Link Between PSA Response and Survival Outcomes Supports Use of Darolutamide Plus ADT/Docetaxel as a SOC in mHSPC

The improvement in undetectable prostate-specific antigen (PSA) responses achieved with the addition of darolutamide (Nubeqa) to docetaxel and androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) enrolled in the phase 3 ARASENS trial (NCT02799602) provides a clear objective for future research in this space, according to Fred Saad, MD, FRCS.¹

Previously reported data from the ARASENS trial showed that darolutamide plus docetaxel and ADT elicited a 32.0% reduction in the risk of death vs docetaxel, ADT, and placebo (HR, 0.68; 95% CI, 0.57-0.80; P < .0001) for patients with mHSPC. Additionally, treatment-related adverse effects (TRAEs) were comparable between both groups. These data led to the FDA approval of darolutamide plus docetaxel and ADT for patients with mHSPC in August 2022.²

A post-hoc analysis of the trial was conducted to evaluate the influence of undetectable PSA (defined as <0.2 ng/mL) on overall survival (OS) and time to PSA progression. According to a presentation at the2023 American Urological Association (AUA) Annual Meeting, undetectable PSA responses were significantly higher with darolutamide, at 48.7% and 57.1% at weeks 24 and 36, respectively, vs 23.9% and 25.1% with placebo. In patients who achieved undetectable PSA with the triplet, the risk of death was reduced by 53% (HR, 0.47; 95% CI, 0.35-0.63) and 63% (HR, 0.37; 95% CI, 0.28-0.49) at these respective time points vs patients who did not. This suggests a correlation between undetectable PSA and improved OS with the triplet.¹

“[This regimen] opens the door both in terms of [improving] prognosis and possibly [changing] the way we should start planning future clinical trials,” said Saad, who is head of Urology at the University of Montreal Hospital Center (CHUM), principal scientist at CHUM Research Center (CRCHUM), and the director of prostate cancer research at Montreal Cancer Institute/CRCHUM, Montreal, Quebec, Canada. “[With the triplet], you [can] get these responses within 6 to 9 months, so you know where [the field is] going.”

In an interview with OncLive^®, Saad, who is also a full professor in the Department of Surgery and the Raymond Garneau Chair in Prostate Cancer at the University of Montreal, expanded on the relationship between PSA responses and OS in the ARASENS trial, explained the use of 0.2 ng/mL as a standard cut off for undetectable PSA within this exploratory analysis, and discussed how this study elucidates future directions for research with triplet regimens in mHSPC.

OncLive: Could you provide some background on the ARASENS trial and describe what was examined in this post-hoc analysis?

Saad: ARASENS is a phase 3 study that looked at whether we can improve on one of the standards of care [in mHSPC], which was ADT plus docetaxel. At the time we started the study, that was the newest, best [option] we could offer patients, especially [those] with higher volume disease. The study included patients that we felt needed chemotherapy and were capable of tolerating chemotherapy. We randomized patients to get ADT and docetaxel compared with ADT, docetaxel plus darolutamide. We already reported that we had a 32% reduction in the risk of death overall [with the triplet]. Then we looked at PSA responses, [specifically] PSA50 [and PSA90].

What data from this analysis of PSA response were presented at the 2023 AUA Annual Meeting?

[The rates of both] 50% decline and 90% decline [in PSA] were significantly better [with the experimental regimen] across the board. The most important PSA response in mHSPC is getting to undetectable PSA, [which is] below 0.2 ng/mL. Here, we more than doubled the likelihood of [achieving] that in patients that got the triplet therapy compared with ADT and docetaxel. [Accordingly] we almost tripled the undetectable PSA response rate [with the experimental regimen]. We’ve always known that [achieving undetectable PSA] leads to better outcomes. In this study, we saw that it significantly prolonged time to resistance, but more importantly, it significantly prolonged OS. We had an over 60% reduction in the risk of death in those that achieved a PSA [level of] 0.2 ng/mL or less compared with those who did not.

Based on these findings, where do you believe that future research efforts should be focused within mHSPC?

The next wave of research [should address] what [to] do with the patients that we can’t get to 0.2 ng/mL. Should we further intensify [therapy for these patients]? On the other hand, [this study] opens the door to patients who have superb responses that are durable. Should we start thinking of pulling back on the hormonally-based therapies [in this population]? [That] would be much appreciated by our patients, [who] would rather not be castrated for the rest of their lives.

Although a PSA level less than 0.2 ng/mL is generally accepted as a measure of undetectable PSA, some clinicians feel that this seems to be an arbitrary cut off. Could you address this point and elaborate on why this cut off was chosen?

[A PSA of] 0.2 ng/mL is the cut off we’ve given ourselves for advanced prostate cancer. In the [phase 3] EMBARK trial [NCT02319837], they also use 0.2 [ng/mL as the cut off]. When we do a radical prostatectomy, we want to be 0.02 [ng/mL], which we would consider the undetectable rate. [However], 0.2 ng/mL has always been our cut off [for] saying that somebody’s recurred. We have to remember that in advanced prostate cancer, many patients haven’t had their prostates removed. We’ve looked at those kinds of analyses in other studies, and the results are comparable whether we [use] 0.2 ng/mL or 0.02 ng/mL. We’ve used that 0.2 [ng/mL] level for all the castration-resistant trials and the metastatic trials, [so] I don’t think we’re going to change that very soon. I think it’s reasonable to keep [using] 0.2 ng/mL as a goal to achieve.

What other studies were you looking forward to seeing the results from at this year’s meeting?

The study that we were all impressed to hear about was EMBARK. This is going in the same [direction as our study]. Intensification in patients that are at high risk of becoming metastatic or dying [from] prostate cancer has become our new goal. I wrote an editorial in Lancet [stating that] if patients are destined to suffer or die from prostate cancer, we have to do the very best we can up front. I might be pushing the limit, but I think that ADT alone in patients who really need it is going out the door. If [a patient] needs ADT, you probably need to do it as optimally as possible. If [they] don’t need it, you’re probably better off leaving the patient alone and intervening adequately and aggressively [only] when they actually need it.

References

1. Saad F, Tombal B, Hussain M, et al. Rapid, durable, and deep prostate-specific antigen response following addition of darolutamide to androgen-deprivation therapy and docetaxel in ARASENS. J Urol. 2023;209(4):e380. doi:10.1097/JU.0000000000003257.01
2. FDA approves darolutamide tablets for metastatic hormone-sensitive prostate cancer. News. FDA. August 5, 2022. Accessed April 10, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide-tablets-metastatic-hormone-sensitive-prostate-cancer