CN1498112A - Combination Therapy for Estrogen-Dependent Diseases - Google Patents

Abstract

This invention relates to a combination therapy for estrogen-dependent cancers in susceptible mammals, including humans, wherein the combination therapy comprises the steps of inhibiting hormone production in the testes or ovaries, respectively, and administering at least one aromatase inhibitor to the mammal.

Description

Combination Therapy for Estrogen-Dependent Diseases

technical field

The present invention relates to the combination therapy of estrogen-dependent cancers in susceptible mammals, wherein said mammals include humans, said combination therapy comprising suppression of testicular or ovarian hormone production, respectively, and administration to said mammal of at least one aromatizing Enzyme inhibitor step.

Background technique

Hormone-dependent breast and endometrial cancers have been studied by various investigators. One known form of endocrine therapy for premenopausal women is oophorectomy, most commonly performed by surgery or radiation, both of which result in irreversible castration. A reversible treatment modality for oophorectomy has been obtained using luteinizing hormone-releasing hormone agonists (“LHRH agonists”), which reduce serum estrogen by inhibiting luteinizing hormone (“LH”) secretion from the pituitary gland. Hormones are reduced to castrating levels (Nicholson et al., Brit. J. Cancer 39, 268-273, 1979).

Several studies have shown that treatment of premenopausal breast cancer patients with LHRH agonists induces responses comparable to those obtained with other forms of castration therapy (Klijn et al., J. Steroid Biochem. 20, 1381, 1984; Manni et al. , Endocr. Rev. 7:89-94; 1986).

US Patent No. 4,775,660 relates to combination therapy for breast cancer in women, wherein the combination therapy includes administering anti-androgens and anti-estrogens to the patient after chemically or surgically blocking hormone production in the patient's ovaries.

U.S. Patent No. 4,775,661 relates to combination therapy for female breast cancer, wherein said combination therapy includes administering to the woman an antiandrogen and selectively administering A sex steroid biosynthesis inhibitor.

U.S. Patent No. 4,760,053 describes the treatment of selected sex steroid-dependent cancers using a combination of an LHRH agonist and/or an anti-androgen and/or an anti-estrogen and/or or at least one sex steroid biosynthesis inhibitor.

U.S. Patent No. 4,472,382 discloses that various LH-RH agonists can be used to treat prostate cancer, benign prostatic hypertrophy, and hormone-dependent breast tumors, and also discloses that various LHRH agonists and anti-androgens can be used Substances to treat prostate cancer and benign hypertrophy.

U.S. Patent No. 5,550,107 relates to the treatment of breast and endometrial cancer in women with a combination therapy comprising administering an anti-estrogen drug to the patient after blocking hormone production in her ovaries , at least one compound selected from eg androgens and progestogens, at least one sex steroid biosynthesis inhibitor and one prolactin secretion inhibitor.

C.W.Taylor, "Goserelin (goserelin) for the treatment of hormone receptor positive premenopausal breast cancer patients after ovariectomy multicenter clinical trial" (J.Clin.Onc.1998(16):994-999) , H.A. Harvey et al., "LH-RH analogs for the treatment of human breast cancer," LHRH and its analogs—a novel contraceptive and therapeutic agent (B.H. Vickery and J.J. Nestor, J., and E.S.E. Hafez, eds. ) Lancaster, MTPPress, (1984) and J.G.M.Klijn et al.'s "Luteinizing hormone-releasing hormone analogue (Buserelin, Buserelin) for premenopausal patients with metastatic breast cancer" Lancet1, 1213-1216 ( 1982) reported that premenopausal women with breast cancer were treated with three LHRH agonists, goserelin, buserelin, and leuprolide. Some clinical improvement occurred.

Stein R.C. et al in British Journal of Cancer: 62, 679-683 (1990) describe the effect of 4-hydroxyandrostenedione (formestane) alone and in combination with goserelin on menopausal Clinical role and endocrine implications in women with pre-existing breast cancer. Celio L. et al. describe triptorelin and 4-hydroxyandrosterol in European Journal of Cancer: S155, 691 (September 17, 1997) and Anticancer Research: 19, 2261-268 (1999) Studies of enediones in the treatment of premenopausal women with breast cancer. Dowsett M. et al., Breast Cancer Research and Treatment: 56, 2435 (1999) describe the combined treatment of premenopausal women with breast cancer with vorozole and goserelin.

Tsuchiya N. et al. International Journal of Clinical Oncology: (200) 5: 183-187 describe the effect of fadrazole and leuprorelin acetate on cell proliferation in human breast cancer cell lines.

It is an object of the present invention to provide a method of treating estrogen-dependent cancers, especially sex steroid-dependent cancers, in mammals, said method being non-invasive of surgery.

Detailed Description of the Invention

The present invention provides a method for treating sex steroid-dependent cancer, which is applicable to mammals in need of such treatment, wherein said mammals include humans, and the method comprises the steps of: administering to said mammal an aromatase inhibitor and an LHRH agonist or antagonist simultaneously, separately or sequentially, and wherein, when the cancer is breast cancer, and a) the LHRH agonist is In the case of triptorelin, the aromatase inhibitor is not formestane, b) when the agonist is goserelin, the aromatase inhibitor is not vorozole ) or formestane, or c) when the LHRH agonist is leuprorelin, the aromatase inhibitor is not fadrazole.

Such persons are preferably premenopausal women.

The present invention also provides the use of an aromatase inhibitor for the preparation of a medicament for the treatment of sex steroid-dependent cancers in mammals including humans, wherein said mammals are simultaneously, separately or sequentially receiving an LHRH agonist or an antagonist, and wherein, when the cancer is breast cancer, and a) when the LHRH agonist is triptorelin, the aromatase inhibitor is not formestane, b) When the agonist is goserelin, the aromatase inhibitor is not vorozole or formestane, or c) when the LHRH agonist is leuprorelin , the aromatase inhibitor is not fadrazole.

The present invention also provides a product comprising an aromatase inhibitor and an LHRH agonist or antagonist as a combined preparation, which can be used simultaneously, separately or sequentially in the treatment of steroid-dependent cancer , and wherein, when the cancer is breast cancer, and a) when the LHRH agonist is triptorelin, the aromatase inhibitor is not formestane, b) the agonist is Ge In the case of goserelin, the aromatase inhibitor is not vorozole or formestane, or c) when the LHRH agonist is leuprorelin, the aromatase inhibitor The drug is not fadrazole.

Estrogen-dependent cancers that can be treated with the combination therapy provided by the present invention are those known in the art as "sex steroid-dependent cancers". Examples of such cancers are testicular cancer, prostate cancer, ovarian cancer, pancreatic cancer, uterine cancer, body cavity epithelial cancer, germ cell ovarian cancer, fallopian tube ovarian cancer, breast cancer and lung cancer.

In one embodiment of the invention, such cancers are prostate cancer, ovarian cancer and breast cancer, especially breast cancer in premenopausal women.

Examples of aromatase inhibitors of the present invention are exemestane, formestane, fadrozole, letrozole, zorozole and anastrozole, preferably Preferred are exemestane, anastrozole and letrozole, with exemestane being particularly preferred.

"Aromatase inhibitor" is meant to include a single aromatase inhibitor or a mixture of two or more, preferably two, aromatase inhibitors as defined above. A single aromatase inhibitor is preferred, or exemestane is one of the components in the mixture.

Examples of LHRH agonists according to the invention are, for example, leuprorelin, deslorelin, triptorelin, buserelin, nafarelin , goserelin, avorelin, histerelin, compound PTL 03001 (5-oxo-L-propyl-L-histidyl-L-tryptophanyl-L-seryl -L-tyrosyl-D-tryptophanyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide (Peptech), compound AN207 (6-[N6-[5- [2-[1,2,3,4,6,11-hexahydro-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-4-[[2,3, 6-trideoxy-3-(2,3-dihydro-1H-pyrrol-1-yl)α-L-lyxose-hexopyranosyl]oxy]-2-tetraphenyl]-1 , 5-dioxopentyl]-D-lysine]-, (2S-cis)-] (ASTA Medica Inc.), compound AN 238L-threonamide, N-[5-[2-[ (2S,4S)-1,2,3,4,6,11-hexahydro-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-4-[[2, 3,6-trideoxy-3-(2,3-dihydro-1H-pyrrol-1-yl)α-L-lyxose-hexopyranosyl]oxy]-2-tetraphenyl] -2-oxoethoxy]-1,5-dioxopentyl]-D-phenylalanyl-L-cysteinyl-L-tyrosyl-D-tryptophanyl-L-lysine Aminoyl-L-valyl-L-cysteinyl-, cyclo(27)-disulfide (ASTA Medica Inc.) and compound SPD 424 (LHRH-hydrogel implant) (Shire Pharmaceuticals Group) , or their pharmaceutically acceptable salts.

In one embodiment of the invention, the LHRH agonist is triptorelin and goserelin, or their pharmaceutically acceptable salts, especially triptorelin or a pharmaceutically acceptable salt thereof used salt.

Examples of LHRH antagonists of the invention are, for example, cetrorelix, abarelix, ramorelix, teverelix, ganirelix, compound A 75998 (acetyl-D-(2 -Naphthyl)alanyl-D-(4-chlorophenyl)alanyl-D-(3-pyridyl)alanyl-seryl-(N-methyl)tyrosyl-N6-( Nicotinyl)-D-lysyl-leucyl-N6-(isopropyl)lysyl-propyl-D-alaninamide) and A84861 (tetrahydrofuran-2-(S)-yl-carbonyl-glycol Aminoacyl-D-(2-naphthyl)alanyl-D-(4-chloro)phenylalanyl-D-(3-pyridyl)-alanyl-L-(N-methyl)tyramide Acyl-D-[N6-(3-pyridylcarbonyl)]lysyl-L-leucyl-L-(N6-isopropyl)lysyl-L-propyl-D-alaninamide) ( Abbot Labs.), GnRH immunogen (Aphton Co.), compound T 98475 (isopropyl 3-(N-benzyl-N-methylaminomethyl)-7-(2,6-difluorobenzyl)- 4,7-dihydro-2-(4-isobutyrylaminophenyl)-4-oxothieno[2,3-b pyridine-5-carboxylate hydrochloride) (Takeda) and compound MI1544 (acetyl Base-D-tryptophanyl-D-cyclopropyl-alanyl-D-tryptophanyl-L-seryl-L-tyrosyl-D-lysyl-L-leucyl-L-arginyl aminoacyl-L-propyl-D-alaninamide), or their pharmaceutically acceptable salts. A typical LHRH antagonist is abarelix or a pharmaceutically acceptable salt thereof.

The inventors of the present invention have also found that the combined administration of a therapeutically effective amount of an aromatase inhibitor and a therapeutically effective amount of an LHRH agonist or antagonist can treat the above-mentioned sex steroid-dependent diseases, which can produce an effect superior to that of merely administering an effective Therapeutic effect achieved by a therapeutic amount of an LHRH agonist or antagonist alone.

More importantly, they found that this newly acquired therapeutic effect was not accompanied by toxic effects, but rather by the use of therapeutically effective amounts of aromatase inhibitors or LHRH agonists or antagonists alone.

As used herein, "treating" means especially "controlling tumor growth", ie, slowing, interrupting, arresting, halting or reversing the formation of tumors, without necessarily showing complete disappearance of tumors.

Thus, in addition to slowing, interrupting, arresting, halting or reversing tumor formation, a "beneficial therapeutic effect" means that the life expectancy of an individual with cancer will be increased, one or more symptoms of the disease are reduced and /or the quality of life is improved.

Method of administration

In practicing the methods of treatment of the present invention on a patient, the aromatase inhibitor and LHRH agonist or antagonist may be administered in any form or manner that results in a therapeutically effective amount of the bioavailable compound, including oral and parenteral Administration by enteral route.

As used herein, "administered" or "administering" refers to any acceptable means of administering a drug to a patient that is medically acceptable, including parenteral and oral administration.

"Parenteral" means intravenous, subcutaneous, intradermal or intramuscular administration.

Oral administration includes administering one or all of the components of the combined preparation in a form suitable for oral administration, wherein the form suitable for oral administration includes, for example, tablets, capsules, suspensions, solutions, emulsions, powders, Syrup and more.

The actual preferred method and order of administration of the combination formulations of the invention may depend on the particular pharmaceutical formulation of the aromatase inhibitor used, the particular pharmaceutical formulation of the LHRH agonist or antagonist used, the particular sex steroid-dependent cancer being treated, and Varies with the particular patient being treated and other factors.

"Close in time" means that in the combination therapy methods that are the subject of the present invention, the aromatase inhibitor and the LHRH agonist or antagonist may be administered simultaneously or sequentially in either order. In conclusion, the method of administration used is capable of simultaneously providing the inhibition of testicular or ovarian hormone production and the inhibition of aromatase in mammals, thereby achieving a beneficial therapeutic effect.

dose

Dosage ranges for the administration of the combination formulations may vary according to the age of the patient and the condition and degree of the disease, and can be determined by those skilled in the art.

Thus, as is customary practice in all treatments, the dosage regimen must be adapted to the patient's situation, response, and specific conditions associated with the treatment, and the established dosage regimen can be modified on a case-by-case basis and/or according to other clinical circumstances. Adjustment.

The effective dose of aromatase inhibitors for tumor inhibition ranges from about 0.5 to about 500 mg per dose, administered 1-2 times a day.

For example, fadrozole can be administered orally in a dose of about 0.5 to about 10 mg, especially about 1 to about 2 mg. For example, letrozole can be administered orally in a dose of about 0.5 to about 10 mg, especially about 1 to about 2.5 mg. For example, formestane can be administered parenterally at a dose of about 250 mg to about 500 mg, especially about 250 to about 300 mg. For example, Anastrozole can be administered orally in a dose of about 0.5 to about 10 mg, especially about 1 to about 2 mg. For example, exemestane can be administered orally at a dose of about 5 mg to about 600 mg per day, particularly about 10 to about 50, more particularly about 10 to about 25 mg, or about 50 to about A dose of 500 mg was administered parenterally.

An effective amount of an LHRH agonist or antagonist is the usual dose for treatment with such compounds. Goserelin can be administered in the form of subcutaneous administration of goserelin acetate, which slowly releases goserelin, at a dose of about 3 to about 12 mg. For example, triptorelin (triptorelin) can be administered by intramuscular administration in the form of a depot formulation of triptorelin pamoate in a dose of about 3 to about 20 mg. When administered, each dose is administered at an interval of about 1, 2, 3 or 4 months. In particular, triptorelin pamoate can be administered intramuscularly in the form of microparticles as described in US 5,225,205 and US 5,776,885, more particularly as a 1-month depot formulation of 3.75 mg Administer intramuscularly. For example, abarelix can be administered intramuscularly alone at doses of slow release abarelix 10 to 200 mg every two weeks or every month.

The present invention provides a method for the treatment of steroid-dependent cancer in premenopausal women in need of such treatment, wherein the sex steroid-dependent cancer is selected from ovarian cancer and breast cancer, the method comprising: The amount of the drug and the time of approaching, the woman is administered exemestane (exemestane) and triptorelin (triptorelin) or their pharmaceutically acceptable salts substantially at the same time.

"Substantially simultaneous" means that exemestane and triptorelin are administered in a manner that can simultaneously provide the effect of suppressing the hormone production of the patient's ovary and the effect of inhibiting aromatase, so as to achieve Beneficial therapeutic effect.

As another embodiment of the present invention, the present invention also provides the use of exemestane (exemestane) in the preparation of drugs for the treatment of sex steroid-dependent cancers in premenopausal women, wherein the sex steroid-dependent cancers are selected from Ovarian cancer and breast cancer, wherein the woman is being treated with substantially concomitant administration of triptorelin or a pharmaceutically acceptable salt thereof. In one embodiment of the invention breast cancer is treated.

In one embodiment of the invention, exemestane and triptorelin, in particular the form of the pamoate, as described, are administered in a substantially simultaneous manner, whereby achieve beneficial therapeutic effects.

In particular, triptorelin pamoate may be administered as a sustained release formulation, where each administration is administered at an interval of about 1 to 4 months, for example as Administered as a 3.75 mg 1-month depot formulation as described in US 5,225,205 and US 5,776,885. Exemestane can be administered parenterally at a dose of about 50 to about 500 mg per injection, or orally at a dose of about 10 to about 25 mg per day.

As mentioned above, the present invention also provides a kit or separate package comprising a pharmaceutical composition for the combination therapy of the above-mentioned selected sex steroid-dependent cancers. The kit or individual package also includes instructions for using the pharmaceutical composition of the present invention.

As an example, the kit of the present invention can supply exemestane (exemestane) oral dosage 25mg or parenteral composition 50-500mg and triptorelin (triptorelin) 1 month depot preparation 3.75mg.

Depot formulations of pharmaceutical compositions comprising triptorelin pamoate for intramuscular administration can be prepared as described in US 5,225,205 and US 5,776,885.

As another example, a pharmaceutical composition comprising exemestane can be prepared according to US 4,808.616.

All references cited in this disclosure are hereby incorporated by reference.

Claims (29)

1. A method for the treatment of sex steroid-dependent cancer, the method is applicable to mammals in need of such treatment, the method comprises using simultaneously, separately or sequentially with the dosages capable of achieving beneficial therapeutic effects to said mammals An aromatase inhibitor and an LHRH agonist or antagonist, and wherein, when the cancer is breast cancer, and a) when the LHRH agonist is triptorelin, the aromatase inhibitor is not thiram b) when the agonist is goserelin, the aromatase inhibitor is not vorozole or formestane, or c) when the LHRH agonist is leuprolide, the aromatase inhibitor is not Fatriazole. 2. The method of claim 1, wherein the sex steroid-dependent cancer is selected from the group consisting of testicular cancer, prostate cancer, ovarian cancer, pancreatic cancer, uterine cancer, body cavity epithelial cancer, germ cell ovarian cancer, fallopian tube ovarian cancer, breast cancer and lung cancer. 3. The method of claim 1, wherein the estrogen-dependent cancer is breast cancer in premenopausal women. 4. The method of claim 1, wherein said mammal is a human. 5. The method of claim 1, wherein the aromatase inhibitor is selected from the group consisting of exemestane, formestane, famazole, letrozole, vorozole, anastrozole and mixtures of two or more thereof. 6. The method of claim 1, wherein the aromatase inhibitor is exemestane. 7. The method of claim 5, wherein, when administered orally, the amount of the aromatase inhibitor is about 5 to about 600 mg of exemestane, about 0.5 to about 10 mg of famizole, about 0.5 to about 10 mg, anastrozole about 0.5 to about 10 mg. 8. The method of claim 5, wherein the aromatase inhibitor is used in an amount of about 5 to about 500 mg of exemestane and about 250 to about 500 mg of formestane when administered parenterally. 9. The method of claim 1, wherein the LHRH agonist is selected from the group consisting of leuprorelin, deslorelin, triptorelin, buserelin, nafarelin, goserelin, avorelin, Histrelin, compound PTL 03001 (5-oxo-L-propyl-L-histidyl-L-tryptophanyl-L-seryl-L-tyrosyl-D-tryptophanyl-L -Leucyl-L-arginyl-N-ethyl-L-prolinamide, compound AN 207 (6-[N6-[5-[2-[1,2,3,4,6,11- Hexahydro-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-4-[[2,3,6-trideoxy-3-(2,3-dihydro-1H -pyrrol-1-yl)α-L-lyxose-hexopyranosyl]oxy]-2-naphthacene]-1,5-dioxopentyl]-D-lysine] -, (2S-cis)-], compound AN 238 L-threonine amide, N-[5-[2-[(2S,4S)-1,2,3,4,6,11-hexahydro- 2,5,12-Trihydroxy-7-methoxy-6,11-dioxo-4-[[2,3,6-trideoxy-3-(2,3-dihydro-1H-pyrrole- 1-yl)α-L-lyxose-hexopyranosyl]oxy]-2-naphthalenyl]-2-oxoethoxy]-1,5-dioxopentyl]- D-phenylalanyl-L-cysteinyl-L-tyrosyl-D-tryptophanyl-L-lysyl-L-valyl-L-cysteinyl-,cyclo(27) - Disulfides and compound SPD 424 (LHRH-hydrogel implants) and their pharmaceutically acceptable salts. 10. The method of claim 1, wherein the LHRH agonist is selected from the group consisting of triptorelin, goserelin and pharmaceutically acceptable salts thereof. 11. The method of claim 1, wherein the LHRH agonist is triptorelin or a pharmaceutically acceptable salt thereof. 12. The method of claim 1, wherein the LHRH agonist is triptorelin pamoate. 13. The method of claim 1, wherein the LHRH agonist triptorelin pamoate is in the form of a depot formulation at a dose of about 3 to about 20 mg. 14. The method of claim 13, wherein the LHRH agonist triptorelin pamoate is a 3.75 mg one-month depot formulation. 15. The method according to claim 1, wherein the LHRH antagonist is selected from the group consisting of cetrirelix, abarelix, remorelix, teverelix, ganirelix, compound A 75998 (acetyl-D-(2- Naphthyl)alanyl-D-(4-chlorophenyl)alanyl-D-(3-pyridyl)alanyl-seryl-(N-methyl)tyrosyl-N6-(nicotine Acyl)-D-lysyl-leucyl-N6-(isopropyl)lysyl-propyl-D-alaninamide) and compound A 84861 (tetrahydrofuran-2-(S)-yl-carbonyl- Glycyl-D-(2-naphthyl)alanyl-D-(4-chloro)phenylalanyl-D-(3-pyridyl)-alanyl-L-(N-methyl)phenol Aminoacyl-D-[N6-(3-pyridylcarbonyl)]lysyl-L-leucyl-L-(N6-isopropyl)lysyl-L-propyl-D-alaninamide) , GnRH immunogen, compound T 98475 (isopropyl 3-(N-benzyl-N-methylaminomethyl)-7-(2,6-difluorobenzyl)-4,7-dihydro-2- (4-isobutyrylaminophenyl)-4-oxothieno[2,3-b pyridine-5-carboxylate hydrochloride] and compound MI 1544 (acetyl-D-tryptophanyl-D-cyclo Propyl-Alanyl-D-Tryptophanyl-L-Seryl-L-Tyrosyl-D-Lysyl-L-Leucyl-L-Arginyl-L-Propyl-D-Propanyl Aminoamides), and their pharmaceutically acceptable salts. 16. A method for the treatment of sex steroid-dependent cancer, which is applicable to premenopausal women who need such treatment, wherein the sex steroid-dependent cancer is selected from ovarian cancer and breast cancer, the method comprises: Amounts for beneficial therapeutic effect Exemestane and triptorelin or their pharmaceutically acceptable salts are administered to the woman. 17. The method of claim 16, wherein the method is capable of simultaneously providing suppression of ovarian hormone production and aromatase inhibition/inactivation in a female patient, thereby achieving a beneficial therapeutic effect. 18. The method of claim 16, wherein the estrogen-dependent cancer is breast cancer. 19. The method of claim 16, wherein triptorelin is in the form of triptorelin pamoate. 20. The method of claim 16, wherein triptorelin pamoate is in the form of a depot formulation. 21. The method of claim 16, wherein triptorelin pamoate is in the form of a 3.75 mg one-month depot formulation. 22. The method of claim 16, wherein exemestane is administered orally in an amount of about 5 to 600 mg/day. 23. The method of claim 16, wherein exemestane is administered orally in an amount of about 10 to 500 mg/day. 24. The method of claim 16, wherein exemestane is administered orally in an amount of about 25 mg/day. 25. The method of claim 16, wherein exemestane is administered parenterally in an amount of about 50 to 500 mg/day. 26. Use of an aromatase inhibitor in the preparation of a medicament for the treatment of sex steroid-dependent cancer in a mammal, wherein said mammal is receiving treatment with an LHRH agonist or antagonist given simultaneously, separately or sequentially, and wherein, when When the cancer is breast cancer, and a) when the LHRH agonist is triptorelin, the aromatase inhibitor is not formestane, b) when the agonist is goserelin, the aromatase inhibitor is not vorozole or formestane, or c) when the LHRH agonist is leuprolide, the aromatase inhibitor is not fatrizole. 27. Use according to claim 26, wherein the mammal is a human. 28. The use according to claim 26, wherein the aromatase inhibitor is exemestane, the LHRH agonist is triptorelin, and the sex steroid-dependent cancer is ovarian cancer and breast cancer. 29. A product comprising an aromatase inhibitor and an LHRH agonist or antagonist as a combined preparation, which can be used simultaneously, separately or sequentially in the treatment of steroid-dependent cancer, and wherein, when When the cancer is breast cancer, and a) when the LHRH agonist is triptorelin, the aromatase inhibitor is not formestane, b) when the agonist is goserelin, the aromatase inhibitor is not vorozole or formestane, or c) when the LHRH agonist is leuprolide, the aromatase inhibitor is not fatrizole.