Washington Editor

Shares of GTx Inc. plummeted 33 percent Wednesday after the firm said top-line Phase III results showed that toremifene 20 mg failed to reach statistical significance in reducing the incidence of prostate cancer in men with high-grade prostatic intraepithelial neoplasia (PIN), a premalignant lesion of the prostate.

The Memphis, Tenn.-based company's stock (NASDAQ:GTXI) closed at $2.02 Wednesday, down $1.

While the incidence of prostate cancer was lower in men receiving toremifene 20-mg compared with placebo, with a 10.2 percent relative-risk reduction observed at three years, there was no statistically significant difference, explained GTx CEO Mitchell Steiner.

GTx currently markets a 60-mg version of toremifene under the brand name Fareston as a treatment for metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors, an indication that was approved in 1998.

But with the failed Phase III PIN trial along with GTx's inability last fall to gain approval of toremifene as a treatment to reduce fractures in men with prostate cancer receiving androgen-deprivation therapy could mean it is "game over" for the drug in the prostate cancer space, said Rodman & Renshaw analyst Simos Simeonidis. (See BioWorld Today, Nov. 3, 2009.)

Even if GTx or a potential partner decide to have another go at it with an additional Phase III trial of toremifene 20 mg, as the firm is planning to do with the 80-mg dose, Simeonidis said he did not believe that an additional study "has a decent chance of providing a different outcome."

The best-case scenario, Simeonidis added, is that any such additional trial would read out in another three to five years.

But Steiner argued that it was not the end of the road for toremifene in prostate cancer. "Not at all," he declared. "Yeah, it is a disappointment, but GTx is moving ahead, and we will analyze the data and determine whether or not it is game over. But at this point now that is not what we are saying," Steiner told BioWorld Today.

"I'm disappointed that our drug, which had activity, didn't have enough activity to hit the endpoint, and that is why we need to go back and look at the data" to see if there was a subset where there was enough activity to "be the basis to go forward."

Steiner said there were no clinically significant differences in the adverse event safety profile in both arms of the randomized, 1,590-patient Phase III trial of toremifene 20 mg in men with high-grade PIN who had received at least one dose and had undergone at least one on-study prostate biopsy.

Adverse cardiovascular and venous thromboembolic events also were similar among men receiving toremifene and those who got the placebo, he added.

From the CEO point of view, Steiner said he wished the trial would have hit its endpoint. But from a physician's viewpoint, the study answered a major scientific question "without a doubt" that men with high-grade PIN are at an increased risk of developing prostate cancer.

The results of GTx's trial demonstrated that 45.5 percent of men in the placebo group developed prostate cancer within three years, Steiner said.

"So that is pretty high," he said. The reason the finding was so important, Steiner said, is that urologists "don't really know how to treat these patients. Some of them take biopsies, and some tell patients not to worry about it. So what this study will do is tell doctors to tell patients that if they have this premalignant lesion that they are at a high risk."

Steiner said he felt "good that we answered that question," and "put that to bed from a scientific and medical point of view," despite the study missing its endpoint. Nonetheless, he insisted that toremifene was "still strong" as an asset for the company, which for now plans to continue to pursue development of the 80-mg dose in preventing bone fractures in prostate cancer patients.

Toremifene 80 mg met its primary goal of reduced vertebral fractures compared with placebo in a two-year Phase III special protocol assessment study of the drug in 1,382 men with advanced prostate cancer, and also met other study objectives related to estrogen deficiency side effects of ADT.

But the FDA in a complete response letter last fall told GTx that it needed to conduct a confirmatory Phase III trial of the 80-mg drug before it could be approved. GTx has submitted to FDA a protocol for the trial and plans to meet with regulators this summer to finalize the study's design, Steiner said.

The company has secured funding for the trial through the expansion of its partnership with Paris-based Ipsen SA, announced in March, he noted. GTx anticipates starting that study, known as the Toremifene for Reduction of fractures and other Estrogen deficiency side effects in men on Androgen deprivation Therapy, or TREAT 2, by the end of the year, Steiner said. He contended that the firm's other assets were also "moving along nicely."

Steiner said GTx is expecting results this summer of its Phase II trial evaluating GTx-758, an oral LH inhibitor under investigation as a first-line treatment for advanced prostate cancer. The company also is planning late-stage trials for Ostarine (GTx-024) for the prevention and treatment of cancer-induced muscle wasting, or cancer cachexia, he added.