Armstrong Highlights Outcomes of Final Survival Analysis of Enzalutamide Plus ADT in mHSPC

The androgen-receptor (AR) inhibitor enzalutamide (Xtandi) may represent a powerful new treatment option for patients with metastatic hormone-sensitive prostate cancer (mHSPC).

In an updated analysis of the phase 3 ARCHES trial (NCT02677896) investigators noted that enzalutamide when added to androgen deprivation therapy (ADT) elicited significant survival benefits among patients with mHSPC. Enzalutamide plus ADT was effective across nearly every patient subgroup examined and reduced the risk of radiographic progression or death by approximately 37% (HR, 0.63; 95% CI, 0.52-0.76). Data from the study showed that the combination was also well tolerated, and no new safety signals were identified.¹

“At least half of patients with metastatic prostate cancer are still being under treated,” Andrew J. Armstrong, MD, said. “It is important to either refer your patient to an academic or specialized center where this [treatment] can be offered to extend their lives or familiarize yourself with these data so you can intelligently prescribe and safely monitor patients during this treatment. The great thing about enzalutamide is it does not require steroids. It is not immune suppressive and is very well tolerated for long periods of time with appropriate safety monitoring.”

In an interview with OncologyLive®, Armstrong, a professor of medicine, professor in surgery, and a professor in pharmacology and cancer biology at the Duke Cancer Institute in Durham, North Carolina, discussed the updated results and the clinical implications of the final survival analysis of the ARCHES trial, which he coauthored.

What was the clinical rationale for initiating the ARCHES trial?

ARCHES was designed in an era when the standard of care for men with mHSPC was ADT. There was emerging data that docetaxel also extended survival. The goal of the ARCHES trial was to test whether a more potent androgen receptor blocker, enzalutamide, could delay the risk of death or progression in these men who either present with metastatic disease or who develop metastatic disease after they have had a radical prostatectomy or radiation and then suffer recurrence.

ARCHES included men who were suitable for [treatment with] ADT and we allowed prior docetaxel. This was the one of the first studies to test that subgroup; [however,] many men do not receive docetaxel or refused chemotherapy. A large part of the ARCHES population were men who chose ADT alone and were randomized to enzalutamide at 160 mg [once daily] continuously until progression.

The primary analysis for ARCHES was published approximately 3 years ago and the more recent update is the final overall survival results, which we were happy to see were positive.

What were the highlights of the final survival data in ARCHES?

I was pleasantly surprised to see that enzalutamide-treated men lived substantially longer [with a] a hazard ratio of 0.66; that is highly statistically significant and clinically significant.

That was seen despite crossover of 30% to 40% of men who were treated with placebo. Even before they [experienced disease] progression, they were offered enzalutamide. When patients’ [disease] did progress, there were commercially availabile drugs [such as] enzalutamide in the castrate-resistant setting, or abiraterone [Zytiga], which is very similar enzalutamide. The life-prolonging benefit of early AR inhibition was seen, despite the common later use of the same drug.

This shows that early use is better before disease resistance sets in. This is really changing the paradigm of how we treat [patients with] prostate cancer. We are using these more potent therapies earlier, where you get greater efficacy [compared with] waiting for castration-resistant progression, when there’s still efficacy and a survival benefit but it is more modest and not as durable.

Please discuss what was observed in the updated data across key secondary end points.

Secondary end points measured clinical efficacy, [such as] radiographic progression-free survival, skeletal events, quality of life, PSA [prostate-specific antigen] progression, delaying castration resistance, and delaying the time to next therapy. All of these [end points] were positive in ARCHES, both at the primary analysis and in this final updated analysis.

In our Journal of Clinical Oncology paper, [both] in the supplement and in the primary manuscript, data are presented [for the] overall [population] and accounting for the crossover effects. When patients cross over that is great for them, but it makes it harder to see the treatment effects. You can actually see [among] the [patients who received] placebo there’s a blunting of their curve because they can be rescued when they start getting enzalutamide.

If you do statistical modeling around those patients where you sensor at crossover, you see a much greater treatment effect with enzalutamide than you do when patients are crossed over, which makes sense. You can really see the rescuing effect and what the hazard ratios might have looked like had we not crossed over patients. But it was ethical to cross over patients, it was the right thing to do, because allowing patients to die without potent AR-inhibitor [therapy] is the wrong thing to do.

Survival benefit was seen across all patient subgroups in the ARCHES trial, except in those with soft tissue localization at baseline—why do you think this could be, and will that affect your use of enzalutamide in this population?

There are 2 groups of patients with soft tissue metastases: men with lymph node only metastases and the group with visceral metastases. These are relatively small subgroups in ARCHES, so they are very underpowered.

Most of the men in ARCHES had bone metastases with lymph node metastases. A small subset, less than 20%, had visceral metastases. We saw significant benefits in those patients with bone and lymph node metastases, but we did not see clear survival benefits in the visceral subgroup, [which were mostly] liver metastases. These patients are characterized as having high volume disease and a very poor prognosis, particularly when prostate cancer spreads into the liver.

Docetaxel and ADT is now offered to these patients, and we are now moving toward triplet therapy for these patients. That approach is what I would recommend for these patients who have a poor prognosis when treated with ADT alone. They [also] have a poor prognosis when treated with doublet therapy with ADT and an AR inhibitor. [There have been] very consistent poor effects with ADT and an AR inhibitor across different trials, including ARCHES.

When in the treatment course should enzalutamide be used in patients with mHSPC vs other agents such as docetaxel, abiraterone, and apalutamide [Erleada]?

When you see a patient with metastatic prostate cancer who is untreated the first step is to start ADT [therapy], either with a GnRH [gonadotropin-releasing hormone] agonist or antagonist and think about treatment intensification. The vast majority of patients need treatment intensification to live longer [and] patients can tolerate this very well and it improves life expectancy. There are only maybe 10% of patients who are too elderly, frail, or who have too many comorbidities to justify treatment intensification.

For those men with high-volume, high-risk disease, particularly de novo metastatic disease, I would consider triplet therapy in patients who are fit for chemotherapy. That was included in [the eligibility criteria for] ARCHES, but it is relevant for many other trials now.

Most patients [have] low-volume disease. If their [disease] is de novo, I would certainly consider a potent AR inhibitor, such as enzalutamide, apalutamide, or abiraterone, based on level 1 evidence. ARCHES is one of those trials that was very positive. I also consider treating the primary prostate tumor with radiation to also prolong survival if they have de novo disease.

If they have relapsed disease, there is also a [noted] substantial delay in progression and improvement in survival. Most patients should be offered a potent AR inhibitor where it is affordable and available. In the United States, that is the vast majority of patients.

Most patients should start this [treatment] within 3 months of starting their ADT. In ARCHES, that is how it was done. Within 3 months of starting ADT, they were randomized, unless they started docetaxel [plus] ADT and then it was within 6 months. It is important to think about it early, and not to delay that treatment intensification.

What should clinicians be aware of when prescribing enzalutamide plus ADT in terms of safety?

Survivorship issues are very important because men are now going to be living a lot longer. We have many more men living 5-plus years. Because of that treatment intensification, they can experience more toxicities, particularly in respect to muscle health, bone health, cardiovascular risk, metabolic risks, and fragility.

[It is important to] encourage exercise monitoring, bone density monitoring, [monitoring of] blood pressure, and other cardiovascular risk factors [such as] hyperlipidemia and diabetes screens. Also, encouraging fitness, taking calcium and vitamin D [supplements], and using bone-antiresorptive therapies to prevent fracture and osteoporosis. If [a patient] develops osteopenia or osteoporosis on bone density testing, [this is] really important. We do see a minority of patients develop cognitive problems. There are patients who do benefit from a dose reduction if they are having trouble with their concentration or because of fatigue.

What does the future hold for enzalutamide?

The ARCHES trial has now formed the backbone for new phase 3 studies. It is no longer ethical to do a placebo-controlled trial with ADT alone because we have level 1 evidence that ADT plus a potent AR inhibitor extends life.

There are some men who still desire to avoid hormonal therapy. There are some trials that are testing for example, metastasis-directed therapies without a potent AR inhibitor, but that is more experimental. We should also be testing metastasis-directed therapies with our best systemic therapies to try to eradicate low-volume or oligometastatic disease. [Investigators of] the STAMPEDE trial [NCT00268476] is now testing that [adding metastasis-directed therapies to standard of care] in a new treatment arm that is [enrolling patients with] up to 5 metastatic lesions in addition to the primary [tumor].

We are also evaluating the value of immunotherapies. Lutetium Lu 177 vipivotide tetraxetan [Pluvicto] is being tested in earlier settings [such as] this hormone-sensitive setting, being layered on top of drugs [such as] ADT and enzalutamide. There are other molecularly stratified [ongoing trials] in hormone-sensitive [disease accounting for factors such as] PTEN loss using an ATP inhibitor.

The number of trials is expanding rapidly based on these successes. There are also parallel AR inhibitors that are emerging, [such as] darolutamide [Nubeqa], apalutamide, abiraterone. Looking at different combinations, triplet therapy, and doublet therapy is the way things are moving.

Reference

1. Armstrong AJ, Azad AA, Iguchi T, et al. Improved survival with enzalutamide in patients with metastatic hormone-sensitive prostate cancer. J Clin Oncol. Published online April 14, 2022. doi:10.1200/JCO.22.00193