Enzalutamide vs. Kalutamide: Who can bring more benefits to patients with nmCRPC?

Editor's note In recent years, the incidence of prostate cancer has ranked second among all malignant tumors in men worldwide
.

At the same time, compared with European and American countries, the vast majority of prostate cancer patients in China are locally advanced or extensively metastatic at the time of diagnosis, and cannot receive local radical treatment, and the prognosis is poor
.

In 2016, the Prostate Cancer Collaborative Group (PCWG) formally proposed the concept of non-metastatic castration-resistant prostate cancer (nmCRPC)
.

nmCRPC, also known as biochemical recurrence (BCR), specifically refers to the fact that only the prostate-specific antigen (PSA) continues to rise while maintaining the castrated state in clinical practice, and has not yet been confirmed by traditional imaging (bone scan, CT, MRI, etc.
) Of prostate cancer patients with distant metastases
.

At present, the treatment of nmCRPC has entered the era of new endocrine drug therapy.
PROSPER research shows that enzalutamide can significantly prolong the time for patients to undergo metastasis and bring patients a longer survival period
.

Compared with the first-generation anti-androgen drug bicalutamide, what are the advantages of enzalutamide? Here, the editor compiled the latest results of the nmCRPC subgroup of the STRIVE study, which will be published in the journal Prostate Cancer and Prostatic Diseases under NATURE in October 2021
.

STRIVE trial: A comparative study of the efficacy of enzalutamide and bicalutamide in the treatment of nmCRPC.
Introduction STRIVE trial 1 is a randomized, double-blind, phase II study.
A total of 139 patients with nmCRPC or mCRPC were enrolled and randomly divided into two groups.
Receive 160 mg/day enzalutamide combined with androgen deprivation therapy (ADT; n=70), or receive 50 mg/day bicalutamide combined with ADT (n=69)
.

The primary endpoint of this subgroup analysis of nmCRPC is progression-free survival (PFS), and secondary endpoints include time to PSA progression (TTPP) and imaging progression-free survival (rPFS)
.

The results of the study showed that in the nmCRPC subgroup, compared with the bicalutamide group, the median treatment time of patients treated with enzalutamide was significantly longer (17.
8 months vs 12.
3 months)
.

The results of a median follow-up of 17 months showed that compared with the bicalutamide group, enzalutamide significantly reduced the risk of progression or death of nmCRPC patients by 76% (HR=0.
24; 95% CI: 0.
14-0.
42; P<0.
0001) And 82% risk of PSA progression (HR=0.
18; 95%CI: 0.
10-0.
34; P<0.
0001)
.

Enzalutamide has the same benefits for PFS and rPFS in all subgroups, including age, Eastern Cooperative Oncology Group (ECOG) status, Gleason score, and baseline PSA level
.

In patients with PSA doubling time (PSADT) <10 months and ≥10 months, the time to PSA progression in the enzalutamide group had the same benefit
.

In patients with PSADT <10 months, compared with the bicalutamide group, the proportion of PSA progression in the enzalutamide group was lower (19.
4% vs 76.
0%, HR=0.
156; 95%CI: 0.
080-0.
301; P< 0.
0001)
.

At the same time, in the PSADT subgroup, the enzalutamide group had a higher remission rate than the Bicalutamide group with a PSA drop of ≥50% from the baseline
.

In the enzalutamide group, the remission rates of PSADT <10 months and ≥10 months were 89.
7% and 100%, respectively; the remission rates of the bicalutamide group were 38.
0% and 66.
7%, respectively
.

Figure 1 Results of the STRIVE study This subgroup analysis of nmCRPC shows that compared with bicalutamide, enzalutamide has an advantage in reducing the risk of progression or death in nmCRPC patients
.

So, why can enzalutamide bring greater benefits to patients with nmCRPC? This stems from the unique mechanism of action of enzalutamide
.

Comparison of mechanism of action Prostate cancer is an androgen receptor (AR) dependent tumor, and enzalutamide can target three key stages of the AR signaling pathway (Figure 2) 2,3: Figure 2 Enzalu Amine potently inhibits the AR signaling pathway.
Enzalutamide and AR strongly bind: A preclinical competitive assay tested the relative AR binding affinity of enzalutamide, bicalutamide and a control ligand (FDHT).
The results showed that the relative affinity of enzalutamide to AR in a preclinical castration-resistant prostate cancer (CRPC) model was 5-8 times that of bicalutamide (Figure 3)
.

Figure 3 The AR binding relative affinity of enzalutamide and bicalutamide.
Enzalutamide effectively inhibits AR nuclear translocation: trials have shown that bicalutamide allows AR nuclear translocation in the preclinical CRPC model, while enzalut Amine can inhibit AR nuclear translocation (Figure 4) and play a more powerful anti-tumor effect
.

Figure 4 Comparison of bicalutamide and enzalutamide on AR nuclear translocation.
Enzalutamide affects the binding of AR and DNA: In cell lines overexpressing AR, enzalutamide affects the binding of AR to DNA And activation, bicalutamide stimulates AR binding to DNA (Figure 5) 3,4
.

Figure 5 The activity of enzalutamide can be seen from this.
Compared with bicalutamide, enzalutamide has a unique mechanism of action and a stronger anti-tumor effect
.

To sum up, whether it is the results of the recent STRIVE trial study or the mechanism of action, we can find that nmCRPC patients benefit more after receiving enzalutamide + ADT treatment
.

Therefore, in the clinical treatment process, for patients who have not yet experienced metastasis, enzalutamide + ADT can be considered as a priority treatment, which can effectively prolong the progression-free survival of the patient, improve the quality of life of the patient, and extend the life of the patient
.

References: 1.
David F Penson,Andrew J Armstrong,et al.
Enzalutamide versus bicalutamide in patients with nonmetastatic castration-resistant prostate cancer: a prespecified subgroup analysis of the STRIVE trial.
Prostate Cancer Prostatic Dis.
2021 Oct 7.
2.
Hu R, et al.
Expert Rev Endocrinol Metab 2010;5:753–64.
3.
Tran C, et al.
Science 2009;324:787–90.
4.
Chen Y, et al.
Lancet Oncol 2009;10:981–91.