A novel radiopharmaceutical has been shown to boost survival when added to standard treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease had progressed after chemotherapy and the use of androgen inhibitors.

The agent, lutetium-labeled PSMA-617 (¹⁷⁷Lu PSMA-617), which is under development by Endocyte/Novartis, delivers high doses of beta radiation to prostate cancer cells.

It achieves this by binding to prostate-specific membrane antigen (PSMA), which is highly expressed on the surface of prostate cancer across the disease spectrum and across disease sites. Expression on normal tissue is limited.

The new results come from the VISION phase 3 open-label trial and are planned to be used in applications for US Food and Drug Administration (FDA) approval of this new agent in this indication.

“These findings warrant adoption of ¹⁷⁷Lu PSMA-617 as a new treatment option in this patient population,” said lead researcher Michael J. Morris, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York City.

“There are ongoing studies in patients with prostate cancer at earlier phases of the disease using this agent,” he said.

The new results will be presented on June 6 at the plenary session of the American Society of Clinical Oncology (ASCO) annual meeting, but some details were released early at a premeeting press briefing.

Results From Earlier Phase 2 Trial

Earlier results with the novel radiopharmaceutical from a phase 2 trial known as TheraP were published in February 2021 in The Lancet. These results showed that ¹⁷⁷Lu PSMA-617 was more active than cabazitaxel against mCRPC and led to fewer grade 3–4 adverse events.

As reported by Medscape Medical News at the time, 66% of men given ¹⁷⁷Lu PSMA-617 achieved a 50% reduction in prostate-specific antigen levels (PSA50) from baseline, vs 37% of those treated with cabazitaxel.

Moreover, median progression-free survival was reduced with ¹⁷⁷Lu PSMA-617 by a significant 37% (P = .0028) in comparison with cabazitaxel after 6 months.

The new results from the phase 3 trial show that adding ¹⁷⁷Lu PSMA-617 to standard of care for patients who have already been treated with androgen receptor pathway inhibitors and chemotherapy significantly improves radiographic progression-free survival (rPFS) by 60% and overall survival by 38%.

However, there is a notable difference between the phase 3 VISION trial and the former phase 2 study, says an expert who was approached for comment. In the phase 3 trial, the comparator is standard of care, which here excluded chemotherapy, immunotherapy, radium-223, and investigational drugs. This means ¹⁷⁷Lu PSMA-617 was compared to “nothing,” inasmuch as the standard of care was “in essence” a placebo, noted Thomas Hope, MD, associate professor of radiology at the University of California, San Francisco.

“So it’s not that surprising that it beats out the control,” Hope told Medscape Medical News.

Hope expects that the findings from the phase 3 trial will “lead to the approval of the drug, as that’s the most important thing here,” but he commented that the results from the phase 2 trial were “more relevant and helpful, because no one is debating between giving ¹⁷⁷Lu PSMA-617 and nothing.

“That’s not the clinical conundrum,” he said.

Hope, who was not involved in either trial, also noted that he would like to see data on the number of patients who crossed over from the standard of care to the active-treatment arm, as well as the PSA50 response rate.

Nevertheless, he welcomed the new results, saying that the improvement in rPFS was “wonderful,” and he pointed out that previous studies “weren’t big enough” to have overall survival results, “so this is stronger data.”

Regarding its eventual FDA approval, Hope said that the role of ¹⁷⁷Lu PSMA-617 in treating mCRPC will depend entirely on the wording of the label.

If, as in this study, the approval will be for patients whose cancer has progressed after chemotherapy and the use of androgen receptor pathway inhibitors, “that’s a pretty narrow label” and “very end-stage.”

Also approached for comment, Jeremie Calais, MD, assistant professor of translational theranostics at the University of California, Los Angeles, pointed out that “there is no robust, established criteria to assess the eligibility” of patients for ¹⁷⁷Lu PSMA-617 “based on the PSMA PET [positron-emission tomography] scan.”

He told Medscape Medical News that PET shows “where the PSMA target is expressed on the whole-body level,” and patients who respond well are those in whom all of the prostate cancer lesions have high PSMA expression.

“What really drives the prognostics,” he continued, “is the lesions with low PSMA lesions” or those that are negative for PSMA.

What that means in practice, Calais said, is that “we should use PSMA PET to exclude patients that have PSMA-negative lesions or lesions with low PSMA expression, rather than including patients with sufficient PSMA positivity.”

Thus, PSMA PET scans should be a tool to “exclude rather than include” patients for this treatment, he added.

With that said, he believes that in pairing PSMA PET with an effective targeted treatment, the study is a “major milestone for the whole theranostics field…and it opens the door to many more trials to come in the PSMA domain,” as well as other areas.

Trialist Morris explained that for the phase 3 VISION trial, patients were required to have mCRPC and PSMA-positive cancer on PET scans and to have been previously treated with at least one androgen receptor pathway inhibitor and one or two chemotherapy regimens.

The team randomly assigned patients in a 2:1 ratio to receive either protocol-permitted standard of care plus ¹⁷⁷Lu PSMA-617 every 6 weeks for four cycles, which could be increased to six cycles, or standard of care alone.

Patients whose conditions responded with residual disease could be given an extra two cycles of active treatment, he added.

Between June 2018 and October 2019, 831 of 1179 screened patients were randomly assigned; 551 received standard of care plus ¹⁷⁷Lu PSMA-617, and 280 received standard of care alone.

The first primary endpoint was met; ¹⁷⁷Lu PSMA-617 plus standard of care was associated with a median rPFS of 8.7 months, vs 3.4 months with standard of care alone (hazard ratio [HR], 0.40; one-sided P < .001).

The alternate primary endpoint was also met; active treatment was associated with a median overall survival of 15.3 months, vs 11.3 months for standard of care alone (HR, 0.62; one-sided P < .001).

All key secondary endpoints were statistically significant between the treatment arms in favor of ¹⁷⁷Lu PSMA-617 plus standard of care.

This included the overall response rate, at 29.8% vs 1.7% with standard of care alone; disease control rate, at 89.0% vs 66.7%; and time to first symptomatic skeletal event, at a median of 11.5 vs 6.8 months (HR, 0.50).

Overall, ¹⁷⁷Lu PSMA-617 was associated with a higher rate of high-grade treatment-emergent adverse events, at 52.7% vs 38.0% with standard of care alone.

Notable differences in grade 3–5 adverse events between the active treatment arm and the standard-of-care-alone arm included bone marrow suppression, at 23.4% vs 6.8%; fatigue, at 7.0% vs 2.4%; kidney effects, at 3.4% vs 2.9%; and nausea and vomiting, at 1.5% vs 0.5%.

Morris said that the most “clinically relevant” of the grade 3–5 bone marrow suppression events was “high-grade anemia, in 13% of patients, and low platelets in 8%.”

Consequently, he said that ¹⁷⁷Lu PSMA-617 was “safe and well tolerated, with no new safety signals.”

Discussing the relatively high rate of bone marrow suppression, Morris said at the press conference that it was not a “significant feature” for this type of treatment. Few patients experienced neutropenia, at around 3.5%; 7% to 8% required platelet transfusions, and around 13% had high-grade anemia.

He underlined that there “are strategies to mitigate all of those” toxicities, including delaying the next cycle of treatment.

However, Hope commented that the “problem with marrow toxicity is that you close the door to other therapies.”

In other words, “what prevents these patients from getting treatment is their marrow can no longer take treatment,” so a grade 3–4 toxicity “might not actually impact that patient, other than the fact they can’t get chemo anymore and therefore they are going to die.”

Hope noted, “Yes, it’s true that it doesn’t actually impact the patient at that moment, but it does have a huge impact on ability to get other treatment, so it’s not totally trivial.”

The study was funded by Endocyte, Inc, a Novartis company. Morris has relationships with Advanced Accelerator Applications, Athenex, Bayer, Curium Pharma, Endocyte, Fujifilm, Johnson & Johnson, ORIC Pharmaceuticals, Corcept Therapeutics (inst), Janssen (inst), Progenics (inst), Roche/Genentech (inst), and Sanofi (inst). Calais and Hope have disclosed no relevant financial relationships.

American Society of Clinical Oncology (ASCO) 2021: Abstract LBA4. To be presented June 6, 2021.

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