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ONCAlert | Upfront Therapy for mRCC

Olaparib/Abiraterone Combo Delays Progression in mCRPC

Jason M. Broderick
Published Online: Jul 17,2018

Noel Clarke, MBBS, FRCS, ChM,
Olaparib (Lynparza) in combination with abiraterone acetate (Zytiga) improved progression-free survival (PFS) compared with the antiandrogen agent alone in patients with metastatic castration-resistant prostate cancer (mCRPC), according to findings from a phase II trial presented at the 2018 ASCO Annual Meeting.1 The results of the trial were also published the same day in Lancet Oncology.2

The median PFS was 13.8 months with the combination compared with 8.2 months with single-agent abiraterone acetate (HR, 0.65; 95% CI, 0.44-0.97; P = .034).

“Olaparib plus abiraterone provided a significant PFS benefit to patients [with mCRPC] 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 in 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 received prior docetaxel for mCRPC, ≤2 prior lines of chemotherapy, and no prior second-generation antihormonal agents.

The primary endpoint was PFS. Key secondary endpoints included PFS by HRR mutation 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 had 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 prostate-specific antigen concentration of 86 μg/L (range, 23-194) versus 47 μg/L (range, 21-199), although the ranges were similar.

Patients in the combination arm also had a heavier disease load burden; 45% had 0 to 4 bone metastases and 55% had 5 to 9. In the control arm, 65% of patients had 0 to 4 bone metastases and 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% were white in each), and prior cabazitaxel (Jevtana; 14% vs 13%, respectively).

Of 142 randomized patients, 96% (n = 136) had HRR mutation testing. Twenty-one (15%) of 142 patients had HRR mutations, detected by either tumor tissue, whole blood germline analysis, or plasma circulating-tumor DNA testing.

In the cohort of patients with HRR mutations, 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 HRR mutation 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 HRR mutation status. Among 45 patients in this subgroup receiving the combination, the median PFS was 13.1 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 and control arms, respectively (HR, 0.79; 95% CI, 0.51-1.21; P = .28).

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% versus 21% and 21% versus 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, with a conversion rate of 46%.

In the experimental arm, the median duration of olaparib treatment 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. Fifteen 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, versus 13%, 0%, and 10% in the control arm.

The rate of serious AEs was 34% versus 18% in the olaparib/ abiraterone and abiraterone-alone arms, 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). AE-related deaths occurred in 4 patients in the combination arm and in 1 patient in the control arm.

Clarke said that based on the findings of this phase II trial, a phase III study is planned to address further questions regarding HRR mutation status in patients with mCRPC.
 
 
References:
  1. 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). meetinglibrary.asco.org/record/160539/abstract.
  2. Clarke N, Wiechno P, Alekseev B, et al. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial [published online June 4, 2018]. Lancet Oncol. doi: 10.1016/S1470-2045(18)30365-6.



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Olaparib/Abiraterone Combo Delays Progression in mCRPC
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