Addressing Fertility Concerns for Female Patients With Sarcoma

While issues with fertility remain adverse effects for many cancer drugs, there is limited research focusing on these impacts. However, the phase 3 DeFi study (NCT03785964) investigated the effects of nirogacestat (Ogsiveo) on female fertility.

The study found that women receiving the drug were more likely to experience ovarian dysfunction compared with those on a placebo. This dysfunction showed in hormone levels and menstrual irregularities. However, the ovarian toxicity appeared to be temporary and most cases resolved, especially among patients who stopped taking the drug. Additionally, a high number of patients experienced resolution of ovarian toxicity while still on the drug.

On the larger scale, the study highlights the importance of monitoring ovarian function during cancer treatment, emphasizing the need for a standardized approach to assess fertility risks associated with cancer drugs.

“One of the most important things when we are clinically interacting with patients is, first and foremost, to understand what their goals are, and then you have to honor that preference, ideally, by getting them to a fertility expert if they actually do want to preserve or protect their fertility,” said Elizabeth Loggers, MD, PhD, who presented findings from DeFi at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.

There are limitations to this study, such as timing of hormone tests and lack of detailed menstrual data. However, it provides valuable insights and supports the use of both clinical observations and hormone testing to evaluate a drug’s impact on fertility.

In an interview with Targeted Oncology^TM, Loggers, associate professor in the clinical research division at Fred Hutch Cancer Center, discussed the study and its implications for clinicians and patients.

Elizabeth Loggers, MD, PhD

Targeted Oncology: What were the goals of this analysis?

Loggers: The goal of this abstract was to highlight the importance of measuring ovarian toxicity and clinical trials consistent with ASCO 2023 Research Statement and to use the DeFi phase 3, randomized, controlled trial as an exemplar of how that can be done and the lessons we can learn from that process.

What was the rationale behind this study?

There are approximately 1.4 million females under the age of 45who will be diagnosed with cancer annually. Here in the United States, there are approximately 45,000 fertile females. This topic is important because the incidence of early onset cancers is increasing in our fertile populations. Our treatments are getting better, and so [patients]are going to live longer, and ovarian toxicity is going to be more important. Investigators need to start paying more attention to this, and we need to do a better job collecting data.

ASCO had 3 primary recommendations. The first was to include measures of ovarian toxicity in all clinical trials. They recommend doing that at baseline and at 12 to 24 months after completion of the trial and to include both clinical measures like menstrual diaries as well as hormonal measures like anti-Müllerian hormone and other things that help us assess the toxicity. I think it is important that clinical trialists begin to incorporate these measures in the early design of their studies to ensure that this is done in an efficient and an effective way, so that we can use that information when we are counseling patients in the future.

Can you summarize your findings?

One of the ways that we tried to demonstrate the importance of this was by focusing on the results from the DeFi study, which was a phase 3 study of nirogacestat, which is an oral gamma secretase inhibitor used in desmoid tumors. Over the course of that trial, we learned that ovarian toxicity was a safety signal, and therefore, needed to do more in-depth study of toxicity and its resolution.In that study, we saw that 75% of females of reproductive potential experienced ovarian toxicity. We learned through this process of measuring ovarian toxicity and assessing its resolution that 78% of those women were going to have the resolution of that toxicity, and of those, 100% would resolve once they stopped the treatment for any reason. Then, 71% had resolution of their ovarian toxicity still on treatment. It is an interesting story, and it teaches us to be more consistent in the way that we measure ovarian toxicity.

What would be your takeaways for clinicians?

For clinicians who are treating with nirogacestat, I think the important take-home message is that this is a temporary effect, and it is probably a class effect of gamma secretase inhibitors in general. However, every cancer treatment is going to have its own [adverse] effect profile with respect to fertility. One of the most important things when we are clinically interacting with patients is, first and foremost, to understand what their goals are, and then you have to honor that preference, ideally, by getting them to a fertility expert if they actually do want to preserve or protect their fertility.

What would you say to patients regarding these fertility concerns?

For patients, I think the most important message is talk to your doctor [and]focus in on this topic with them because we have good research that suggests that oncologists may not be discussing this with their patients and that only a small proportion, probably 25% or less, of fertile populations are actually having fertility consults and preservation before they begin or cancer treatment. After you start treatment, you may already have some lasting effects on your fertility. It is important to have that conversation upfront and to act if it is important to you.

REFERENCE:

Loggers ET, Chugh R, Hartner LP, et al. Monitoring ovarian function in oncology studies: Results and insights from the DeFi phase 3 study of nirogacestat in desmoid tumor. J Clin Oncol. 2024;42(suppl 17): 11520. doi:10.1200/JCO.2024.42.16_suppl.11520