Assessing the efficacy of enzalutamide plus ADT in oligometastatic prostate cancer

Immunotherapies are becoming increasingly popular as a form of treatment for patients with prostate cancer. Even more so are combination therapies.

Andrew J. Armstrong, MD

At the recent 2021 Society of Urologic Oncology Annual Meeting, Andrew J. Armstrong, MD, MSc, presented the promising finding of the study, “The efficacy of enzalutamide (Enza) plus androgen deprivation therapy (ADT) on oligometastatic hormone-sensitive prostate cancer: extended post hoc analysis of ARCHES.”^1-2 Armstrong is a profession or medicine, surgery, and pharmacology and cancer biology at Duke University and a member of the Duke Cancer in Durham, North Carolina.

Please discuss the background for this study.

ARCHES was designed as a global, randomized trial to test the efficacy of enzalutamide[, or enza,] in men with metastatic hormone-sensitive disease.² When we designed ARCHES, it was many years ago, when the only standard of care that had improved survival beyond [androgen deprivation therapy, or ADT,] was docetaxel. So, this was a global study that permitted men with both high- and low-volume disease, high-risk [or] low-risk prior local therapy or de novo metastatic disease, and allowed [patients to be treated with] prior docetaxel. [It] was a randomized study of enza/ADT vs ADT alone to see if enzalutamide could extend the amount of time a man had without disease progression or death. The study has previously been published and presented and [it] was a positive study [that] led to the FDA approval and global regulatory approvals of enzalutamide in this hormone sensitive setting.

What were some of the notable findings? Were any of them surprising to you or your co-authors?

This particular poster is an exploratory retrospective subset analysis, asking the question of whether enzalutamide plus ADT extended survival and delayed progression in men with a smaller amount of metastatic disease. We use the term oligometastatic disease, defined as a few number of metastatic sites (5 or less), and focused here on patients with bone metastases. We counted the number of bone metastases on standard conventional bone scans and looked at the relative efficacy of enzalutamide over ADT and the long-term outcomes of these patients in terms of progression-free and overall survival. The good news for patients is that the survival and radiographic progression-free survival was substantially improved in all subsets, even down to patients that just had a solitary metastasis. So, regardless of whether there was 1, 2, 3, 4, 5 (oligometastatic), or 6 or more (polymetastatic disease), enzalutamide had substantial benefits in delaying progression and improving survival.

How do these data build on previous findings from ARCHES?

ARCHES reported an improvement in radiographic progression-free survival when we published the original data.³ At [the European Society for Medical Oncology Virtual Congress] this past year, I presented updated survival data that demonstrates that enzalutamide also significantly improved long term overall survival. This poster is the first look at that extended follow-up survival data but in a subset of patients that hadn't been previously reported, based on the amount of metastatic disease. We looked at other secondary end points, like time to castration resistance, time to next therapies, [and] PSA remissions which were all substantially improved with the addition of enzalutamide to ADT. You can see really profound, undetectable PSA rates that are much higher in patients with the low-volume disease. The message for patients is that even if there's a small amount of metastatic disease on bone scan, there's a benefit from these potent AR inhibitors. Our data suggests that we shouldn't just be relying on ADT or metastasis-directed therapy alone as the benefits of these approaches are only short term. These men really have level 1 evidence suggesting systemic therapy with a potent AR inhibitor and ADT improves survival and is now based on level 1 evidence, and that we should be studying metastasis-directed therapy layered on top of that to further extend remissions and benefits to our patients. Perhaps for patients who obtain a complete remission with ADT/AR inhibition plus metastasis directed and primary prostate radiation, these men could eventually stop their systemic therapy, but this needs to be prospectively evaluated.

Is further research on this topic planned, and if so, what will its focus be?

The STAMPEDE study in the United Kingdom is studying that metastasis-directed therapy layered on top of the best systemic therapy,⁴ where the goal for men is to really get off these drugs eventually, see if we can actually cure some metastatic prostate cancer, and see if durable remissions can be obtained without long-term therapy, or maybe even with intermittent periods of therapy. We're still not there yet as we know that many men with oligometastatic disease on conventional imaging have actually polymetastatic disease on more sensitive PET imaging and thus would not likely be cured with metastasis directed therapy alone. Most patients still will develop metastatic progression over time and hormone-resistant prostate cancer, but adding on metastasis-directed therapy to these low-volume patients may extend their lives further. That's the subject of a number of randomized controlled studies and adding PET imaging such as PSMA PET imaging along with PET-directed therapy could further extend benefits.

What is the take-home message for the practicing urologist?

We know from practice patterns in urology practices around the United States that many men, even with metastatic disease, are just receiving ADT alone and not receiving these potent AR inhibitors or docetaxel. They're just receiving ADT alone, which is really inferior care long term. While some men can have durable benefits with ADT alone, as yet we don’t have a biomarker that can select patients who do not need more intensified therapy, as even the low risk/low volume men are living longer with more potent AR blockade. Men can live longer, they can have delays in their progression, including symptomatic progression with combination approaches, and it really should not be a standard of care to withhold these potent therapies in addition to ADT at this point unless there are specific circumstances related to frailty, life expectancy, or comorbidity that may increase the risks of this more intensive approach.

Is there anything else you feel our audience should know about the research?

We looked at safety according to polymetastatic vs oligometastatic disease and treatment with enza/ADT vs ADT alone. Of course, with efficacy and long term and more potent hormonal therapy there's always some increased risk. Enzalutamide does have long-term toxicities. It's really important if you're treating patients for many years with these therapies to pay particular attention to diet, to lifestyle, to exercise, to cardiovascular risk reduction, blood pressure monitoring. Fatigue, bone loss, fracture risks can accumulate with longer term use. These drugs are very safe, but they can carry a burden on patients because of the long-term hormonal side effects. Exercise, attention to bone density monitoring, and cardiovascular risk reduction is really critical for survivorship.

References

1. Armstrong AJ, Holzbeierlein J, Iguchi T, et al. The efficacy of enzalutamide (enza) plus androgen deprivation therapy (ADT) on oligometastatic hormone-sensitive prostate cancer: extended post hoc analysis of ARCHES. Paper presented at: 2021 Society of Urologic Oncology Annual Meeting; December 1-3, 2021; Orlando, Florida. Poster #62

2. Armstrong AJ, Iguchi T, Azad AA, et al. Final overall survival (OS) analysis from ARCHES: A phase III, randomized, double-blind, placebo (PBO)- controlled study of enzalutamide (ENZA) + androgen deprivation therapy (ADT) in men with metastatic hormone-sensitive prostate cancer (mHSPC). Annal Oncol. 2021;32(5):S1283-S1346. doi: 10.1016/annonc/annonc741

3. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: A randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. Journal of Clinical Oncology; 37, no. 32 (November 10, 2019) 2974-2986. doi: 10.1200/JCO.19.00799

4. National Institutes of Health US National Library of Medicine ClinicalTrials.gov. Systemic therapy in advancing or metastatic prostate cancer: Evaluation of grud efficacy (STAMPEDE). Updated November 13, 2020. Accessed December 23, 2021. https://clinicaltrials.gov/ct2/show/NCT00268476