Continuous Enzalutamide/Docetaxel May Represent Future Option for Select mCRPC Who Progress on Enzalutamide Alone

The continuation of treatment with enzalutamide (Xtandi) plus docetaxel and prednisolone improved progression-free survival (PFS) vs placebo plus chemotherapy in patients with chemotherapy-naïve, metastatic castration-resistant prostate cancer (mCRPC), according to Axel S. Merseburger, MD, who added that these data address key questions about therapy intensification and sequencing in this population.¹

Data from the phase 3b PRESIDE trial (NCT02288247), which were presented during the 2022 Genitourinary Cancers Symposium, showed that the enzalutamide combination arm resulted in a median PFS of 9.53 months (95% CI, 8.25-10.87) vs 8.28 months (95% CI, 6.28-8.71) with placebo/chemotherapy (HR, 0.72; 95% CI, 0.53-0.96; P = .027).

Enzalutamide also significantly reduce the risk of prostate-specific antigen (PSA) progression vs placebo, at 8.44 months (95% CI, 8.18-9.00) vs 6.24 months (95% CI, 5.42-8.31), respectively (HR, 0.58; 95% CI, 0.41-0.82; P = .002). Moreover, enzalutamide plus docetaxel and prednisolone elicited an objective response rate (ORR) of 31.6% (95% CI, 23.9%-40.1%) vs 25.9% (95% CI, 18.8%-34.2%) with docetaxel plus prednisolone.

“We learned that it is safe to combine enzalutamide with docetaxel; [this is in line with what] we have [seen] in other indications such as metastatic hormone-sensitive prostate cancer [mHSPC],” Merseburger said. “For mCRPC, this [approach] resulted in a statistically significant and clinically meaningful PFS benefit. [These are] exciting times for advanced prostate cancer [treatment], and [we are] heading toward [the exploration of more] combinations and hitting [the disease] earlier.”

In an interview with, OncLive®, Merseburger, chairman at the Clinic of Urology at the University Hospital Schleswig-Holstein, Lübeck, Germany, further discussed the safety and efficacy results from the phase 3b PRESIDE trial examining continued enzalutamide treatment with docetaxel in select patients with mCRPC who had progressed on enzalutamide monotherapy and the significance of the data for the treatment paradigm.

OncLive^®: What were the key objectives of the PRESIDE trial?

Merseburger: The randomized, double-blinded, placebo-controlled, phase 3b PRESIDE study [evaluated] enzalutamide, which is a potent androgen receptor inhibitor that is approved [for use] in [those with] advanced prostate cancer.

The objective [of the trial] was to compare the efficacy of enzalutamide plus docetaxel and prednisolone [with that of] placebo plus docetaxel and prednisolone in men with chemotherapy-naïve mCRPC who progressed on enzalutamide monotherapy. We hypothesized that the continued administration of enzalutamide would maintain control of the tumor lesions and enable docetaxel to target clonal subpopulations that adopt accessory pathways to enhance survival and proliferation.

Could you expand on the trial design and the methods used?

The trial was designed [to be comprised of] 2 periods. In period 1, [patients] received open-label treatment with enzalutamide. Period 2, [which was] the double-blind phase, [looked at] 2 [treatment] arms: docetaxel plus prednisolone plus or minus enzalutamide. Patients in period 1 received open-label enzalutamide, and then at week 13, all patients were assessed for response by PSA and imaging. Those with a confirmed PSA response continued participation in period 1 until disease progression, and they were then randomized in period 2.

A total of 816 patients were screened in period 1, and 687 [of them] received the treatment. Of those, 392 experienced progressive disease, and 237 met the eligibility criteria [to undergo] randomization in period 2. Overall, 271 men were treated in period 2, which divided into 136 [patients randomized to] enzalutamide plus docetaxel [and prednisolone] and [135 patients] randomized to placebo plus chemotherapy.

The primary end point of the trial was PFS. We also looked at select subgroups. In a post-hoc analysis, we looked at PSA response, time to PSA progression, PSA change [from] baseline to week 13, and importantly, safety.

What were some of the efficacy data reported from this trial?

In those 2 groups, the baseline characteristics were well balanced, as we can expect from a large phase 3 trial. The primary end point of PFS was met, [with a] statistically significant advantage with the combination or the continuous treatment with enzalutamide compared [with] just giving placebo.

Continuation with enzalutamide plus docetaxel and prednisolone demonstrated a statistically significant and clinically meaningful reduction in the risk of [disease] progression [or death] compared [with] placebo plus docetaxel and prednisolone, with a hazard ratio of 0.72 in favor of the enzalutamide combination and a corresponding P value of .027.

What was the safety profile of this approach?

The overall number of treatment-emergent adverse effects [TEAEs] and drug-related TEAEs were comparable between the enzalutamide and the placebo groups. [Compared with what] we know from other trials [that have examined] enzalutamide, [we did not see any] new safety signals. [Safety] is important [to examine] when we [try to] combine drugs in advanced metastatic prostate cancer. We saw that continuation with enzalutamide did not add any toxicity compared [with] placebo/[chemotherapy], and that it resulted in a PFS benefit.

How could these findings potentially change treatment for this population?

This is an important question. Most men start with the novel hormone-targeting agents like apalutamide [Erleada], enzalutamide, and abiraterone acetate [Zytiga]. The PRESIDE trial has answered the question of whether it might make sense in mCRPC situations to continue with the androgen receptor–targeting agents when adding another substance or changing the mode of action in this situation, looking at docetaxel.

[The trial] answers a question on therapy intensification. [Additionally,] the trial showed that the combination is safe, and with regard to sequencing, it is better to [give] a combination up front, [rather] than wait until further progression and then go into third, fourth, and fifth line.

Reference

1. Merseburger AS, Attard G, Boysen G, et al. A randomized, double-blind, placebo (PBO)-controlled, phase 3b study of the efficacy and safety of continuing enzalutamide (ENZA) in chemotherapy-naïve, metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with docetaxel (DOC) plus prednisolone (PDN) who have progressed on ENZA: PRESIDE. J Clin Oncol. 2022;40(suppl 6):15. doi:10.1200/JCO.2022.40.6_suppl.015