Andrew Armstrong, MD, MSc, Discusses Survival Data in mHSPC From ARCHES Trial at 2021 ESMO

Andrew Armstrong, MD, MSc

During the 2021 European Society for Medical Oncology Congress (ESMO), the updated findings from the phase 3 ARCHES trial (NCT02677896) showed that patients with de novo or relapsing metastatic hormone-sensitive prostate cancer (mHSPC) taking enzalutamide (Xtandi) plus androgen deprivation therapy (ADT) saw extended survival compared with those in the placebo plus ADT group.¹

The FDA has previously approved enzalutamide for treating men with metastatic castration-sensitive prostate cancer based previously presented results from the study in 2019.²

In an interview with CancerNetwork^®, Andrew J. Armstrong, MD, MSc, discussed the rationale behind this study, commented on adverse effects, and talked about why it was ethically important to allow crossover to patients in the placebo group. Armstrong, a medical oncologist, and professor of medicine at Duke University, discusses his latest research and how it will positively affect patients in this setting. 

CancerNetwork®: Can you discuss the rationale behind this research?

Armstrong: The motivation many years ago, when we designed the global phase 3 ARCHES trial was to improve outcomes for men who have metastatic prostate cancer and who have not yet been treated with hormonal therapy.² We call that metastatic hormone-sensitive prostate cancer. When men start this journey, from the beginning, we call it de novo disease when the metastatic disease is present at diagnosis [whereas] some men develop metastatic disease after local therapies such as radical prostatectomy or radiation. All these men were included in the ARCHES trial. At the time that we designed ARCHES, the standard of care for men in this setting was androgen deprivation therapy as it has been for 70 years. The data around docetaxel were just emerging. We allowed prior docetaxel on the ARCHES trial which is typically given nowadays for patients [with high-volume disease] based on their bone scan and pattern of spread into visceral organs. These men were permitted on ARCHES. Basically, the idea was to identify these patients and treat them in a randomized way with enzalutamide or a placebo, in addition to the best standard of care to see if this potent AR [androgen receptor] blocker would extend progression-free [survival] and overall survival as compared with the standard of care alone.

What were the study’s key findings?

As presented at ESMO 2 weeks ago, we updated the overall survival results, which is a key secondary endpoint. About 3 years ago, we had presented the radiographic progression-free survival results, which was the primary end point; this was a very positive study. In fact, the data on radiographic progression-free survival was so substantial that the FDA approved enzalutamide in this setting for men with metastatic hormone-sensitive disease, as well as the European Union.³Enzalutamide is a standard of care option that is now used. However, at the time in 2018 when we presented and published our results, we did not have mature survival data. Having data on survival really will add to the clinical benefits that are in treatment decision making these men are faced [with] in this setting. With additional follow-up, 342 patients now have passed away with longer-term follow-up at about 44 months. We see that enzalutamide improved overall survival with a hazard ratio 0.66, which was highly clinically meaningful, and [with] a P value that was less than .0001. That means a 34% delay in the risk of death over time as compared with standard of care alone. This is a great result for our patients. We’re seeing these results despite about 40% of patients [in the placebo group] crossing over as part of the study. We crossed over patients [because] ethically that was the right thing to do for this study; [we needed to] to offer patients who were receiving the placebo access to enzalutamide so they could have benefits from the study too. We’re seeing survival benefits despite many men receiving enzalutamide, and many other life prolonging hormonal and chemotherapies after the study.

Were there any surprising outcomes that you experienced for patients in the crossover group? What about in terms of safety?

It’s important when you’re using an agent for many years. The great news for patients is that there can be some cumulative [adverse] effects that we’re seeing both in the enzalutamide group as well as in the patients initially treated with placebo who moved over to enzalutamide. This therapy, enzalutamide, is very well known globally and it’s been approved for men with castration-resistant prostate cancer.⁴ Worldwide, there’s been a huge experience with this therapy. In this case, we’re using it very early and we’re using it for a very long time and treatment is given continuously until disease progression.

We do see some notable adverse effects such as hypertension, fatigue, and some increased risk of falls and fractures, emphasizing the importance of blood pressure monitoring, exercise, cardiovascular fitness, and attention to bone health. Fortunately, we did not see a strong increased risk of significant cardiovascular disease or seizures. Overall, the drug was well tolerated without any effects on organ function, and without any immune suppression or increased risk of infections and no prednisone required. This is an oral agent that was very well tolerated [with] lots of experience, but with some notable [adverse] effects that are due to the long-term hormonal nature of this therapy.

How can patients with metastatic hormone-sensitive prostate cancer benefit from this research?

The benefit is that we now have many options for these men with metastatic hormone-sensitive prostate cancer. When you’re in the clinic talking to your doctor or if you’re a doctor talking to your patient, you now have a menu of options. Some patients may be most appropriate for ADT plus docetaxel, particularly those with visceral metastases, liver metastases, or high-volume disease. Some patients may be most appropriate for an AR [androgen receptor] therapy such as enzalutamide, apalutamide [Erleada], or abiraterone [Zytiga]. These choices are very similar in their efficacy, but they differ in their [adverse] effects and their costs and their availability worldwide. All of these are very effective at prolonging survival.

There may be some patients [for whom] you might choose triplet therapy, meaning ADT and docetaxel followed by a potent AR inhibitor.

We saw from ESMO that the PEACE-1 study [NCT01957436] found a better survival for high-volume patients treated with that triplet therapy with abiraterone and docetaxel.⁵ In our data, there is a suggestion of improved survival both from ENZAMET trial [NCT02446405] and now ARCHES with enzalutamide following docetaxel. There are options where you’re trying to extend life as long as possible, particularly for those men at highest risk of disease progression, and those with the most aggressive disease features where 3 therapies used sequentially may be the most effective option. In addition, for low-volume patients and those with very few metastases, there may be patients that are benefit from radiation to the primary [tumor] but ADT plus a potent AR inhibitor such as enzalutamide as life-prolonging [therapy] and should be considered the standard of care for those men who are eligible to receive this.

How do you see this research being utilized in the real-world setting?

Having added data on the long-term survival benefits certainly can affect the label and the regulatory approval, which is already there but adding to the benefits [that we can talk about] when patients are facing this decision. Certainly in 2018, there were already benefits, but having data on the long-term life expectancy and prognosis and improved prognosis with enzalutamide is very helpful in making management decisions. Certainly, when we look across the world, many men with metastatic prostate cancer are still receiving just ADT alone, which is really an inferior standard of care based on overall survival in the metastatic setting. We hope that this will really be a call for more intensive therapy for these patients so that they can live longer.

What do you hope your colleagues take away from this research?

Armstrong: Certainly, with ARCHES, TITAN [NCT02489318], LATITUDE [NCT01715285], and STAMPEDE [NCT00268476], we have great news along with [enzalutamide] as well on improving survival and [giving patients] many choices. I think physicians, providers, and researchers will look at this network of clinical trials as being a major advance over the past 5 years that have moved these potent androgen receptor inhibitors as well as chemotherapy into earlier settings where these resistance mutations have not developed, or cross resistance has not yet developed and where the tumor is not as genetically heterogeneous and complicated. We see even better survival advantages when these agents are used earlier. The hope is that these agents may improve cure rates, as we saw at ESMO for the STAMPEDE study, even in the nonmetastatic settings.⁶ We’re seeing clear benefits, for example, with radiation, where the earlier use of these agents can really knock out the cancer and improve survival even before metastatic disease has taken hold. The goal here is to improve survival, maintain quality life, and in some cases, cure the disease in earlier settings.

References

1. 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

2. 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. J Clin Oncol. 2019;37(32):2974-2986. doi:10.1200/JCO.19.00799

3. FDA approves enzalutamide for metastatic castration-sensitive prostate cancer. News Release. FDA. December 16, 2019. Accessed October 6, 2021. https://bit.ly/3iEDR9x

4. FDA approves enzalutamide for castration-resistant prostate cancer. News Release. FDA. July 13, 2018. Accessed October 6, 2021. https://bit.ly/2Yuy7II

5. Fizazi K, Maldonado X, Foulon S, et al. A phase 3 trial with a 2x2 factorial design of abiraterone acetate plus prednisone and/orlocal radiotherapy in men with de novo metastatic castration-sensitive prostate cancer (mCSPC): first results of PEACE-1. Annal Oncol.2021;32(5): S1283-S1346. doi: 10.1016/annonc/annonc741

6. Attard G, Brown LC, Clarke N, et al. Abiraterone acetate plus prednisolone (AAP) with or without enzalutamide (ENZ) added to androgen deprivation therapy (ADT) compared to ADT alone for men with high-risk non-metastatic (MO) prostate cancer (PCa): Combined analysis from two comparisons in the STAMPEDE platform protocol. Annal Oncol. 2021; 32(5): S1283-S1346. doi: 10.1016/annonc/annonc741