Novartis Breast Cancer drug Kisqali wins market approval in European Union as first-line treatment for HR+/HER2-

European Medicines Agency (EMA) panel approves Kisqali (CDK4/6 inhibitor ribociclib) in combination with hormone therapy as a first-line treatment for hormone receptor positive, human epidermal growth factor receptor-2 negative locally advanced or metastatic breast cancer.

FDA has already cleared Kisqali in March 2017.

This approval challenges the market share of rival, Pfizer's Ibrance which is in market since 2015.

Kisqali is sold in US packaged with aromatase inhibitor letrozole but, the Committee for Medicinal Products for Human Use (CHMP) recommends combining Kisqali with any aromatase inhibitor like letrozole, anastrozole or exemestane, giving the physician the discretion to select the therapy they believe is most appropriate for each individual patient.

This approval is based on results of a pivotal Phase III  MONALEESA-2 trial that showed Kisqali plus letrozole reduced risk of disease progression or death by 44% over letrozole alone among postmenopausal women with HR+/HER2- advanced breast cancer.

After nearly one year of additional follow-up, Kisqali plus letrozole demonstrated median progression-free survival (PFS) of 25.3 months compared to 16.0 months for placebo in combination with letrozole.

Bruno Strigini, CEO, Novartis Oncology said, "This positive CHMP opinion brings us one step closer to improving the lives of women diagnosed with advanced or metastatic breast cancer throughout Europe. There is currently no cure for advanced breast cancer, and approximately 30 percent of those affected by early-stage breast cancer will go on to develop advanced disease.”

Current options for ovulation induction in Polycystic Ovarian Syndrome (PCOS).

Image courtesy: pcosdatabase.org

Polycystic Ovarian Syndrome (PCOS) affects 1 in 10 women of childbearing age and have important metabolic and reproductive repercussion.[1] The treatment approach varies per the age of the patient, desire for pregnancy and the presenting symptoms.  

Approximately 80% of women who suffer from anovulatory infertility have PCOS. The treatment approaches towards ovulation induction varies per efficacy, patient BMI and other associated metabolic abnormalities.

A recent paper published in the December issue of Human Reproduction Update summarizes the evidence based recommendations for the management of anovulatoryinfertility in PCOS patients.[2] 

The evidence will form the basis for WHO to develop global guidelines. Management includes lifestyle changes, pharmacotherapy, bariatric surgery and laparoscopic surgery.

Lifestyle management, weight loss and exercise is recommended as the first line of treatment to improve general health and decrease insulin resistance. Morbidly obsess women should seek expert advice. At present, there is no evidence supporting the role of bariatric surgery in PCOS associated infertility. [3]

courtesy: iconfinder.com

Clomiphene citrate is recommended as primary agent to bring about ovulation. It is simple, inexpensive and induces ovulation in 75% of the patients.[4] Letrozole, an aromatase inhibitor is fast catching on clomiphene citrate as first place option.[5]

Metformin alone is not very effective in improving the live birth rates. It is added to clomiphene citrate regimen in older women with visceral obesity.  

Gonadotrophins and laparoscopic ovarian drilling are reserved as second line of treatment in patients who do not respond to lifestyle modification and oral therapies. Gonadotropin releasing hormone (GnRH) antagonist protocol is safe and combined with IVF. When GnRH agonist is the choice for treatment, metformin should be used as an adjunct to reduce the risk of ovarian hyperstimulation syndrome(OHSS).

Laparoscopic ovarian drilling is specifically used when there are other indications for laparoscopic surgery. It should not be used as first line of treatment. Concerns about long term effect of drilling on ovarian functions are still unanswered. [6]

IVF can be of use in those patients who do not respond to lifestyle modifications and oral ovulation induction drugs. It is specifically useful in those patients who also have additional causes for infertility.

No evidence supported the use of acupuncture or herbal remedies in ovulation induction. 

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[1] https://www.womenshealth.gov/publications/our-publications/fact-sheet/polycystic-ovary-syndrome.html

[2] https://humupd.oxfordjournals.org/content/22/6/687.abstract

[3] https://www.ncbi.nlm.nih.gov/pubmed/27965894

[4] https://www.ncbi.nlm.nih.gov/pubmed/27151490

[5] https://www.ncbi.nlm.nih.gov/pubmed/27866938

[6] https://www.ncbi.nlm.nih.gov/pubmed/22696324

ACOG updates the recommendations for use of aromatase inhibitors in gynecology practice.

Aroma-tase is a microsomal cytochrome P450 hemoprotein-containing enzyme with a wide expression in different kind of tissues like ovary, testes, endometrium, brain, breast, placenta, skin, bone, and fat. In these tissues it mediates the conversion of androstenedione to estrone and the conversion of testosterone to estradiol in situ. 

Therefore, for tissues which express this enzyme it creates a hyperestrogenic state leading to proliferation of the tissue.

Based on these varied effects aromatase inhibitors are used in treatment of breast cancer, ovulation induction, endometriosis, and other estrogen-modulated conditions.

Currently three aromatase inhibitors are commercially available. Out of which Exemestane is a steroid-derived aromatase inhibitor that binds irreversibly to aromatase and permanently inactivates the available enzyme while Letrozole and anastrozole are reversible inhibitors of aromatase competing with androgens for aromatase binding sites.

The American College of Obstetricians and Gynecologists supports the following recommendations and conclusions: They were published in June issue of Journal of obstetrics and gynecology.

• For women with breast cancer, bone mineral density screening is recommended with long-term aromatase inhibitor use because of risk of osteoporosis due to estrogen deficiency.
• Based on long-term adverse effects and safety data, when compared with tamoxifen, aromatase inhibitors are associated with a reduced incidence of thrombosis, endometrial cancer, and vaginal bleeding.
• For women with polycystic ovary syndrome and a body mass index (BMI) greater than 30, letrozole should be considered as first-line therapy for ovulation induction because of the increased live birth rate compared with clomiphene citrate. Lifestyle changes that result in weight loss should be strongly encouraged.
• For women with unexplained infertility (regular menstrual cycles, all known male or female factors excluded), a large multicenter study demonstrated that ovulation induction with letrozole resulted in lower live birth rates and multiple gestation rates compared with gonadotropins; however, live birth and multiple gestation rates did not differ significantly between ovulation induction with letrozole compared with clomiphene citrate.
• Aromatase inhibitors are a promising therapeutic option that may help manage endometriosis-associated pain in combination therapy with progestins.

References:

http://journals.lww.com/greenjournal/Fulltext/2016/06000/Committee_Opinion_No__663_Summary___Aromatase.38.aspx#

http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Gynecologic-Practice/Aromatase-Inhibitors-in-Gynecologic-Practice