Frontline Abiraterone/Olaparib Prolongs Survival vs SOC in mCRPC

Noel W. Clarke, MBBS, FRCS, ChM

Frontline treatment with abiraterone acetate (Zytiga) plus olaparib (Lynparza) led to improved median overall survival (OS) in patients with metastatic castration-resistant prostate cancer, according to a final analysis of the phase 3 PROpel study (NCT03732820) which pitted the regimen against standard-of-care abiraterone and placebo.¹

At the final data cutoff for OS of October 12, 2022, the median OS was 42.1 months in the abiraterone/olaparib cohort (n = 399) vs 34.7 months in the abiraterone/placebo cohort (n = 397) for a 19% reduction in the risk of death (HR, 0.81; 95% CI, 0.67-1.00; P = .0544). The maturity for survival was 47.9%.

The results, though not statistically significant, were noted to be the longest OS reported in a first-line phase 3 trial in mCRPC, said Noel W. Clarke, MBBS, FRCS, ChM, who presented the data during the 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium. He noted that the results support the combination of abiraterone plus olaparib as a new first-line treatment option for this patient population.

“PROpel has [previously] met this primary end point demonstrating a statistically significant and clinically meaningful radiological progression-free survival [rPFS] benefit of the intention-to-treat population,” said Clarke, who is an honorary professor of urological oncology at Manchester University and a consultant urologist at Salford Royal Hospital and The Christie, both in England. “This represents one of the largest reported in the phase 3 trials in first-line mCRPC.”

The primary end point data, reported in NEJM Evidence in 2022, showed that the addition of olaparib resulted in a median rPFS of 24.8 months compared with 16.6 months with standard of care (HR, 0.66; 95% CI, 0.54-0.81; P < .0001) per investigator review. The blinded independent central review confirmed these findings (HR, 0.61; 95% CI, 0.49-0.74; nominal P < .0001).²

The subgroup analysis of the secondary OS end point also demonstrated trends in improvements across specified groups. The largest improvement was seen among patients with homologous recombination repair (HRR)-mutated mCRPC, which accounted for 28.4% of the overall population. The median OS was not reached in the abiraterone/olaparib arm vs 28.5 months in the placebo arm (HR, 0.66; 95% CI, 0.45-0.95). In the non-HRR mutation population, the median OS was 42.1 months in the experimental arm vs 38.9 months in the control arm (HR, 0.89; 95% CI, 0.70-1.14).¹

“The HRR-mutated cases are more effectively treated, but there is still a big effect in non–HRR-mutated or wild-type disease,” Clarke said. “[One] important thing to recognize from this is that one has to be careful in interpreting subanalyses of populations. The second thing is to look at the control arm in the 2 different groups and what you can see is that the control arm and the HRR-mutated patients have a much more aggressive phenotype than those in the non–HRR-mutated [group]. Notwithstanding that, there is an improvement in survival.”

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

The median prostate-specific antigen levels at baseline were 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 prevalent in 11.8% of patients in the olaparib arm and in 9.6% of patients in the placebo arm. Brief Pain Inventory—Short Form and opioid use was used to assess whether patients were symptomatic at baseline. This was reported as being positive for 25.8% of patients in the olaparib arm and 20.2% of patients in the placebo arm.

Patients were eligible for enrollment if they had no prior abiraterone, but treatment with other next-generation hormonal agent was permitted so long as the last dose was at least 12 months prior. Abiraterone was administered at 1000 mg once daily with olaparib administered at 300 mg twice daily for those randomly assigned to the experimental arm.

Additional secondary end points were reported. The median time to first subsequent therapy following abiraterone/olaparib was 24.6 months vs 19.4 months with abiraterone alone (HR, 0.76; 95% CI, 0.64-0.90). Among those who went on to subsequent treatment—179 patients (44.9%) in the experimental arm and 215 (54.2%) in the control arm—the most common therapies were cytotoxic chemotherapy or hormonal therapy. Three patients in the experimental arm when on to receive a PARP inhibitor as first subsequent therapy.

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

No new safety signals were observed in the updated analysis. In the abiraterone/olaparib group (n = 398), 26 patients died due to an adverse effect (AE). Dose interruptions, reductions, and discontinuations because of olaparib-related AEs were reported for 49.0%, 22.6%, and 17.3% of patients, respectively. In the placebo arm (n = 396), 20 patients died due to an AE. The rates of dose interruptions, reductions, and discontinuation because of placebo-related AEs were 28.3%, 6.1%, and 8.6%, respectively. Forty-five patients in the experimental arm discontinued treatment due to abiraterone-related AEs and 37 discontinued in the placebo arm.

AEs of special interest for olaparib included the development of myelodysplastic syndrome/acute myeloid leukemia in 2 patients. Eighteen cases of new primary malignancies were reported in the abiraterone/olaparib arm and 14 cases in the abiraterone/placebo arm.

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

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

“The class effect that we know with PARP inhibition, anemia, was seen, Clarke said. “The majority of the AEs occurred early and within 6 months, most of them had begun to settle down with the exception of fatigue, they were all very manageable.”

Quality-of-life outcomes using the Functional Assessment of Cancer Therapy-Prostate scale were similar between arms indicating that there was no detriment with the addition of olaparib, Clarke explained.

In December 2022, the combination was approved in the European Union following the second interim analysis of PROpel.³ Additionally, in December 2022, AstraZeneca, announced that the FDA delayed the priority review decision timeline by 3 months to review the supplementary new drug application.⁴

References

1. Clarke NW, Armstrong AJ, Thiery Vuillemin A, et al. Final overall survival (OS) in PROpel: abiraterone (abi) and olaparib (ola) versus abiraterone and placebo (pbo) as first-line (1L) therapy for metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2023;41(suppl 6):LBA16. doi:10.1200/JCO.2023.41.6_suppl.LBA16
2. Clarke NW, Armstrong AJ, Thiery Vuillemin A, et al; PROpel Investigators. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evid. 2022;1(9). doi:10.1056/EVIDoa2200043
3. Lynparza in combination with abiraterone approved in the EU as 1st-line treatment for patients with metastatic castration-resistant prostate cancer. News release. AstraZeneca. December 21, 2022. Accessed February 16, 2023. https://www.astrazeneca.com/media-centre/press-releases/2022/
4. Update on US regulatory priority review of Lynparza in combination with abiraterone in metastatic castration-resistant prostate cancer. News release. AstraZeneca. December 15, 2022. Accessed February 16, 2023. https://www.astrazeneca.com/media-centre/press-releases/2022/