olaparib.

De Bono and his colleagues have recently published more data in Cancer Discovery on the molecular characteristics of tumors that responded to olaparib in the TOPARB trial.

"We've shown that patients with BRCA2 [homozygous deletion] have much much longer rPFS than if they have a BRCA2 mutation. We've shown that you really generally have biallelic loss for BRCA2 if you have one hit that you can detect. Usually.... you have missed that second hit but it's there," he said.

"We've shown that some ATM patients do benefit but the ones that benefit almost always have biallelic loss, and ATM [immunohistochemistry] may be a better way of identifying those patients.... Interestingly we've also seen PALB2 alterations benefit, and most of the PALB2 alterations are actually germline."

In terms of combinations, he said, "I'm not sure I really have a favorite. I think it's all about data and getting that data."