Safety and tolerability of relugolix in combination with abiraterone or apalutamide for treatment of advanced prostate cancer: Data from a 52-week clinical trial.
Authors: De La Cerda Jose , Belkoff Laurence , Courtney Kevin Dale , Diamond Elan , D'Olimpio James Thomas , Dunshee Curtis , Gervasi Lawrence , Goodman Michael Moses , Mittal Kriti , Morris David , Sieber Paul R , Tutrone Ronald , Ryan Michael , Zhong Yi , Ufer Mike , Shore Neal D. 
Published: February 2025

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Background:
Relugolix (REL) is the only oral androgen deprivation therapy (ADT) indicated for advanced prostate cancer (aPC). Combining ADT with androgen receptor signaling inhibitors (ARSIs) has shown improved clinical outcomes in hormone-sensitive and castration-resistant PC. This study evaluated the safety and tolerability of REL with the ARSIs abiraterone (ABI) or apalutamide (APA).
Methods:
In this open-label, two-part study, patients (pts) with aPC, including ADT-experienced, were treated for 52 weeks (wks). In Part 1, pts received REL 120 mg qd + ABI 1000 mg qd + either prednisone 5 mg qd or bid or methylprednisolone 4 mg bid. In Part 2, pts received REL 240 mg qd + APA 240 mg qd. Pts with metastatic castration-sensitive PC were eligible for Part 1 & 2. Castration-resistant pts were eligible for Part 1 with metastatic and for Part 2 with non-metastatic PC. The primary objective was to assess safety and tolerability. Testosterone (baseline, wk 2, 4, 12) and PSA (baseline, wk 12) levels were also evaluated. REL, APA, and N-desmethyl APA concentrations were determined at baseline, wks 2, 4, 8, and 12 in Part 2. REL adherence was measured by pill count.
Results:
Twenty-four pts were enrolled in each part, with 21 and 20 completing Part 1 & 2, respectively. Most pts were white with a mean age of 71 and 69 years in Part 1 & 2, respectively. Mean REL treatment adherence was > 97% in the study. The majority of reported adverse events (AEs) were mild (grade 1 or 2) in Part 1 & 2. The most commonly reported AE was hypertension in Part 1 and rash in Part 2. No relevant post-treatment changes in laboratory, ECG, or vital sign parameters were noted. Mean testosterone levels were maintained below castration level (50 ng/mL) through the 12-wk treatment. Mean (SD) and median PSA levels were 28.1 (127.1) and 0.04 ng/mL (1 pt with 611 ng/mL) in Part 1 and 0.2 (0.3) and 0.04 in Part 2 at wk 12, respectively. REL, APA, and N-desmethyl APA concentrations were stable over 12 wks indicating steady-state conditions.
Conclusions:
REL used in combination with ABI or APA showed safety profiles consistent with individual drugs over 52 wks. REL levels were stable, and testosterone was sustained below castration level. These findings support the safety and tolerability of REL combination therapy with ABI or APA for aPC. Clinical trial information:
NCT04666129
.

Part 1 (N=24)
Part 2 (N=24)

Age
1
(years), mean (SD)

71 ± 7
69 ± 7

Race
1
, White, n (%)

19 (79)
16 (67)

Adherence
2
, mean (SD)

98.5% (3.2)
97.8% (8.0)

Any TEAE, n (%)
22 (91.7)
21 (87.5)

Most common TEAE
2
, n (%)

Hypertension, 6 (25.0)
Rash 5 (20.8)

Any Serious TEAE
2
, n (%)

3 (12.5)
1 (4.2)

Testosterone
3
(ng/dL), mean (SD)

2.9 (6.9)
15.3 (12.4)

Relugolix
4
(ng/dL), mean (SD)

-
10.9 (10.7)/11.1 (9.7)

Apalutamide; N-desmethyl apalutamide
4
(ng/dL), mean (SD)

-
4088.3 (1046.8)/3666.4 (1154.0);4767.4 (1133.3)/4717.5 (1362.7)

1
Baseline;
2
Week 52;
3
Week 12;
4
Weeks 2/12. TEAE = treatment emergent adverse events.