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PRIORITY PRESS - Society of Urologic Surgeons of Ontario Meeting

Toronto, Ontario / October 21, 2009

As discussed here by Dr. David Crawford, Professor of Surgery, Urology and Radiation Oncology, University of Colorado Health Sciences Center, Denver, most men prefer injections to surgical castration and the gonadotropin-releasing hormone (GnRH) agonists are comparable in efficacy to bilateral orchiectomy in terms of patient outcomes. However, agonists initially stimulate GnRH receptors in the pituitary, causing testosterone to surge and thus delay achievement of castration levels of testosterone. Historically, castrate levels were defined as <u><</u>0.5 ng/mL but new standards have been benchmarked to levels <u><</u>0.2 ng/mL. “As testosterone goes up, symptomatic patients can get worse,” Dr. Crawford told delegates, with increases in bone pain in patients with bone metastases and the potential risk of other serious complications depending on tumour size and location of metastases.

Antiandrogens may be used to protect against flare but they complicate the treatment regimen, Dr. Crawford noted. In his opinion, the greatest concern with the GnRH agonists is the phenomenon of microsurges. Following the initial luteinizing hormone-releasing hormone (LHRH) surge, testosterone gradually decreases. Over time, however, pituitary cells can develop new LHRH receptors and, with subsequent agonist injections, some patients respond with testosterone microsurges. Studies also indicate that testosterone control with GnRH agonists is not comparable with that achieved by orchiectomy. Depending on the castrate levels used, between 12.5% and 46% of patients do not achieve the necessary nadirs of 0.5 ng/mL and 0.2 ng/mL, respectively.

Avoiding Testosterone Microsurges

In contrast, the GnRH receptor antagonist, a new class of androgen deprivation therapy (ADT), binds immediately and reversibly to GnRH receptors in the anterior pituitary, suppressing testosterone to castrate levels within three days in over 90% of patients. At the same time, the antagonist causes an immediate fall in both luteinizing hormone and follicle-stimulating hormone (FSH). Consequently, the antagonist is not associated with testosterone surges, microsurges or symptomatic clinical flares.

Dr. Crawford cited a phase III randomized trial of degarelix and leuprolide. Klotz et al. (BJU Int 2008; 102:1531-8) randomized a total of 610 patients, most of whom had either localized or locally advanced disease, to either degarelix at a starting dose of 240 mg followed by a maintenance dose of either 80 mg or 160 mg or to leuprolide at a starting and maintenance dose of 7.5 mg. The maintenance dose of both agents was initiated on day 28 and continued until study end point. Both patient groups received a total of 12 doses of either agent given once a month.

With suppression of testosterone to <0.5 ng/mL between days 28 and 364 as the primary end point, there were no differences in response rates between the three treatment arms at 98.3% for the 160-mg arm, 97.2% for the 80-mg arm and 96.4% for the leuprolide 7.5-mg arm. Unlike the testosterone flare seen between days 0 and 7 following leuprolide injection, testosterone was immediately reduced following injection with degarelix (P<0.001), Dr. Crawford observed.

The antagonist also suppressed testosterone significantly faster than the agonist, he added, with approximately 96% of patients in both antagonist arms achieving castration levels of <u><</u>0.5 ng/mL by day 3 compared to no patient in the agonist arm (P<0.001). Reductions in prostate-specific antigen (PSA) were also achieved significantly more quickly in the antagonist groups with 64% of men in the antagonist arms achieving a significant reduction in PSA values by day 14 vs. 18% of those in the agonist arm (P<0.001). Nor was there any evidence of testosterone microsurges in the antagonist arms whereas 5% of patients in the leuprolide arm had a testosterone microsurge of >0.25 ng/mL on day 3 or 7 after the tenth injection. Testosterone breakthrough (>0.5 ng/mL) was reported in 2% of agonist-treated patients.

Dr. Crawford also noted that PSA failures, defined as having two consecutive increases of >50% (<u>></u>5.0 ng/mL), occurred in 26 out of 201 patients in the agonist arm vs. 16 out of 207 patients in the 240/80 mg antagonist arm for a probability of PSA failure of 14.1% and 8.9%, respectively.

The risk of PSA failure was also higher among patients with metastatic disease, where eight patients failed to achieve target PSA levels in the degarelix arms vs. 17 in the leuprolide arm. PSA failure was also more likely to occur among patients with a baseline PSA level of <u>></u>5.0 ng/mL while the time to PSA failure or death was also 34% longer in the antagonist arms than in the agonist arm (HR 0.664).

The incidence of adverse events was similar between the two treatment strategies, although a higher incidence of injection site reactions and chills was seen with the antagonist, while there were more cases of urinary tract infections and arthralgias seen with the agonist. “If you are going to lower testosterone, you have to do it quickly and you have to do it effectively,” Dr. Crawford told delegates, “and degarelix was better than leuprolide in doing this.”

Importance of FSH Suppression

As Dr. Crawford also discussed, both FSH and FSH receptors contribute to the proliferation of androgen-dependent and androgen-independent prostate cancer. Interestingly, orchiectomy patients have increased levels of FSH following the procedure and the GnRH agonists do not always adequately suppress FSH. This may have important implications for the treatment of prostate cancer, as in vitro models suggest that FSH stimulates the growth of animal and human prostate cancer cells. In an experimental pharmacology study (J Pharmacol Exp Ther 2007; 320:1113-8), degarelix maintained greater suppression of FSH over an interval of 450 days compared with leuprolide and had superior tumour volume control over both an agonist and orchiectomy, possibly because of its greater suppression of FSH, as Dr. Crawford suggested.

Increasing Survival with New Testosterone Castrate Levels

Failure to achieve or maintain castrate testosterone levels appears to negatively affect survival. Regarding six-month testosterone levels, Perachino et al. (J Urol 2008;179:179-80) found that only 28.4% of patients treated with goserelin 10.8 mg every three months achieved the new castration levels of <0.2 ng/mL compared to 73.5% who achieved the old castration levels of <0.5 ng/mL.

The same investigators then identified predictors of cancer-specific survival in bone-only prostate cancer patients on continuous ADT and found that higher six-month testosterone levels increased the risk of death by 1.33 which was only slightly less than the Gleason score at a HR of 1.39. Based on these observations, investigators then compared the survival probability in two hypothetical patients. Both patients were 60 years of age and had a Gleason score of 7 but one had a six-month testosterone level of 0.75 ng/mL (over the old castration threshold) and the other 0.1 ng/mL (under the new castration threshold). The probability model predicted that the patient with a six-month testosterone level under the new castration threshold would have a 10-month survival advantage over a patient with a six-month testosterone level in excess of the old castration threshold.

In another important study reported by Morote et al. (J Urol 2007;178:1290-5), 73 patients with non-metastatic prostate cancer underwent medical castration, 38% of whom also received bicalutamide to achieve maximal androgen blockade.

During a mean follow-up of 51 months, 41 events (67.1%) of androgen-independent progression were identified and these events were then correlated with breakthrough testosterone increases above 0.5 ng/mL and 0.2 ng/mL. Breakthrough increases in testosterone between 0.2 and 0.5 ng/mL were observed in 31.5% of the cohort and increases of >0.5 ng/mL were observed in 24.7%.

Mean survival free of androgen-independent progression in patients with breakthrough testosterone increases >0.5 ng/mL was 72 months vs. 90 months for those with breakthrough increases between 0.2 and 0.5/ng mL and 106 months for those with increases not exceeding 0.2 ng/mL. The lowest testosterone castration level with clinical relevance in this particular cohort was 0.32 ng/mL; breakthrough increases greater than this level predicted a lower survival free of androgen-independent progression. These findings support the need to monitor testosterone levels in patients on ADT, Dr. Crawford remarked.