The Role of Goserelin and LHRH Antagonists in Prostate Cancer

Tanya B. Dorff, MD

With the high incidence rate of prostate cancer among men across the world, continuous advancements and new therapeutic strategies are always needed in the space. However, older luteinizing hormone-releasing hormone (LHRH) agents like goserelin (Zoladex) continue to play an important role when treating this patient population, according to Tanya B. Dorff, MD.

Goserelin is an LHRH agonist used in the treatment of prostate cancer. The choice of goserelin or other LHRH agonists, like leuprolide or triptorelin (Trelstar), for the treatment of patients with prostate cancer depends on a variety of factors, including curative settings, salvage radiation, intermittent use in recurring cancer, for metastatic disease and more. The decision often varies among physicians, based on their different practice patterns and comfort levels.

With the introduction of LHRH antagonists, the landscape of prostate cancer therapy options has evolved, and allowed clinicians a number of options to use when tailoring treatment plans to individual patient needs.

As for the future of goserelin, LHRH antagonists may lead to increased adoption due to advantages in their depth of testosterone suppression. However, agents like goserelin will likely maintain their role in prostate cancer treatment, given their historical use and established efficacy.

“There will always be a role for these drugs like goserelin. There is a long history, lots of studies in various settings across prostate cancer using this, and perhaps now that we're in the era of of doublets with these very potent anti androgen receptor pathway inhibitors, maybe the depth of testosterone suppression won't be quite as important when we're layering on doublet and triplet therapy,” Dorff, a medical oncologist, section chief of Genitourinary Disease Program, and professor in the Department of Medical Oncology & Therapeutics Research at City of Hope, told Targeted Oncology^TM in an interview.

prostate cancer under the microscope: © heitipaves - stock.adobe.com

In the interview, Dorff discussed the role of goserelin in the ever-changing treatment landscape for patients with prostate cancer.

Targeted Oncology: What is the mechanism of action of goserelin?

Dorff: Goserelin is 1 of our luteinizing hormone-releasing hormone agonists, so it's an LHRH agonist. It induces chemical castration by initially stimulating the pituitary gonadal axis, which results in secretion of a surge of testosterone that then downregulates stimulation of the axis, and eventually, the testicular production of testosterone will shut down.

When would you choose this therapy for the treatment of prostate cancer?

We have a number of different LHRH agonists and we also now have antagonists that have been added into the mix, so there's a wide variety of choices. There's sort of not 1 right answer. I think different physicians might have a different practice pattern or different comfort level, but these drugs generally are used across a broad variety of indications for prostate cancer. They're used in the curative setting when we use definitive radiation. They're used in the biochemically recurrent setting together with salvage radiation, they're used intermittently beyond that when cancer recurs again, and for metastatic disease. A lot of patients with prostate cancer are going to receive 1 of these agents. Again, there's not 1 strong driving factor that might lead us to choose goserelin vs leuprolide or triptorelin. I think the bigger question is now with the antagonists and when those might be chosen.

Can you explain some of the US-based research in prostate cancer that's focused on this agent?

There hasn't been a lot that's new. Going back a while, SWOG ran a study with the question of adding an androgen receptor antagonist on top of an LHRH agonist, like goserelin, in order to address that sort of testosterone flare, and maybe the incomplete testosterone suppression that we see with these agents. That did show some advantage. That's 1 of the seminal studies of this class of drugs. Then there have been studies of intermittent vs continuous use of these agents, although nowadays, we're using not only continuous, but doublet and sometimes triplet therapy in the metastatic setting.

One of the most interesting pieces of research that came out recently, not specific for goserelin, but I'm sure some of the patients in the study got goserelin and others probably got leuprolide or triptorelin [Trelstar], was a presentation of data looking at large randomized trials of radiation with adjunctive hormone therapy, showing that a significant proportion of patients never recover their testosterone after they stop. Also, the longer the duration of using these medical castration agents, the less likely it was that testosterone would recover.

That was 1 of the most important new pieces of data with these types of agents that I think physicians need to be aware about because when we're telling our patient they are going to be on this treatment for 6 months, or 18 months, or 2 years, there's now this tale of well, your testosterone won't recover immediately. It'll feel like you're still on this drug for a bit longer and giving patients more accurate expectations about when testosterone may recover after the use of 1 of these depot formulations of these drugs and if it will recover. This is important now that we've seen these eye opening data.

What is the potential future use for goserelin considering the introduction of novel drugs?

There's been a slow adoption of the LHRH antagonists, in part because the first drug in that class, degarelix [Firmagon] requires monthly injection, whereas drugs like goserelin and leuprolide have these nice 3 month, and sometimes even 6 month formulations, which are much more convenient for patients. They also tend to hurt less. Despite the fact that this new class of drugs, these LHRH antagonists, were introduced predominantly, people were still continuing to use agonists like goserelin and leuprolide. Now with the availability of the oral agent, relugolix [Orgovyx], we may see more adoption of LHRH antagonists since they do have some advantage in terms of rapidity of testosterone suppression, depth of testosterone suppression, as well as rapidity of reversal.

There will always be a role for these drugs like goserelin. There is a long history, lots of studies in various settings across prostate cancer using this, and perhaps now that we're in the era of of doublets with these very potent anti androgen receptor pathway inhibitors, maybe the depth of testosterone suppression won't be quite as important when we're layering on doublet and triplet therapy. We still need more information, but it's likely that these drugs will continue to be used.

Are there any next steps for assessing this agent in prostate cancer?

It's probably being utilized in a lot of the big cooperative group studies. Some of the exciting studies that are happening for instance, in NRG, are looking at treatment intensification or deintensification using decipher to select patients and put them into risk buckets, with high-risk going into an intensification study, and low-risk going into the deintensification study. Trying to optimize how we use drugs, how long we're doing castration therapy, and how intensely, is exciting, because we've been doing a one-size-fits-all [approach]. Every patient with prostate cancer who we put into a category gets treated the same way. Now, trying to personalize it and incorporating genomic prognostic information is an exciting direction that the field is taking.

What do you expect to see for the prostate cancer field in the next year or so?

There are a number of important frontiers in the prostate cancer field. A lot of it's happening in metastatic castration-sensitive prostate cancer where we're studying a lot of novel agents and anticipating that their benefits will be amplified as they're moved earlier into the disease state, which is a trend we've seen over the last 7 or 8 years. There are also novel types of therapies being studied.

One of the major overarching hopes is that eventually we'll get a treatment or a combination of treatments that induce significant remission and that would allow patients to come off of their castration therapy that stops these medications that we currently give lifelong to patients with metastatic prostate cancer. Novel immunotherapies, novel radioligand therapies are these 2 big frontiers that are leading the charge in the hope that we could induce durable remissions and reduce the amount of drugs like goserelin that we use for patients over their lifetime.

REFERENCE:

Hormone therapy for prostate cancer. News release. City of Hope. Updated August 17, 2023. Accessed September 27, 2023. https://tinyurl.com/25uec26u