Noel Clarke, MBBS, FRCS, ChM
Combining the PARP inhibitor olaparib (Lynparza) with the antiandrogen agent abiraterone acetate (Zytiga) reduced the risk of disease progression or death by 35% compared with abiraterone alone in pretreated patients with metastatic castration-resistant prostate cancer (mCRPC), according to phase II data presented at the 2018 ASCO Annual Meeting.
The median progression-free survival (PFS) was 13.8 months with the combination compared with 8.2 months with single-agent abiraterone (HR, 0.65; 95% CI, 0.44-0.97; P
“Olaparib plus abiraterone provided a significant PFS benefit to mCRPC patients, who had previously received docetaxel, compared with abiraterone alone. The benefit was seen independent of homologous recombination repair (HRR) status,” said Noel Clarke, MBBS, FRCS, ChM, professor of Urological Oncology, Christie NHS Foundation Trust, Manchester, United Kingdom.
The double-blind trial evenly randomized 142 patients in a 1:1 ratio to 1000 mg/daily of oral abiraterone plus either placebo or olaparib tablets at 300 mg twice daily. Patients had prior docetaxel for mCRPC, ≤2 prior lines of chemotherapy, and no second-generation antihormonal agents.
The primary endpoint was PFS. Key secondary endpoints included PFS by HRR mutation (HRRm) status, time to second progression (PFS2), overall survival (OS), objective response rate (ORR), circulating tumor cell (CTC)-conversion rate, and safety/tolerability.
There were some discrepancies in patient characteristics between the 2 study arms. Patients in the combination arm were slightly older, with a median age of 70 years (range, 65-75) compared with 67 years (range, 62-74) in the control arm. The olaparib cohort also had a higher median PSA concentration at 86 ug/L (IQR, 23-194) versus 47 ug/L (21-199), although the ranges were similar.
Patients in the combination arm also had a heavier disease load burden. Forty-five percent of patients had 0 to 4 bone metastases and 55% of patients had 5 to 9 in the olaparib/abiraterone arm. In the control arm, 65% of patients had 0 to 4 bone metastases, while 35% had 5 to 9.
The characteristics were otherwise well matched between the combination and control arms. These included ECOG performance status (>95% of each group were 0 or 1), race (94% white in each), and prior cabazitaxel (14% in combination arm vs 13% in control arm).
Of 142 randomized patients 96% (n = 136) had HRR mutation testing. Twenty-one (15%) of 142 patients had HRR mutations.
In the cohort of 21 HRRm patients, 11 received the combination and 10 were treated with abiraterone alone. The median PFS was 17.8 months in the experimental arm compared with 6.5 months in the control arm (HR, 0.74; 95% CI, 0.26-2.12).
Among 35 HRRm wild-type patients, the median PFS was 15.0 months for 15 patients receiving olaparib/abiraterone compared with 9.7 months for 20 patients receiving abiraterone alone (HR, 0.52; 95% CI, 0.24-1.15).
A third subgroup of 86 patients had unknown HRRm status. Among 45 patients in this subgroup receiving the combination, the median PFS was 13.1 months versus 6.4 months in 41 patients treated with abiraterone alone (HR, 0.67; 95% CI, 0.40-1.13).
With the secondary endpoint of PFS2 in the overall population, the median was 23.3 versus 18.5 months in the olaparib/abiraterone versus control arms, respectively (HR, 0.79; 95% CI, 0.51-1.21; P
The median OS was 22.7 versus 20.9. months, respectively (HR, 0.91; 95% CI, 0.60-1.38; P
= .66). “The was no difference in overall survival in either group,” said Clarke.
The ORR was 27% with the combination compared with 32% with abiraterone alone. All responses in both arms were partial. The stable disease and progressive disease rates were 48% vs 21% and 21% vs 47% in the 2 arms, respectively.
CTC conversion was defined as ≥5 cells/7.5 mL at baseline converted to <5 cells/7.5 mL post-baseline. In the combination arm, 30 patients had baseline CTC ≥5 and the CTC-conversion rate with treatment was 50%. In the abiraterone monotherapy arm, 28 patients had baseline CTC ≥5 and the CTC-conversion rate was 46%.
In the experimental arm, the median duration of olaparib was 309 days and the median duration of abiraterone was 338 days. The median duration of abiraterone in the control arm was 253 days.
The rate of grade ≥3 adverse events (AEs) was 54% versus 28% in the combination versus control arms, respectively. Of note, 15 patients in the olaparib/abiraterone arm had grade ≥3 anemia compared with no grade ≥3 anemia cases in the abiraterone monotherapy arm. Clarke explained that anemia is “a well described complication known to be manifest in olaparib-treated patients”
AEs led to dose interruption, reduction, and treatment discontinuation in 34%, 18%, and 30% of the olaparib/abiraterone arm, respectively. The corresponding rates were 13%, 0%, and 10%, respectively, in the control arm.
The rate of serious AEs was 34% versus 18% in the olaparib/abiraterone and abiraterone-alone arm, respectively. Serious cardiovascular AEs occurring with the combination included myocardial infarction (n = 4), fatal cardiac failure (n = 1), chronic cardiac failure (n = 1), and fatal ischemic stroke (n = 1). Thrombotic stroke was the 1 serious cardiovascular AE in the control arm. AE-related deaths occurred in 4 patients in the combination arm and 1 patient in the control arm.
Clarke said that based on the findings of this phase II trial, a phase III study is planned.
Clarke N, Wiechno PJ, Alekseev B, et al. Olaparib combined with abiraterone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): A randomized phase II trial. J Clin Oncol. 2018;36 (suppl; abstr 5003).