We appreciate the comments of Drs Tombal and Crawford. It is true that the only phase III study performed for registration purposes of degarelix included 610 patients. Nevertheless, it should be kept in mind that the design of this dose-finding study consisted of three arms: one with a 240-mg degarelix loading dose followed by a 160-mg maintenance dose (n = 202), one with the comparator leuprorelin 7.5 mg (n = 201), and one with the actually approved dosing regimen for degarelix with a loading dose of 240 mg and a maintenance dose of 80 mg (n = 207). Thus, the apparently high patient number of n = 610 needs to be put into perspective; 207 patients were treated for 1 year with the degarelix dosing schedule used in today's approved product. Compared with the 862 patients treated with 150 mg bicalutamide, the approved dosing regimen for bicalutamide monotherapy in the verum arm of its phase III programme [2, 3], we leave it to our readers to judge whether 207 patients in the verum arm of a pivotal phase III programme for global registration purposes of a product for treatment of prostate cancer should be considered small or large scale.
We agree with our colleagues Drs Tombal and Crawford, that hypersensitivity reactions of degarelix are rather uncommon. Actually, we were not able to identify any wording in our text which claims the opposite. Nevertheless, it is in the nature of a review on hormonal therapy not only to look at one single agent but also to look at drug classes. For the whole class of LHRH antagonists we still feel it is appropriate to mention histamine-mediated side effects as does the European Association of Urology (EAU) in their guidelines on prostate cancer: ‘However, practical shortcomings have limited clinical studies, as many LHRH antagonists have been associated with serious and life-threatening histamine-mediated side effects …’ .
In addition, we do not think that we misinterpret the characteristics of LHRH antagonists when we state that ‘… LHRH antagonists achieve a rapid decrease in LH, FSH and testosterone levels that, in contrast to LHRH agonists, is without the initial surge in testosterone associated with LHRH agonists’ . In the EAU guidelines, the following conclusion is drawn on the use of LHRH antagonists: ‘Overall, this new family of agents seems appealing, but their advantages over LHRH agonists are far from proven. Further trials are needed to confirm the preliminary observed increased efficacy compared to leuprorelin … Suppression of the initial flare with monotherapy is only clinically relevant in a few symptomatic metastatic patients’ . This EAU statement is in line with Bubley's  discussion on the clinical significance of the flare phenomenon at the start of LHRH agonist treatment. Bubley came to the conclusion that clinical flare has to be distinguished from biochemical manifestations of increased testosterone exposure, such as increasing PSA levels. By reviewing the available clinical literature, Bubley found that the risk of clinical flare is predominantly limited to stage D2 prostate cancer patients, i.e. those patients with distant metastasis in lymph nodes, bones or other organs. The overall frequency of flare in these patients ranged from 4 to 10% in most studies, with two exceptions finding a higher incidence of 41 and 63%, respectively.
In the leuprorelin arm of the phase III degarelix study it was at the discretion of the treating physician to add bicalutamide at the start of treatment for clinical flare protection. Only in 11% of the leuprorelin patients was concomitant bicalutamide deemed to be necessary by the physician. A total of 161 patients in this comparator arm experienced an increase in testosterone levels ≥15% from baseline during any 2 days in the first 2 weeks, but none of these patients are reported to have shown symptoms of clinical flare, e.g. bone pain, BOO, cord compression or cardiovascular effects. The incidence of side effects which could point towards clinical flare, e.g. back pain and hypertension, did not differ significantly between the degarelix 240/80mg arm and the leuprorelin arm, the only exception being arthralgia with a significantly higher (P<0.05) incidence in the leuprorelin arm, although with very low absolute numbers (n = 11 [5%] vs n = 18 [9%]) .
Finally, we are grateful to Drs Tombal and Crawford for bringing to our attention a few mistakes that found their way into our text. It is correct that in the cited paper by Calais da Silva et al.  314 patients were randomized to the intermittent treatment arm and 312 to the continuous arm. The numbers n = 127 in the intermittent arm and n = 107 in the continuous arm refer to the number of patients showing any progression. We apologize for this mistake and any confusion it may have caused. In addition we apologize for the wrong citing of the literature reporting on MDV3100. Of course these data are not on file at Takeda, but are derived from a poster session at the 2012 ASCO Genitourinary Cancer Symposium held by Scher et al. . Last but not least, it is of course true that cetrorelix is not approved for treatment of prostate cancer, but there are published laboratory investigations on its effect on prostate cancer cells . This was the reason it found its way into Table 1 of our review.