CZ20031349A3 - Combined treatment of estrogen-dependent diseases - Google Patents

Abstract

The present invention relates to a combination therapy for treating estrogen dependent cancers in susceptible mammals, including humans, comprising the steps of inhibiting hormone output of their testis or ovaries, respectively, and administering to said mammal at least one aromatase inhibitor.

Description

COMBINATION TREATMENT OF ESTROGEN-dependent DISEASES

Technical field

The present invention relates to estrogen-dependent combinations in susceptible mammals, comprising the steps of inhibiting production or ovaries and administering at least aromatase to the mammal.

BACKGROUND OF THE INVENTION

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· J treatment of cancers including human, testicular hormones, one inhibitor

Hormone-dependent carcinomas of the breast and endometrium (uterine mucosa) have been studied many times. A known form of endocrine therapy in premenopausal women is oophorectomy, most often performed by surgery or by irradiation, both of which result in irreversible castration. A reversible form of oophorectomy has been achieved using a luteinizing hormone releasing hormone (LHRH agonist) agonist where, following inhibition of luteinizing hormone (LH) secretion by the pituitary, serum estrogen levels have decreased to levels of castrated individuals (Nicholson et al., Brit. J. Cancer 39, 268-273, 1979).

Several studies have shown that treatment of premenopausal breast cancer patients with LHRH agonists induced responses comparable to those achieved by other forms of castration (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 the treatment of breast cancer in women using combination therapy comprising 9 9 999 4 9 9 999 99 And administering antiandrogen and antiestrogen to a woman after her ovarian hormone production has been blocked by a chemical or surgical intervention.

United States Patent No. 4,775,661 relates to treating breast cancer in women using therapy that involves administering to a woman after her ovarian hormone production has been blocked by a chemical or surgical intervention, an anti-androgen, and optionally a sex steroid biosynthesis inhibitor.

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

U.S. Patent No. 4,472,382 discloses that prostate adenocarcinoma, benign prostate hypertrophy and hormone-dependent breast tumors can be treated with various LH-RH agonists, and that prostate adenocarcinoma and benign prostate hypertrophy can be treated using various LHRH agonists and antiandrogen.

US Patent No. 5,550,107 relates to the treatment of breast and endometrial cancer using therapy comprising administering to a woman after her ovarian hormone production has been blocked by an antiestrogen and at least one compound selected from, for example, androgen and progestin, at least one biosynthesis inhibitor sex steroids and one prolactin secretion inhibitor.

Some clinical improvement in premenopausal women with breast cancer has been reported using three LHRH agonists, goserelin, buserelin and leuprolide: C. W. Taylor

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* «To to to to to to to to to to to to surg to surg surg surg surg surg surg surg surg surg surg surg surg surg surg surg One 1998 (16): 994-999), H.

A. Harvey et al. LH-RH analogues in the treatment of human breast cancer, LHRH and its Analogs-A new Class of Contraceptive and Therapeutic Agents (H. H. Vickery and JJ Nestor, J., and ESE Hafez, eds) Lancaster, MTP Press, 1984 and JGM Klijn et al. Treatment with luteinizing hormone analogues (Buserelin) in premenopausal patients with metastatic breast cancer, Lancet 1, 1213-1216,

1982.

Stein, R. C. et al., British Journal of Cancer: 62, 679683, 1990, describe the clinical and endocrine effects of 4-hydroxyandrostenedione (fonnestan) alone and in combination with goserelin in premenopausal women with breast cancer. Celio L. et al. . European Journal of Cancer: S 155, 691 (September 17, 1997) and in Anticancer Research: 19, 2261-268, 1999, reported research on the effects of triptorelin and 4-hydroxyandrostenedione in premenopausal women with breast cancer. Dowsett M. et al., Breast Cancer Research and Treatment: 56, 2435, 1999, disclose a combination treatment of breast cancer in premenopausal women by administering vorozole and goserelin.

Tsuchiya N. et al., International Journal of Clinical Oncology: (200) 5: 183-187, describing the effects of fadrazole and leuproline acetate on cell proliferation of the human breast cancer cell line.

It is therefore an object of the present invention to provide a method for treating estrogen-dependent cancers of mammals, in particular sex steroid-dependent cancers, which method is not as invasive as surgery.

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SUMMARY OF THE INVENTION

The invention relates to the treatment of sex steroid-dependent cancer in a mammal in need of such treatment, including a human, comprising administering, concurrently, separately or sequentially, an aromatase inhibitor and an LHRH agonist or antagonist, in an amount and near time range; sufficient to achieve a therapeutically beneficial effect, wherein when the cancer is breast cancer aa) the LHRH agonist is triptorelin, the aromatase inhibitor is a different inhibitor than formestane, b) the LHRH agonist is goserelin, the aromatase inhibitor is a different inhibitor than vorozole or formestane, or c) The LHRH agonist is leuprorelin, then the aromatase inhibitor is a different inhibitor than fadrozole.

Preferably, the human being treated according to the invention is a premenopausal woman.

The present invention also relates to the use of an aromatase inhibitor for the manufacture of a medicament for the treatment of sex steroid dependent cancer in a mammal, including a human, undergoing concomitant, separate or sequential treatment with an LHRH agonist, wherein when the cancer is breast cancer and aa) the LHRH agonist is triptorelin aromatase is a different inhibitor than formestane, b) the LHRH agonist is goserelin, then the aromatase inhibitor is other than vorozole or formestane, or c) the LHRH agonist is leuprorelin, then the aromatase inhibitor is other than fadrool.

The invention also relates to a product comprising an aromatase inhibitor and an LHRH agonist or antagonist as a combination preparation for simultaneous, separate or sequential use in the treatment of sex steroid dependent cancer, wherein when the cancer is breast cancer and a) LHRH

* * · · · · · · • ♦ · · · · · 0 • 9 «· _φ *« * ···· ·· · «·« · «·» agonist is triptorelin, then the aromatase inhibitor is other than an inhibitor formestane b) the LHRH agonist is goserelin, then the aromatase inhibitor is a different inhibitor than vorozole or formestane, or c) the LHRH agonist is leuprorelin, then the aromatase inhibitor is a different inhibitor than fadrozole.

Estrogen-dependent carcinoma that can be treated with the combination therapy of the present invention are carcinomas known in the art as sex steroid-dependent carcinomas. Examples of such cancers include testicular cancer, prostate cancer, ovarian cancer, pancreas cancer, uterine cancer, ovarian cancer, coeloma epithelial cancer, germ cell cancer breast cancer, and lung cancer.

fallopian tube cancer,

In one embodiment, the cancer is prostate cancer, ovarian cancer, and breast cancer, particularly breast cancer in premenopausal women.

Examples of the aromatase inhibitor of the invention are exemestane, formestane, fadrozole, letrozole, vorozole and anastrozole, preferably exemestane, anastrozole and letrozole, especially exemestane.

The term aromatase inhibitor is meant to refer to both one aromatase inhibitor and a mixture of two or more, preferably two, aromatase inhibitors as defined above. Preferably one aromatase inhibitor or one of the components of the composition is exemestane.

Examples of LHRH agonists of the invention are, for example, leuprorelin, deslorelin, triptorelin, buserelin, nafarelin, goserelin, avorelin, histerelin, compound PTL 03001 (5-oxoL-propyl-L-histidyl-L-tryptophyll-L-seryl-L-tyrosyl- D-tryptophyll-L-leucyl-L-arginyl-N-ethyl-L-prolinamide) (Peptech), compound AN 207 (6- [N6- [5- [2- [1,2,3,4,6, 11- hexahydro-2,5,12-trihydroxy * 9-4

9 9 · 9 9 9 ·· 9 4 • ♦ »♦ 9 4 • · 9 9 4

7-methoxy-6,11-dioxo-4 - [[2,3,6-trideoxy-3- (2,3-dihydro-1H-pyrrol-1-yl) -α-L-lyxohexopyranosyl] oxy] -2-naphthacenyl] -1,5-dioxopentyl] -D-lysine] -, (2S-cis) -) (ASTA Medica Inc), Compound AN 238 (L-threoninamide, 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)] -pyrrl-1-yl) α-Llyxohexopyranosyl] oxy] -2-naphthacenyl] -2-oxoethoxy] -1,5-dioxopentyl] -D-phenylalanyl-L-cysteinyl-L-tyrosyl-D-tryptophyll-L-lysyl-L-valyl -L-cysteinyl-, cyclic (2,7) disulfide) (ASTA

Medica Inc) and SPD 424 (LHRH-hydrogel implant) (Shire Pharmaceuticals Group), or a pharmaceutically acceptable salt thereof.

In one embodiment, the LHRH agonists are triptorelin and goserelin or a pharmaceutically acceptable salt thereof, especially triptorelin or a pharmaceutically acceptable salt thereof.

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) alanylseryl- ( N-methyl) tyrosyl N6- (nicotinoyl) -D-lysylleucyl-N6- (isopropyl) lysylpropyl-Dalaninamide) and A84861 (tetrahydrofuran-2- (S) ylcarbonylglycylD- (2-naphthyl) alanyl-D- (4-chloro) phenylalanyl-D- (3-pyridyl) alanyl-L- (N-methyl) tyrosyl-D- [N6- (3-pyridylcarbonyl)] lysyl-L-leucyl-L- (β-isopropyl) lysyl-L-propyl-D-alanylamide) (Abbot Labs.), GnRH immunogen (Aphton Co.), compound T 98475 (isopropyl-3- (N-benzyl-N-methylaminomethyl) hydrochloride) -7- (2,6-difluorobenzyl) -4,7-dihydro-2- ( 4-isobutyrylaminophenyl) -4-oxothieno [2,3-b] pyridine-5-carboxylate) (Takeda) and compound MI 1544 (acetyl-D-tryptophyll-D-cyclopropylalanyl-D-tryptophyll-Leryl-L-tyrosyl-D-lysyl-L) (leucyl-L-arginyl-L-propyl-Dalaninamide) or a pharmaceutically acceptable salt thereof. An example of an LHRH antagonist is abarelix or a pharmaceutically acceptable salt thereof.

An acceptable salt.

The present inventors have also found that treatment of the aforementioned sex steroid dependent conditions by administering a combination of a therapeutically effective amount of an aromatase inhibitor and a therapeutically effective amount of an LHRH agonist or antagonist can produce a therapeutic effect greater than that achieved by administering an effective amount of LHRH alone. agonists or antagonists.

Most importantly, this newly achieved therapeutic effect is not accompanied by toxic effects that are otherwise caused by the administration of either a therapeutically effective amount of the aromatase inhibitor alone or the LHRH agonist or antagonist alone.

As used herein, the term treatment means in particular "controlling neoplasm growth, in particular slowing, interrupting, arresting, arresting or reversing neoplasm formation, and does not necessarily indicate complete neoplasm removal.

Therefore, retardation, neoplasm, term therapeutically beneficial effect, in addition to interrupting, arresting, arresting or reversing the formation also simply means that the life expectancy of an individual affected by the cancer will be increased, that one or more symptoms of the disease will be reduced and / or quality of life will be improved.

Routes of administration

In the treatment of a patient by the therapeutic method of the invention, the aromatase inhibitor and the LHRH agonist or antagonist may be administered in any form or by a method that allows these compounds to be bioavailable in an effective amount, inter alia. thus by the oral and parenteral routes.

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The term administration or administration as used herein means any acceptable method of administering a drug to a patient that is medically acceptable, and includes parenteral and oral administration.

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

Oral administration includes administration of one or both components of the combination preparation in a suitable oral form such as, for example, a tablet, capsule, suspension, solution, emulsion, powder, syrup and the like.

A truly preferred mode and order of administration of the combination preparations of the invention may vary, e.g., according to the particular pharmaceutical aromatase inhibitor formulation that is used, the particular LHRH agonist or antagonist pharmaceutical formulation that is used, the particular sex steroid dependent cancer being treated, and of the particular patient being treated.

The term in the near time range means that in a method of combination treatment of a patient of the invention, the aromatase inhibitor may be administered concurrently with an LHRH agonist or antagonist, or the compounds may be administered sequentially, in any order. However, the compounds are administered such that both inhibition of the production of testis or ovarian hormones in the mammal and inhibition of the aromatase enzyme occur simultaneously, thereby achieving a therapeutically beneficial effect.

Dose

Dosage ranges for administration of the combination preparation may vary with the age, disease state and extent of the disease in the patient, and may be determined by one skilled in the art.

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Therefore, the dosage regimen must be adapted to the particular patient's condition, response and associated treatment in a manner that is customary for any other therapy and can be adjusted to respond to changes in the condition and / or depending on other clinical conditions.

An effective amount of an aromatase inhibitor as an antitumor agent may be from about 0.5 to about 500 mg per dose administered 1-2 times per day.

Fadrozole, by way of example, may be administered orally in a dosage range varying from about 0.5 to about 10 mg, and in particular from about 1 to about 2 mg. For example, letrozole may be administered orally in a dosage varying from about 0.5 to about 10 mg, and in particular from about 1 to about 2.5 mg. For example, formestan may be administered parenterally at a dose varying from about 250 to about 500 mg, and in particular from about 250 to about 300 mg. For example, Anastrozole may be administered orally in a dosage varying from about 0.5 to about 10 mg, and in particular from about 1 to about 2 mg. For example, Exemestane may be administered orally at a dose varying from about 5 mg per day to about 600 mg per day, especially from about 10 to about 50, and particularly from about 10 to about 25 mg per day, or parenterally at a dose ranging from about 50 to about 500 mg per injection.

An effective amount of an LHRH agonist or antagonist is generally as generally used in the treatment of such compounds. Goserelin can be administered as goserelin acetate by administering slow-release goserelin by the subcutaneous route at a dose of from about 3 to about 12 mg. Triptorelin can be administered, for example, as triptorelin pamoate by administering a depot preparation by the intramuscular route at a dose of from about 3 to about 20 mg, wherein the interval is about

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1, 2, 3 or 4 months between two administrations. In particular, the triptorelin pamoate can be administered intramuscularly in the form of microparticles as described in U.S. Patent Nos. 5,225,205 and 5,776,885, and more particularly as a monthly depot formulation of 3.75 mg. For example, abarelix can be administered as a single intramuscular slow release abarelix dose of 10 to 200 mg once every 2 weeks or once a month.

The invention provides a method of treating sex steroid-dependent cancer selected from the group consisting of ovarian and breast cancer in premenopausal women in need of such treatment, the treatment comprising administering substantially simultaneously to the woman exemestane and triptorelin or a pharmaceutically acceptable salt thereof, in amounts and near time which are sufficient to produce a therapeutically beneficial effect.

The term substantially simultaneously means that exemestane and triptorelin are administered in such a way that both the inhibition of ovarian hormone production and the inhibition of the aromatase enzyme are achieved simultaneously, and thus a therapeutically beneficial effect is achieved.

Another embodiment of the invention is the use of exemestane for the manufacture of a medicament for the treatment of sex steroid dependent cancer selected from ovarian cancer and breast cancer in premenopausal women undergoing substantially concurrent treatment with triptorelin or a pharmaceutically acceptable salt thereof. In one embodiment of the invention, breast cancer is treated.

In one further embodiment of the invention, exemestane and triptorelin, in particular as pamoate, are administered substantially simultaneously as described herein to achieve a therapeutically beneficial effect.

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9999 • 9

In particular, the triptorelin pamoate can be administered as a sustained release formulation in such a way that there is an interval of about 1 to 4 months between two consecutive administrations, eg in the form of a one month depot of 3.75 mg formulation as described in U.S. Pat. 225,205 and 5,776,885. Exemestane can be administered parenterally at a dosage range of from about 50 to about 500 mg per injection or orally at a dose of from about 10 to about 25 mg per day.

As mentioned above, the invention also provides kits or simple packages containing pharmaceutical compositions useful for the combination treatment of selected sex steroid-dependent cancers as discussed above. The kits or packages may also contain instructions for use of the pharmaceutical composition of the present invention.

By way of example, the kit of the present invention provides exemestane in 25 mg oral form or 50-500 mg parenteral form and triptorelin formulated in a one-month depot preparation of 3.75 mg.

A pharmaceutical composition for intramuscular administration comprising triptorelin pamoate in the form of a depot preparation can be prepared as described in United States Patent Nos. 5,225,205 and 5,776,885.

For example, a pharmaceutical composition comprising exemestane may be prepared according to U.S. Patent No. 4,808,616.

All publications cited in this specification are incorporated by reference.

on the genitals this treatment,

Claims (29)

PATENT CLAIMS A method of steroids in the treatment of a cancer dependent mammal in need thereof comprising simultaneous, separate or sequential administration of an aromatase inhibitor and an LHRH agonist or antagonist in an amount sufficient to achieve a therapeutically beneficial effect, wherein the cancer is breast cancer aa) LHRH agonist b) the LHRH agonist is goserelin, then the aromatase inhibitor is other than vorozole or formestane, or c) the LHRH agonist is leuprorelin, then the aromatase inhibitor is other than fadrozole. 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, coeloma epithelial cancer, ovarian germ cell cancer, fallopian tube cancer, breast cancer and lung cancer. The method of claim 1, wherein the estrogen-dependent cancer is breast cancer in a premenopausal woman. The method of the mammal is a human. claim 1, characterized in that: 5. The method of claim 1 wherein the anastrozole is anastrozole. exemestane, fonnestane, fadrozole, letrozole, vorozole, and a mixture 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 is oral, the amount of exeraestane aromatase inhibitor is about 5 to 600 mg, fadrozole about 0.5 to 10 mg, letrozole about 0.5 to 10 mg, and anastrozole about 0, 5 to 10 mg. The method of claim 5, wherein when the administration is parenteral, the amount of exemestane aromatase inhibitor is about 5 to 500 mg and formestane is about 250 to 500 mg. The method of claim 1, wherein the LHRH agonist is selected from the group consisting of leuprorelin, deslorelin, triptorelin, buserelin, nafarelin, goserelin, avorelin, histerelin, compound PTL 03001 (5-oxo-L-propyl-Lhistidyl- L-tryptophyll-L-seryl-L-tyrosyl-D-tryptophyll-L-leucyl-Larginyl-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-pyrrole)] -1-yl) α-Llyxohexopyranosyl] oxy] -2-naphthacenyl] -1,5-dioxopentyl] -Dlysine] -, (2S-cis) -), Compound AN 238 (L-threoninamide, 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-lyxohexopyranosyl] oxy] -2-naphthacenyl] -2-oxoethoxy] ··· 9 9 9 9 • 9 9 99 99 99 99 99 99 9 9 9 9 9 9 9 9 9 9 9 9 9 1,5-dioxopentyl] -D-phenylalanyl-L-cysteinyl-L-tyrosyl-Dtryptophyll-L-lysyl-L-valyl-L-cysteinyl-, cyclic (2,7) disulfide) and compound SPD 424 (LHRH-hydrogel) implant) or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein the LHRH agonist is selected from the group consisting of triptorelin, goserelin, and pharmaceutically acceptable salts thereof. The method of claim 1, wherein the LHRH agonist is triptorelin or a pharmaceutically acceptable salt thereof. The LHRH agonist method of claim 1 is characterized by triptorelin pamoate. that is The method of claim 1, wherein the LHRH agonist pamoate triptorelin is in the form of a preparation at a dose of about 3 to about 20 mg. by depot The method of claim 13, wherein the LHRH agonist pamoate triptorelin is in the form of a one-month depot preparation of 3.75 mg. The method of claim 1, wherein the LHRH antagonist is selected from the group consisting of cetrorelix, abarelix, ramorelix, teverelix, ganirelix, compound A 75998 (acetyl-D- (2-naphthyl) alanyl-D- (4-chlorophenyl) alanyl-D- (3-pyridyl) alanylseryl- (N-methyl) tyrosyl 9 9 · 9 · 9 N6- (nicotinoyl) -D-lysylleucyl-N6- (isopropyl) lysylpropyl-Dalaninamide), Ά84861 (tetrahydrofuran-2- (S) ylcarbonylglycyl-D (2-naphthyl) alanyl-D- (4-chloro) phenylalanyl-D - (3-pyridyl) alanyl-L (N-methyl) tyrosyl-D- [N 6 - (3-pyridylcarbonyl)] lysyl-L-leucyl-L (N 6 -isopropyl) lysyl-L-propyl-D-alanylamide), 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- bpyridine-5-carboxylate), compound MI 1544 (acetyl-D-tryptophyll-D-cyclopropylalanyl-D-tryptophyll-L-seryl-L-tyrosyl-D-lysyl-Lleucyl-L-arginyl-L-propyl-D-alaninamide) and their a pharmaceutically acceptable salt. 16. A method of treating sex steroid dependent cancer selected from ovarian and breast cancer in a premenopausal woman in need of such treatment comprising administering to the woman exemestane and triptorelin or a pharmaceutically acceptable salt thereof in an amount sufficient to produce a therapeutically beneficial effect. . 17. The method of claim 16, wherein both inhibiting the production of female ovarian hormones and inhibiting / inactivating the aromatase enzyme occur simultaneously, and a therapeutically beneficial effect is achieved. 18. The method of claim 16, wherein the estrogen-dependent cancer is breast cancer. 19. The method of claim 16, wherein: 99 9 Triptorelin is in the form of triptorelin pamoate. The method of claim 16, wherein the triptorelin pamoate is in the form of a depot preparation. The method of claim 16, wherein the triptorelin pamoate is in the form of a one-month depot of 3.75 mg. The method of claim 16, wherein about 5 to 600 mg / day of exemestane is administered orally. The method of claim 16, wherein about 10 to 500 mg / day of exemestane is administered orally. 24. The method of claim 16 wherein about 25 mg / day of exemestane is administered orally. 25. The method of claim 16 wherein about 50 to 500 mg / day of exemestane is administered parenterally. Use of an aromatase inhibitor for the manufacture of a medicament for the treatment of sex steroid-dependent cancer in a mammal undergoing simultaneous, separate or sequential treatment with an LHRH agonist or antagonist, and wherein when the cancer is breast cancer and a) the LHRH agonist is triptorelin, the aromatase inhibitor b) LHRH agonist is goserelin, then aromatase inhibitor is other than vorozole or formestane, or c) LHRH agonist is leuprorelin, then inhibitor • 9 9 9 11 • 11111 • 11 11 L of aromatase is different from fadrozole. The use of claim 26, wherein the mammal is a human. The use of claim 26, wherein the aromatase inhibitor is exemestane, the LHRH agonist is triptorelin and the sex steroid-dependent carcinoma is ovarian carcinoma and breast carcinoma. 29. A product comprising an aromatase inhibitor and an LHRH agonist or antagonist as a combination preparation for simultaneous, separate or sequential use in the treatment of sex steroid dependent cancer, and wherein when the cancer is breast cancer and a) the LHRH agonist is triptorelin, then the aromatase inhibitor is other than formestane, b) the LHRH agonist is goserelin, then the aromatase inhibitor is other than vorozole or fonnestan, or c) the LHRH agonist is leuprorelin, then the aromatase inhibitor is other than fadrozole.