ADT Plus Darolutamide Is Associated With Lower Rates of PSA Progression in nmCRPC

Alicia Morgans, MD, MPH

Treatment with the combination of androgen deprivation therapy (ADT) and darolutamide (Nubeqa) led to a decreased risk of prostate-specific antigen (PSA) progression alone or with radiological progression vs ADT plus placebo for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), according to findings from a follow-up analysis of the phase 3 ARAMIS trial (NCT02200614), which were presented at the 2024 ASCO Annual Meeting by Alicia Morgans, MD, MPH.

The rate of PSA progression alone was lower in the darolutamide arm (n = 905) vs the placebo arm (n = 515), at 7.8% vs 35.9%, as was the rate of both PSA and radiological progression (darolutamide arm, 5.4%; placebo arm, 21.4%). Additionally, in the darolutamide arm, patients who achieved PSA levels of less than 0.2 ng/mL had a lower risk of radiological progression vs those with PSA levels greater than or equal to 0.2 ng/mL, with respective 24-month progression rates of 8.7% and 33%.¹

In an interview with OncLive^®, Morgans explainedthat“patients who were treated with darolutamide [had a] deep response, and they had a 50-fold higher chance of getting that deep response, which is important from a clinical perspective. We want to make sure we get the most benefit for our patients.”

Morgans is a genitourinary medical oncologist and the medical director of the Survivorship Program at Dana-Farber Cancer Institute, as well as an associate professor of medicine at Harvard Medical School in Boston, Massachusetts.

OncLive: What data have been previously reported from the ARAMIS trial?

Morgans: ARAMIS was a phase 3 international registration trial that evaluated patients who had nmCRPC. [These patients] were all receiving ADT and had rising PSA levels despite that, but they had no radiographic evidence of metastatic disease on conventional CT scans and bone scans. [Patients also] had to have high-risk nmCRPC, [defined as] a short PSA doubling time of 10 months or less. In the original [readout of the] ARAMIS trial, the addition of darolutamide to ADT was superior [to ADT alone] in terms of metastasis-free survival [MFS], with a 22-month MFS improvement. There was also an improvement in overall survival, and this led to the FDA approval of darolutamide in the nmCRPC setting.

What was the rationale for combining ADT with darolutamide?

In this analysis, we used the data that were already gathered within the ARAMIS trial to try to pull [together] more information to understand and prognosticate so when we see patients in clinic, we might have a better sense of what to anticipate for each. [First, we observed] the way patients progressed on different treatments to try to understand whether patients who had intensified therapy with the addition of darolutamide may have cancer progression that was different, or perhaps more difficult to detect, than patients who had standard treatment with ADT plus placebo. We also aimed to determine whether a PSA of an undetectable level by an international standard [< 0.2 ng/mL] was [associated with] longer disease control than a PSA that met or exceeded that undetectable level [≥ 0.2 ng/mL].

What were the key findings observed in this study?

When we evaluated the ways patients [exhibited] disease progression, we found that there was a [cohort] of patients who progressed with radiographic progression before PSA progression, [which] warned us that [PSA progression] was going to happen. [The rates of radiographic progression were] 4.2% in patients who were treated with ADT plus darolutamide and 5.0% among patients who were treated with ADT plus placebo.

In general, we always have the concern that if we intensify treatment, particularly regarding the [hormonal activity pathway], we might push more patients to have more aggressive disease that behaves more like a neuroendocrine phenotype and develop radiographic progression before PSA progression. We did not see this, and that was important. Numerically, there was a lower percentage of patients who progressed radiographically in the darolutamide arm vs the placebo arm.

It was important that we didn’t see a divergence in the way that patients had progression of disease. However, since we saw that some patients progressed on scans before they had PSA progression, we need to think about a temporal interval of repeating scans to make sure we catch patients who are having progression of disease before they develop clinical symptoms. It is possible they could have this progression before the PSA warns us, and patients who have clinical progression by pain in any state are always going to have more difficult outcomes than patients whose disease is caught a little earlier. [Conducting] routine scans, whether they’re every 6 months or every year, is going to be important in clinical practice.

In the analysis of whether patients reached the international standard of PSA levels of less than 0.2 ng/mL, more patients who were treated with darolutamide achieved a PSA level less than 0.2 ng/mL [than those who received placebo]. Intensifying therapy and having that additional, effective disease control allowed more patients to achieve that [undetectable PSA] level, which was important.

Additionally, patients [in the darolutamide arm] who achieved a PSA level of less than 0.2 ng/mL had an extremely low rate of metastasis over the course of follow-up, such that by 36 months, that rate was only 8.7%. For patients who had suboptimal responses, [meaning their] PSA levels did not reach or fall below 0.2 ng/mL, the rate of progression or metastasis at 36 months was 50%. This showed a dichotomy in clinical behavior among patients who have a deep response and patients who do not achieve a deep response.

What are the potential clinical implications of these findings?

We need to consider the use of temporally based scanning algorithms. [Rather than relying solely on] a low PSA level to [decide to] monitor a patient who shows no symptoms during treatment, [it may be beneficial to schedule scans for] that patient every 6 to 12 months, even if they have nmCRPC, to ensure they do not have evidence of cancer progression, despite their PSA levels not progressing.

[Another important aspect for clinicians to consider] is that when patients don’t achieve that deep PSA response of less than or equal to 0.2 ng/mL, we probably need to watch them a little more closely, because they have, by 3 years, a 50% chance of developing metastatic disease. From a clinical perspective, [ADT plus darolutamide] is an approved combination [for patients with nmCRPC], and it can increase the number of patients who achieve that deep response and have cancer control. Therefore, we want to try to use these treatments when they’re available and when patients fit the algorithm that would allow them to be treated [with this approach].

What future questions remain based on these findings?

There were patients who did not achieve that deep PSA response, and this is a population that is in need of clinical trial development and potentially enhanced therapeutic direction. This is supposed to be a patient population that has relatively indolent disease. However, at 3 years, these patients [are at high risk of] developing metastatic disease, and we can identify patients who are at the highest risk by their PSA response to this treatment. As we’re designing clinical trials, we need to maybe carve out this population as one that might be in need of additional treatment and might benefit from targeted therapies that might augment their response against that cancer and enhance cancer control.

How do these findings and implications extend to community practice?

In the community, we should be aware that PSA is not always going to tell us when [progression is] happening in patients, and we need to think about conducting scans for patients at least every 6 to 12 months, even when they have nmCRPC. Additionally, in clinical practice, we need to recognize that patients who don’t achieve the deep PSA response of less than 0.2 ng/mL will have a higher rate of recurrence; we need to watch those patients especially closely.

Based on these findings, could the frequency of conventional imaging for disease progression be reassessed?

[Currently], there isn’t necessarily an imaging standard that has been [established] for patients with nmCRPC. In this study, the scans were conducted every 16 weeks, and still 4.2% to 5.0% of patients had progression on scans before they had progression on PSA. It seems impractical for every patient to be scanned every 16 weeks, however, some interval should be designated to keep an eye on patients and make sure we’re identifying when they have progression of disease before they develop symptoms. Development of symptoms such as increased pain is associated with a poorer prognosis and shorter survival.

Reference

Morgans AK, Sweeney C, Wallis CJD, et al. Association between prostate-specific antigen (PSA) level <0.2 ng/mL and risk of radiological progression in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC): follow-up analysis of ARAMIS. J Clin Oncol. 2024;42(suppl 16):5022. doi:10.1200/JCO.2024.42.16_suppl.5022