Frontline abiraterone/olaparib prolongs survival in mCRPC compared to SOC


Noel W. Clarke, MBBS, FRCS, ChM

Frontline Treatment with Abiraterone Acetate (Zytiga) and Olaparib (Lynparza) Improves Median Overall Survival (OS) in Patients with Metastatic Castration-Resistant Prostate Cancer, According to Final Analysis of Phase 3 PROpel Trial (NCT03732820) Did. Against standard of care abiraterone and placebo.1

With the final data cutoff for OS on 12 October 2022, median OS was 42.1 months in the abiraterone/olaparib cohort (n = 399) and 34.7 months in the abiraterone/placebo cohort (n = 397), with no deaths. risk (HR, 0.81; 95% CI, 0.67–1.00; P. = .0544). The maturity for survival was 47.9%.

The results, although not statistically significant, were noted to be the longest OS reported in a phase 3 first-line trial of mCRPC, said Noel W. Clarke, MBBS, FRCS, ChM. rice field. 2023 American Society of Clinical Oncology Genitourinary Cancer SymposiumHe said the results support the combination of abiraterone and olaparib as a new first-line treatment option for this patient population.

“PROpel is [previously] Met this primary endpoint, demonstrating statistically significant and clinically meaningful radiological progression-free survival [rPFS] “This is reported in a phase 3 trial of first-line mCRPC,” said Clarke, emeritus professor of urological oncology at the University of Manchester and a consultant urologist at the Royal Salford Hospital and Christie, UK. It’s one of the biggest ever.”

Primary endpoint data reported in NEJM evidence showed that the addition of olaparib resulted in a median rPFS of 24.8 months in 2022 compared to 16.6 months with standard therapy (HR, 0.66; 95% CI, 0.54-0.81; P. < .0001) by investigator review.A blinded independent central review confirmed these findings (HR, 0.61; 95% CI, 0.49-0.74; nominal P. < .0001).2

Subgroup analyzes of secondary OS endpoints also showed improvement trends across specific groups. The greatest improvement was seen in patients with homologous recombination repair (HRR)-mutated mCRPC, accounting for his 28.4% of the total population. Median OS was not reached in the abiraterone/olaparib group compared to 28.5 months in the placebo group (HR, 0.66; 95% CI, 0.45-0.95). In the non-HRR mutant population, median OS was 42.1 months in the experimental group and 38.9 months in the control group (HR, 0.89; 95% CI, 0.70-1.14).1

“HRR-mutated cases are treated more effectively, but non-HRR-mutated or wild-type disease still has a large impact,” said Clarke. “[One] An important thing to recognize from this is that care must be taken when interpreting population subanalyses. The second is to examine two different groups of control arms. We find that the control arm and HRR-mutated patients have a much more aggressive phenotype than non-HRR-mutated patients. [group]Nonetheless, survival rates are improving. ”

At baseline, other key characteristics were balanced between experimental and placebo groups, with most patients with ECOG performance status 0 (71.7% and 68.5%, respectively), median age approximately 70 years , most patients with metastatic disease included bone (87.5% vs 85.4%). Other metastatic sites included distant lymph nodes (33.3% vs. 30.0%), regional lymph nodes (20.6% vs. 22.4%), lung (10.0% vs. 10.6%), and liver (3.8% vs. 4.5%). was

Median prostate-specific antigen level at baseline was 17.90 ug/L (interquartile range [IQR]6.09-67.00) in the experimental arm and 16.81 ug/L (IQR, 6.26-53.30) in the control arm. BRCA Mutations were found in 11.8% of patients in the olaparib group and 9.6% of patients in the placebo group. A brief pain inventory – short form and opioid use was used to assess whether patients were symptomatic at baseline. It was reported to be positive in 25.8% of patients in the olaparib group and 20.2% of patients in the placebo group.

Patients were eligible for enrollment if they had not previously taken abiraterone, but were allowed treatment with other next-generation hormonal agents as long as their last dose was at least 12 months old. mg once daily and olaparib at 300 mg twice daily and randomly assigned to experimental groups.

Additional secondary endpoints were reported. Median time to first follow-up treatment following abiraterone/olaparib was 24.6 months vs. 19.4 months for abiraterone alone (HR, 0.76; 95% CI, 0.64-0.90) . Cytotoxic chemotherapy or hormonal therapy was the most common treatment among patients who proceeded to subsequent treatment (179 (44.9%) in the experimental group and 215 (54.2%) in the control group). Three patients in the experimental group receiving a PARP inhibitor as the first subsequent treatment.

Median time to second disease progression or death was not reached in either group (HR, 0.76; 95% CI, 0.59-0.99).1

No new safety signals were observed in the latest analysis. In the abiraterone/olaparib group (n = 398), 26 patients died from adverse reactions (AEs). Dose interruptions, dose reductions, and discontinuations due to olaparib-related AEs were reported in her 49.0%, 22.6%, and 17.3% of patients, respectively. Twenty patients died from AEs in the placebo group (n = 396). Rates of dose interruption, dose reduction and discontinuation due to placebo-related AEs were 28.3%, 6.1% and 8.6%, respectively. Forty-five patients in the experimental group discontinued treatment due to abiraterone-related AEs, and her 37 patients in the placebo group discontinued treatment.

AEs of particular note with olaparib included development of myelodysplastic syndrome/acute myeloid leukemia in two patients. Eighteen new primary malignancies were reported in the abiraterone/olaparib group and 14 in the abiraterone/placebo group.

Pneumonitis was reported in 5 cases in the experimental group and 3 cases in the placebo group.1

The most common AEs of any grade in the olaparib and placebo groups, respectively, included anemia (49.6% vs. 17.7%), fatigue or asthenia (38.7% vs. 30.3%), nausea (30.7% vs. 14.4%), and back pain. Pain (21.6%) was included. % vs 19.9%), and diarrhea (20.6% vs 10.6%). The most common grade ≥3 AEs in the abiraterone/olaparib arm were anemia (16.1%), hypertension (3.8%), COVID-19 infection (3.8%), urinary tract infection (2.5%), and fatigue (2.5%). ) was. The most common grade 3 or higher AEs in the placebo group were hypertension (4.5%), fatigue (3.3%), COVID-19 (2.0%), back pain (1.5%), and urinary tract infection (1.0%). %) was.

“We saw anemia, a class effect known from PARP inhibition,” Clarke said. was starting to calm down, except for the fatigue, and it was all very manageable.”

Functional assessment of cancer treatment-quality of life outcomes using the Prostate Scale were similar between the two groups, indicating no harm from the addition of olaparib, Clark explained.

In December 2022, the combination was approved in the EU following a second interim analysis of PROpel.3 Additionally, in December 2022, AstraZeneca announced that the FDA has delayed its Priority Review decision timeline by three months to review additional new drug applications.Four


  1. Clarke NW, Armstrong AJ, Thiery Vuillemin A, et al. Final overall survival (OS) in PROpel: abiraterone (abi) and olaparib (ola) as first-line (1L) therapy in metastatic castration-resistant prostate cancer (mCRPC) compared with abiraterone and placebo (pbo). J Clin On Call2023;41(suppl 6):LBA16.doi:10.1200/JCO.2023.41.6_suppl.LBA16
  2. Clarke NW, Armstrong AJ, Thiery Vuillemin A, et al. Propel Detective. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM EvidMore2022;1(9).doi:10.1056/EVIDoa2200043
  3. The combination of Lynparza and abiraterone is approved in the EU for the first-line treatment of patients with metastatic castration-resistant prostate cancer. news release. AstraZeneca. December 21, 2022. Accessed 16 February 2023.
  4. Update on U.S. Regulatory Priority Review of Lynparza in Combination with Abiraterone for Metastatic Castration-Resistant Prostate Cancer. news release. AstraZeneca. December 15, 2022. Accessed 16 February 2023.

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