GTx Estrogen Agonist For Prostate Cancer Looks Effective At Low Doses

On the rebound after venous embolisms led to a clinical hold, Capesaris is getting good results at a significantly lower dose than what was used in that fated trial, and GTx is betting the novel estrogen receptor agonist can improve on the efficacy of androgen deprivation therapy while ameliorating its symptoms.

GTx Inc.’s hormonal prostate cancer therapy Capesaris (GTx-758) is proving effective against metastatic castrate-resistant prostate cancer at a fraction of the dose used in a trial that was halted for safety reasons a year ago, a panel of the company’s scientific advisors said Feb. 15.

The Phase II open-label ‘712 trial is testing the efficacy of capesaris as a secondary hormonal therapy in patients already on androgen deprivation treatment. Enrollment in the first 25-man cohort of the trial, planned to test 125 mg, 250 mg and 500 mg strengths of the drug in three successive groups, will be complete by the end of March, Thomas Flaig, University of Colorado, said.

And although the numbers are small, Flaig said, in all of the patients enrolled so far, the results are already in a range similar to what was seen with the earlier 2,000 mg dose. Importantly, at least at this preliminary stage, the drug also appears to be well tolerated, he said during an analyst call from the American Society of Clinical Oncology Genitourinary Cancer symposium in Orlando, Fla.

“The first positive step for us is to see that at 125 mg a day, which is almost 20-fold lower than the dose we used in our ‘707 study, we see efficacy, so now it’s all up to safety,” CEO Mitchell Steiner said.

Memphis, Tenn.-based GTx was told by FDA last February to halt all Phase II trials of Capesaris after signals of venous thromboembolism were seen in the ‘707 trial. The company was allowed to restart the program in May 2012 after FDA approved the design of the current trial (Also see "GTx Restarts Development Of Prostate Cancer Drug Capesaris" - Pink Sheet, 8 May, 2012.).

A Possible Quality Of Life Advantage

At least six agents have shown a meaningful survival benefit in prostate cancer in recent years, with another, Bayer AG/Algeta ASA’s Alpharadin (radium-223 dichloride), under review in the EU and U.S. (Also see "Radiotherapeutics Market Snapshot: This Sector Is Getting Hot" - Pink Sheet, 3 Dec, 2012.). Bayer and Algeta announced Feb. 13 that FDA has granted priority review to the application to treat castration-resistant prostate cancer patients with bone metastases.

All these other agents have been looking in the post chemo setting and the pre-chemo setting for metastatic castration-resistant prostate cancer, said Steiner.

But, “with an agent like this, the earlier the better,” added Evan Yu, Fred Hutchinson. “Earlier is better as long as the lower doses show good biologic effect, clinical efficacy and are very safe.”

With a number of new options available for patients with metastatic disease, GTx plans to test Capesaris as part of a primary hormonal therapy regimen in early prostate cancer patients, a population that Phil Kantoff, Dana Farber, observed “hasn’t been competitive for many, many years.”

Amgen Inc. tried its bone preserving biologic Xgeva (denosumab) in the space, but was not able to improve the time to metastasis in high-risk non-metastatic prostate cancer patients more than four months, and FDA found that amount of time not sufficient for approval, Kantoff pointed out (Also see "Beauty Of Amgen Bone Drug Results Is In Eye Of The Beholder" - Pink Sheet, 14 Dec, 2010.). With the denosumab failure, “we at least have some indication that if you can do better than four months, and it’s progression-free survival not overall survival, you have a way forward,” Steiner said.

The clinician researchers were particularly hopeful about evidence that the addition of Capesaris to androgen deprivation therapy appears to ameliorate some of ADT’s side effects. With men living longer with their disease, sometimes on androgen deprivation for years, “quality of life becomes a meaningful issue” and “if you can improve [that] it’s going to be very important,” Kantoff said.

Indeed, adding Capesaris, a selective estrogen receptor alpha agonist, to castration therapy apparently is ameliorating the cumulative effects of ADT, he said, adding that the cumulative side effects of the therapy and of persistent and more intense androgen depletion “cannot be underestimated.” Among those advantages, Capesaris appears to be bone-sparing, it mitigates hot flashes and it overcomes the insulin resistance associated with androgen deprivation therapy. In fact, said Kantoff, evidence is amassing that androgen deprivation is causing metabolic syndrome. Capesaris may even make it possible to stop using anti-absorbing agents such as denosumab and zoledronic acid.

And because Capesaris is a selective estrogen, a targeted agent, it has the advantages of diethylstilbestrol (estrogen), which has a long history of use for prostate cancer, without its side effects – the largest and most significant of which is gynecomastia (enlarged breasts). As well, traditional estrogen is associated with deep vein thrombosis at a rate of 3%-8%, said Flaig. The product also comes from compounding pharmacies, a real limitation because it is difficult to obtain, he said.

If the current Phase II trial is successful – results are expected in the third quarter of 2013 – GTx plans to take Capesaris forward in the most favorable dose strength in a Phase III program that tests it in combination with Abbott Laboratories Inc.’s Lupron (leuprolide) compared to Lupron alone in hormone-naïve prostate cancer patients with co-primary endpoints of total testosterone and free testosterone. Secondary endpoints include an improved side effect profile. A second test will try the combination in non-metastatic castration- resistant disease.

“From a regulatory standpoint, if you demonstrate that the addition of Capesaris to Lupron diminishes side effects, I think that would be a good regulatory path to pursue, to demonstrate equivalence at the same time,” said Kantoff.