麻豆传媒

An investigational radioligand therapy targeting prostate-specific membrane antigen (PSMA) delayed disease progression and improved survival for patients with metastatic castration-resistant prostate cancer (CRPC), a phase III study showed.

The so-called VISION trial met both of its primary endpoints, demonstrating that the addition of lutetium-177 PSMA-617, a targeted systemic radiation treatment, to standard of care improved radiographic progression-free survival (PFS) and overall survival (OS) versus standard treatment alone:

• Median OS: 15.3 vs 11.3 months (HR 0.62, 95% CI 0.52-0.74, P<0.001)

• Median radiographic PFS: 8.7 vs 3.4 months (HR 0.40, 99.2% CI 0.29-0.57, P<0.001)

"These findings do warrant adoption of lutetium PSMA as a new treatment option in this patient population, pending FDA review," said Michael Morris, MD, of Memorial Sloan Kettering Cancer Center in New York City, presenting the findings during a press briefing ahead of the virtual American Society of Clinical Oncology (ASCO) annual meeting.

"Metastatic CRPC is the terminal phase of this disease and has a limited number of effective and durable treatment options," he said, explaining that men enrolled in the trial had already progressed on both androgen receptor pathway inhibitors as well as chemotherapy.

Despite the nearly 40% reduction in the risk for death with the radioligand therapy, "I find myself disappointed," said ASCO-designated discussant Mary-Ellen Taplin, MD, of Dana-Farber Cancer Institute in Boston, following the full study presentation at the meeting's plenary session of top abstracts.

"The disappointment stems from 30 years of trials in metastatic [CRPC] that prolong median survival by 2 to 4 months, and I had hoped for more," she said.

Discussing the tail of the survival curve in the investigational arm, Taplin noted that only 10% remained alive at 2 years and beyond. "A small tail, more a corgi size than a shepherd."

However, one benefit of lutetium-177 PSMA-617, she said, is the completely different mechanism of action compared to currently available hormone agents and chemotherapies in the metastatic CRPC setting, making it an option sequentially in appropriately selected patients.

"If FDA approved, this therapy will add to our armamentarium of palliative systemic treatment options for metastatic CRPC," she concluded.

PSMA expression is 100 to 1,000 times greater in prostate tumors than in normal tissue, and expression is further increased in patients with metastatic CRPC. PSMA-617 is a small molecule that binds to PSMA, and with lutetium-177 attached, delivers beta-radiation directly to tumor cells.

"This an exciting and promising new field within molecular targeting," Ash Tewari, MBBS, MCh, of Mount Sinai Health System in New York City, told 麻豆传媒, adding that the more-rapid clearance from the body makes lutetium PSMA easier to work with and could lead to broad acceptance of the therapy.

"This should be [used] after the time-tested treatments," he said, noting that the ideal candidate would be men with CRPC who have exhausted standard treatments.

A prior randomized phase II study of lutetium-177 PSMA-617 showed improved PFS over cabazitaxel (Jevtana) in men with previously treated metastatic CRPC, and resulted in fewer toxicities and better quality of life.

In the current study, 831 men with PSMA-positive metastatic CRPC were randomized 2:1 to either physician-determined standard of care alone or with lutetium-177 PSMA-617 (7.4 GBq every 6 weeks for six cycles). All patients had previously been treated with a contemporary androgen receptor pathway inhibitor and chemotherapy. Radium-223 dichloride (Xofigo), immunotherapy, and investigational drugs were excluded as standard of care options.

Response rates were higher with lutetium-177 PSMA-617, at 51% (including complete responses in 9.2%) versus 3.1% in the standard treatment arm (with no complete responses).

Of note, the OS analysis involved the full intent-to-treat population, while the radiographic PFS analysis involved a smaller subset (n=581) of patients enrolled following measures implemented to reduce early dropout in the control arm. OS with lutetium-177 PSMA-617 was similarly improved in the smaller data set (14.6 vs 10.4 months).

Overall, 87% of patients screened for enrollment had positive PSMA scans, begging the question whether imaging requirements are really needed prior to treatment, said Taplin.

Morris said the treatment was safe and well tolerated, with no new safety signals.

Overall, adverse events (AEs) were more frequent in the investigational arm. The most common AEs with lutetium-177 PSMA-617 included fatigue (49.1% vs 29.3% with placebo), bone marrow suppression (47.4% vs 17.6%), dry mouth (39.3% vs 1.0%), and nausea or vomiting (39.3% vs 17.1%).

Common grade ≥3 AEs between the investigational arm and control arm, respectively, included bone marrow suppression (23.4% vs 6.8%), fatigue (7.0% vs 2.4%), and kidney effects (3.4% vs 2.9%).

The most clinically relevant AEs were high-grade anemia in 13% of patients, said Morris, and low platelets in 8%.

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