Enzalutamide/ADT Shows Survival Benefit in mHSPC Cohort Previously Treated With Local Therapy

Neal D. Shore, MD, FACS

Long-term survival benefit was demonstrated with the combination of enzalutamide (Xtandi) and androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC), compared with placebo and ADT, according to post-hoc analysis data from the phase 3 ARCHES study (NCT02677896) presented during the AUA 2022 Annual Meeting.

The post-hoc analysis focused on outcomes of patients who had prior local therapy, defined as previous radical prostatectomy and/or radiation therapy to the prostate area in the adjuvant or salvage settings. A total of 1150 patients with mHSPC were randomized 1:1 in a blinded fashion to receive either combination.

The median duration of treatment with enzalutamide plus ADT was 40.2 months vs 13.8 months with placebo plus ADT. At a median follow-up of 44.6 months, enzalutamide plus ADT achieved a 46% reduction in the risk of death compared with placebo and ADT (HR, 0.54; 95% CI, 0.31-0.94). The survival benefit shown was consistent with prior data, even with substantial crossover from placebo/ADT to enzalutamide/ADT. The median OS was not reached in either arm (HR, 0.56; 95% CI, 0.34-0.92; P =0.02).

Findings from the post-hoc analysis confirm the survival benefit previously observed with enzalutamide plus ADT vs placebo and ADT (HR, 0.66; 95% CI, 0.53-0.81; P <0.0001) during the primary analysis of the ARCHES study, according to Neal D. Shore, MD, FACS.

The post-analysis also showed that prostate-specific antigen (PSA) undetectability and objective response rate were better with the combination of enzalutamide and ADT vs ADT monotherapy, irrespective of prior local therapy. The PSA undetectable rate was 84.5% with enzalutamide vs 45.4% without among those who received prior local therapy. In comparison, those with no prior local therapy had a PSA undetectable rate of 67.5% with enzalutamide/ADT vs 10.6% with placebo/ADT.

In terms of ORR, 72.4% of patients with prior local therapy treated with enzalutamide/ADT responded to treatment compared with 59.2% of the placebo/ADT arm. Among those who did not receive prior local therapy, the ORR was 83.2% with enzalutamide/ADT vs 61.4% with placebo/ADT

In an interview with Targeted Oncology™, Shore, the US chief medical officer of Surgery and Oncology at GenesisCare and the director and certified principal investigator at the Carolina Urologic Research Center, discussed the use of enzalutamide plus ADT in mHSPC and how post-hoc findings from the ARCHES study can be applied to practice.

TARGETED ONCOLOGY: What was demonstrated in the primary analysis of the ARCHES study?

Shore: The first analysis of ARCHES demonstrated that we met the primary end point of radiographic progression-free survival [rPFS], which had a highly statistically significant P value. Essentially, the study design was looking at patients who had both low and high volume, metastatic castration-sensitive prostate cancer being randomized to receive traditional androgen deprivation therapy with a placebo vs the treatment arm which was androgen deprivation therapy, and enzalutamide 160 milligrams, which is FDA approved in nmCRPC and all aspects of mCRPC.

Why was it important to look at overall survival in the prior local therapy or radiation subgroup?

After we met the primary end point of rPFS, a secondary end point of overall survival [OS] was also very nicely met and previously published and demonstrated. For the analysis presented at AUA, we looked at a subset analysis of the patients who would have had prior radical prostatectomy or radiation to the primary or even both. What we found in that population, many would fall under the category of oligoprogressive disease, or they may have had a high volume progressive disease. Additionally, patients with mHSPC also did exceptionally well with the combination of ADT and enzalutamide vs conventional monotherapy ADT.

I think this is important for urology, radiation oncology, and medical oncology colleagues to recognize the absolute importance of combination therapy now for the mHSPC population of ADT and enzalutamide, and not to hold on to the traditional monotherapy ADT. That’s what our data demonstrated in this subpopulation.

Can you describe the baseline characteristics of the patients who were included in the post-hoc analysis?

The patients are not surprising. They tend to be of a younger age group than our castration-resistant patients. They tend to be more in their mid to late 60s. These patients had on average, grade group 3 and higher 4 and 5. Some of the patients had received a prior ADT. It was not dissimilar to what we would see in a real-world analysis. I think the subsequent analysis of this population is further corroborating confirming to the overall findings that we had in the entirety of the ARCHES trial.

What else is important about the results of this post-hoc analysis?

I think the most important thing to highlight is that if you have patients who have either de novo mHSPC, or recurrent mHSPC, whether they've had an active treatment for the primary, the prostate, whether it was a searchable extra patient or radiation, or both, regardless, when they go on to develop metastatic disease, the patients did remarkably better from an rPFS and OS standpoint, for those who received combination ADT and enzalutamide vs monotherapy ADT.

How can these additional findings be applied?

I think the most important thing that we do today, in addition to having a multidisciplinary team evaluate patients who have advanced disease, is to make sure that we as healthcare providers are very articulately discussing with our patients and their caregivers, all their options so that they can achieve what we oftentimes described as the optimal shared decision-making choice. If we can do that, then patients won't have regret if they don't have the best outcomes that they can get. We're now at a point in time, particularly with our mHSPC patients that they require 2 therapies and more vigilant monitoring.

_REFERENCE:

_{Shore NE, Iguchi T, Villers A, et al. Overall survival in patients with metastatic hormone-sensitive prostate cancer treated with enzalutamide or placebo plus androgen deprivation therapy who had prior local therapy: post hoc analysis of the phase 3 ARCHES trial. J Urol. 2022;207(5):e455. doi: 10.1097/JU.0000000000002570.14}