Hormone therapy for prostate cancer (PCa) started to change in a big way a decade or so ago when abiraterone (=Zytiga) came on the market. That change accelerated when second generation anti-androgens—i.e., enzalutamide (=Xtandi), apalutamide (=Erleada), and darolutamide (=Nubeqa)—also became available to treat PCa. Those four drugs, plus similar compounds in development, are collectively known as androgen-receptor targeted agents (ARTAs) or androgen-receptor signaling inhibitors (ARSI) [and by a few other names as well].
In the last few years there has been a wave of PCa clinical trials involving not just standard ADT, but ADT in combination with various ARTAs. These combinations of treatments are known as hormonal intensification. Adding an ARTA to ADT as a double therapy has been shown to improve survival in certain populations of PCa patients. Those include men with metastatic disease, which can’t be controlled by standard ADT alone; i.e., men with metastatic, castrate resistant PCa (often abbreviated mCRPC).
If that combination doesn’t control the cancer, these men typically progress to chemotherapy. Often their PSA is rising rapidly after localized treatment, such as a radical prostatectomy or brachytherapy. Imaging may confirm metastatic spread of their disease. ADT plus chemotherapy is also an established form of double therapy, which has been shown to provide some disease control for men with a high disease burden (i.e., who are symptomatic). But recent trials have shown that for some of these patients adding an ARTA helps even more. The combination of these three treatments is one form of triple therapy.
In addition, there are yet newer drugs, such as PARP inhibitors and radioligand PSMA agents, under investigation in combination with the treatments mentioned above. As such, we envision even more treatment protocols becoming available as hormonal intensification, and these are likely to include triple, or perhaps even quadruple therapies.
That gets to the key question here: What should a patient on ADT, experiencing a rise of PSA indicative of biochemical progression, make of the many new treatment options arising from all these trials? Is more treatment indeed better treatment?
While we think this research is encouraging, there are a handful of issues that patients who are experiencing a rising PSA after localized treatments, should be aware of.
Here are a few:
Because abiraterone blocks testosterone production, not just from the testes but from the adrenal glands, treatment with abiraterone is sometimes called “androgen annihilation.” That label emphasizes its dramatic capability to suppress testosterone production.
Unfortunately, abiraterone suppresses not only testosterone production from the adrenal glands, but also glucocorticoid production. The predominant glucocorticoid is cortisol; a steroid produced by the adrenal glands with a vast array of functions in the body. These functions include processing sugars, controlling inflammation, and regulating the salt concentrations in the body that influence fluid balance and the risk of cardiovascular disease. As such, if one is taking abiraterone, they need to take it along with a synthetic steroid, such as prednisone, to correct for the loss of cortisol caused by abiraterone. Every patient on abiraterone needs that steroid replacement, plus regular blood tests to assure that the dosages of the two drugs are precisely right for them. In general, the health of patients on ARTAs combined with standard ADT needs to be monitored even more rigorously than those on ADT alone. This is particularly true when prednisone or similar drugs are added in for they are associated with their own additional side effects.
Not all the trials that found a benefit for double and triple therapies have had the same outcome. One might assume that the endpoint for any trial for advanced cancer patients would be overall survival (OS). However, clinical trials that use this outcome as their end point, usually need to run a decade or so to get enough data to know, for sure if the new treatment is truly better than the old treatment.
Thus, researchers often use surrogate outcomes that can capture useful data earlier. These include evidence of disease progression (i.e., progression free survivor; PFS) or signs of progression on radiographic scans (i.e., radiographic progression-free survival, rPFS). In some trials, new treatments have shown better PFS, yet in the long run haven’t shown an advantage in OS. Patients need to be aware of what the outcomes are for any trial they might enter, or the rationale for any double or triple therapy protocol they might elect to go on to treat their cancer. A drug combination may slow disease progression, which can be reassuring in the short-term. However, that doesn’t necessarily translate to prolonged life or better quality of life in the long term.
Increasingly oncologists are recommending double and triple therapies for patients, with rising PSA after localized PCa treatment. A potential and not uncommon drawback, when patients go on hormonal intensification treatments, is they are at risk of more intense side effects. This is an unavoidable reality of cancer treatments that involve multiple drugs; i.e., the more effective the combination, the more diverse and/or intense the side effects are likely to be.
The side effects that are most likely to be intensified with double and triple therapies vary with the ARTA used. Whatever the side effects, hormonal intensification does not make managing ADT side effects any easier.
There is increased use of PSMA diagnostic PET scans that can find metastases long before they become symptomatic. As more patients get PSMA PET scans, more will be considered candidates for double and triple therapies. With research increasingly suggesting that many PCa patients will benefit from combining ARTAs with ADT, we can expect more PCa patients to be offered hormonal intensification…and be on those treatments for a longer time. Again, earlier attention to managing ADT side effects will become that much more important.
With all new drug combinations that get approved for clinical use, there is a chance that some rare, but serious side effects will come to light only after the treatments is used by many more patients than in the trials. This is an inevitable trade off in making promising cancer treatments available as soon as their benefits are documented.
What we learn about novel treatments after the clinical trials are over is called “real world data.” And real world data are starting to come in for double and triple PCa treatments. Real world studies, for example, show that patients on ADT combined with some ARTAs versus others, are slightly more likely to fall and fracture a bone. Therefore, maintaining bone strength is increasingly important.
If a person has any signs of conditions that may be exacerbated by ADT—for example, heart disease, problems with memory, osteoporosis, or diabetes—alone or by the drugs combined with it, those specific risks needs to be taken into consideration when considering hormonal intensification. It is not yet possible to say, for example, that a combination of A+B+C is better than just A+B or A+C for every patient.
This gets into the realm of personalized medicine. The overall health of each patient has to be individually assessed and monitored for any patients considering any double or triple PCa therapies.
The bottom line—
If you are likely to be offered a hormonal therapy that combines ADT with other agents, such as ARTAs, this may indeed offer some benefits such as slowing down disease progression. However, only time will tell if this will impact overall survival.
To better manage the probable increase in side effect burden accompanying hormonal intensification, it is increasingly important to pre-emptively take up a lifestyle that keeps you as fit as possible in advance of going on the therapy. With hormonal intensification, it becomes more important than ever patients do what they can to manage ADT side effects as early as possible. We have been campaigning for years for patients on ADT to do everything they can to maintain good health—particularly cardiovascular health—when starting ADT. With more patients starting on double and triple therapy with ADT, ARTAs, and chemotherapy, management of side effects is more critical than ever.
References:
Note—this is a sample. The literature from just the last year examining double and triple therapies is enormous. As such, we will not attempt now (or in the future) to review each individual trial involving ADT and ARTAs.
De Giorgi U, Hussain H, Shore N et al. Consistent survival benefit of enzalutamide plus androgen deprivation therapy in men with nonmetastatic castration-resistant prostate cancer: PROSPER subgroup analysis by age and region. Eur. J. Cancer 159, 237–246 (2021).
Hussain A, Jiang S, Varghese D, Appukkuttan S, Kebede N, Gnanasakthy K, Macahilig C, Waldeck R, Corman S. Real-world burden of adverse events for apalutamide- or enzalutamide-treated non-metastatic castration-resistant prostate cancer patients in the United States. BMC Cancer. 2022 Mar 22;22(1):304. doi: 10.1186/s12885-022-09364-z. PMID: 35317768; PMCID: PMC8939229.
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Kostos L, Murphy DG, Azad AA. Double or Triple Trouble in Metastatic Hormone-sensitive Prostate Cancer? Eur Urol Oncol. 2022 Oct;5(5):503-504. doi: 10.1016/j.euo.2022.07.001.
Jazayeri, S. B., Cooley, L. F., Srivastava, A., & Shore, N. (2022). Hormonal Intensification Should Start at the Low-risk Stage in Metastatic Prostate Cancer. European urology open science, 45, 38–40. https://doi.org/10.1016/j.euros.2022.05.015
Wang, E. C., Lee, W. R., & Armstrong, A. J. (2022). Second generation anti-androgens and androgen deprivation therapy with radiation therapy in the definitive management of high-risk prostate cancer. Prostate cancer and prostatic diseases, 10.1038/s41391-022-00598-3. Advance online publication. https://doi.org/10.1038/s41391-022-00598-3
Loguidice, C. T. (2022) Novel AR-Targeted Therapies for Metastatic Hormone-Sensitive Prostate Cancer: Which One to Choose. https://www.onclive.com/view/novel-ar-targeted-therapies-for-metastatic-hormone-sensitive-prostate-cancer-which-one-to-choose