Fertility preservation may need to be a future consideration for young women being treated with the PARP inhibitor olaparib according to Australian researchers who found it disrupts primordial follicle oocyte maintenance and survival in an animal model.
Because direct measures of primordial follicle numbers is not possible in women, the findings have important implications for the future management of young women with breast cancer, say developmental biologists at Monash University, Melbourne.
The study, led by a team from the Ovarian Biology Laboratory at Monash, investigated the effect of olaparib compared to saline, either alone or in combination with chemotherapy, on the ovaries in mice.
Following treatment, follicle enumeration and immunohistochemical analysis of primordial follicle remnants, DNA damage, and analysis of apoptosis were measured in the harvested ovaries.
The study found that olaparib alone significantly depleted primordial follicles by 36% compared to the controls (p<0.05) but did not impact the growing follicle populations.
Olaparib did not affect serum anti-Müllerian hormone (AMH) concentrations, corpora lutea number or oestrous cycling compared to the controls but did lead to a significant accumulation of primordial follicle remnants.
DNA damage was undetectable in controls, but evident in approximately 10% of surviving primordial follicles in olaparib treated ovaries.
When used after agents including cyclophosphamide, doxorubicin or carboplatin, olaparib did not enhance chemotherapy-mediated primordial follicle depletion.
“This is possibly attributed to the severe follicle depletion observed, even in response to a single dose of each chemotherapy, making it difficult to detect any additive effects of the combined treatment, and this is the subject of ongoing investigation,” the study authors said.
They also found that the extent of follicle depletion might be enhanced in BRCA1 and BRCA2 mutation carriers.
Lead author Dr Amy Winship told the limbic that even though the effect of olaparib on fertility was not as severe as chemotherapy, it was still significant.
“Olaparib is killing the growth arrested primordial stockpiles of oocytes which is the most alarming type of ovarian damage because if it was killing ones that had already been activated and growing, new ones could just become activated. Because olaparib is killing the stockpile, that’s what would cause premature infertility and premature menopause.”
She said fertility was commonly overlooked as a safety issue in pre-clinical and clinical studies of new cancer drugs.
Co-author Professor Kelly-Anne Phillips, a medical oncologist at the Peter MacCallum Cancer Centre, said in a statement that olaparib was currently approved only for use in women with metastatic breast cancer for whom fertility preservation was not appropriate.
“However, in future olaparib and similar drugs may be approved for use in young women, with the intention of curing them of the disease, and for these women fertility preservation is an important consideration.”
“Therefore, it is very important to understand its effects on ovarian function and we encourage researchers to consider measuring ovarian function and fertility in future clinical trials so that we have data from humans to support or refute the findings of our study in mice.”
AstraZeneca declined to provide a specific comment on the research which was published in Human Reproduction.
“AstraZeneca is committed to ensuring the safety and efficacy of our medicines for patients. The safety profile of each AstraZeneca product is continuously monitored, and the product information is updated when new safety issues are identified,” a company spokesperson said.