Patient Deaths Cause Media Storm in Prostate Cancer Study

Roxanne Nelson

January 31, 2014

SAN FRANCISCO — A first-in-class targeted agent has demonstrated activity in patients with very advanced prostate cancer who were refractory to taxane and had progressed on abiraterone (Zytiga) and/or enzalutamide (Xtandi).

In the phase 2 trial of the prostate-specific membrane antigen (PSMA) antibody drug conjugate (ADC), which is under development by Progenics, there was a reduction in several biomarkers. About 45% of patients experienced a reduction in prostate-specific antigen (PSA) levels of at least 30% and a conversion from unfavorable to favorable circulating tumor cells (CTCs).

The study results were presented here at the 2014 Genitourinary Cancers Symposium.

Adverse events in this phase 2 study were similar to what had been observed in the initial phase 1 trial, except 2 patients died of sepsis. These deaths sparked a media response, which culminated in Progenics shares dropping as much as 30%.

Brian Klein, an analyst at Stifel Nicolaus & Co., an investment firm in New York City, told Bloomberg News that the deaths suggest that the drug has "a major impact on the immune system."

Patients Were at Very High Risk

The media attention surrounding these deaths is perplexing. "I'm not sure why this got so much publicity," said Robert Israel, MD, one of the study authors and executive vice president of medical affairs at Progenics. "This is not going to make a difference to clinicians. Anytime you drop the white blood cell count, there is a risk associated with it."

He pointed out that both of the patients who died had predisposing conditions. "One had an indwelling central line and the other had repeated urinary tract infections," Dr. Israel told Medscape Medical News. "The patients were also heavily pretreated and didn't have much in the way of other options."

 
Any cytotoxic agent carries a risk.
 

Overall, PSMA ADC is generally well tolerated. In fact, he said, it is probably better tolerated "than most chemotherapy drugs. It is more targeted to prostate cancer, but any cytotoxic agent carries a risk."

Klein is cited in the Bloomberg report as saying in that PSMA ADC appears to offer "little benefit" considering the "apparent toxicity."

Dr. Israel disagrees. He pointed out that the drug is still in development, so the "risk/benefit profile still needs to be written." He also explained that this very heavily pretreated group "included patients with a performance status of 2, which is pretty poor."

"There is no reason that those 2 deaths should affect the development of this drug," he added.

Another expert agrees. "The deaths were unrelated to treatment," Susan Slovin, MD, PhD, a medical oncologist in the genitourinary oncology service at the Memorial Sloan-Kettering Cancer Center in New York City, told Medscape Medical News.

"One death was due to line sepsis and the other to urosepsis," she explained. "These are events that can occur during any other cancer treatment and, therefore, are of minimal concern."

An Unmet Need

The researchers note that treatment after taxane and androgen-deprivation therapy is an area of unmet medical need, and that biomarker-guided patient selection could be more predictive of clinical benefit in castration-resistant prostate cancer.

PSMA ADC is a fully human antibody to PSMA that is linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE). It binds PSMA and is internalized and cleaved by lysosomal enzymes releasing free MMAE, which causes cell-cycle arrest and apoptosis.

In their study, Dr. Israel and colleagues assessed the antitumor activity and tolerability of PSMA ADC in 80 patients who had progressed on abiraterone and/or enzalutamide and who were previously treated with taxanes.

In the study cohort, median age was 70.5 years, and ECOG performance status was 0, 1, or 2. All participants had bone disease and 37% had visceral and soft tissue metastases.

Safety, CTCs, imaging, biomarkers, and clinical progression were evaluated, and PSA was used to indicate tumor response.

Intravenous PSMA ADC was administered every 3 weeks for up to 8 cycles. Dosing was initiated at 2.5 mg/kg and adjustment for tolerability was allowed; 46 patients received 2.3 mg/kg and 34 received 2.5 mg/kg.

Of the 15 evaluable patients, radiologic RECIST indicated that 3 patients (20%) had progressive disease and 12 (80%) had stable disease.

The researchers found higher PSMA expression was associated with PSA and CTC responses (P = .019). In addition, 78% of patients with lower neuroendocrine markers experienced a reduction in CTCs of more than 50%.

Table. Most Common Grade 3/4 Adverse Events

Event 2.3 mg Dose 2.5 mg Dose
Fatigue 17.4% 20.6%
Neutropenia 17.4% 32.4%
Decreased electrolytes 15.2% 32.4%

 

Real-World Patients

The patient population in this study is very representative of a "real-world" population, said Hagop Youssoufian, MD, executive vice president of research and development at Progenics, during a company presscast.

"We have identified the dose and schedule that is effective," he said. "We believe that the 2.3 mg dose is safe and effective, and we have confirmed the results of the phase 1 trial."

Dr. Youssoufian noted that the 2 sepsis deaths associated with neutropenia occurred at the 2.5 mg/kg dose.

A trial in taxane-naïve patients is currently ongoing.

The study was sponsored by Progenics. All study authors report relationships with Progenics.

2014 Genitourinary Cancers Symposium (GUCS): Abstract 83. Presented January 30, 2014.

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