February 17, 2022— San Francisco, California—Adding olaparib to abiraterone therapy improves outcomes in patients with castration-resistant metastatic prostate cancer, regardless of homologous recombination repair (HRR) status, according to results of PROpel, presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium, which took place here and online from February 17 to 19.
“PARP inhibition is reported [in preclinical data] to increase activity of next-generation hormonal agents via androgen receptor-dependent transcription, and next-generation hormonal agents are reported to induce HRR deficiency and increased susceptibility to PARP inhibition,” said lead author Fred Saad, MD, of the University of Montreal Hospital Center (CHUM) in Canada, during his presentation of the data. "What we hope is that this combined effect will lead to better antitumor activity, whether or not patients harbor HRR gene alterations. In a recent phase II study, adding the PARP inhibitor olaparib to abiraterone therapy resulted in improved radiographic progression-free survival (PFS), compared with placebo plus abiraterone.”
For the phase III PROpel study, 796 patients with metastatic castration-resistant prostate cancer undergoing first-line treatment after failure of primary androgen deprivation therapy were randomized 1:1 to receive olaparib 300 mg twice daily (n = 399) or placebo (n = 397). All patients additionally received abiraterone 1000 mg once daily plus prednisone or prednisolone 5 mg twice daily. Patients were enrolled independent of HRR status. None of the patients had received prior abiraterone therapy, but previous treatment with docetaxel was permitted at the metastatic hormone-sensitive prostate cancer stage. Patients were stratified based on site of distant metastases and prior taxane use.
The primary endpoint was investigator-assessed radiographic PFS. There were multiple secondary endpoints, including overall survival (OS), time to first subsequent treatment, time to second PFS or death, and objective response rate (ORR).
Patients’ median age was about 70 years. Most had an ECOG performance status of 0, and more than 85% had metastasis to bone. Other sites of metastasis were distant lymph nodes in about one-third of patients and locoregional lymph nodes in about one-fifth. Nearly 23% of patients had received prior docetaxel, and nearly 30% had HRR mutations.
At ASCO GU 2022, Dr. Saad presented the results of a pre-planned interim analysis. At this time, the addition of olaparib was associated with a significantly prolonged radiographic PFS irrespective of HRR status, at 24.8 vs 16.6 months (hazard ratio 0.66, 95% confidence interval 0.54–0.81, P < .0001). Findings were similar when the outcome was assessed by blinded independent central review (hazard ratio 0.61, 95% confidence interval 0.49–0.74, P = .0001).
In predefined subgroup analyses, benefits of olaparib in terms of radiographic PFS were evident for all subgroups, including patients with HRR mutations (hazard ratio 0.50, 95% confidence interval 0.34–0.73) and without HRR mutations (hazard ratio 0.76, 95% confidence interval 0.60–0.97) detected by circulating tumor DNA testing.
The OS data are currently immature, with 228 deaths (28.6%). However, a trend toward improved OS was observed with the addition of olaparib (hazard ratio 0.86, 95% confidence interval 0.66–1.12).
Secondary endpoints were also improved among patients who received olaparib, compared with placebo. With the addition of active therapy, the hazard ratio for time to first subsequent treatment was 0.74 (95% confidence interval 0.61–0.90). For time to second progression or death, it was 0.69 (95% confidence interval 0.51–0.94).
Of the 796 patients, 321 (40.3%) had measurable disease at baseline. Among these patients, the ORR was 58.4% with olaparib and 48.1% without, for a hazard ratio of 1.60 (95% confidence interval 1.02–2.53). Quality of life was comparable between the two groups.
The most common adverse event of grade 3 or greater was anemia, occurring in 15.1% taking olaparib and 3.3% on placebo. Overall, 13.8% of patients on olaparib discontinued this therapy due to an adverse event, compared with 7.8% on placebo. The rate of adverse events leading to abiraterone discontinuation was similar in both arms, at 8.5% and 8.8% with olaparib and placebo, respectively. There were no reported cases of myelodysplastic syndrome or acute myeloid leukemia. The incidence of new primary malignancies was similar in both arms, as were rates of cardiac failure and thromboembolic events. Venous thromboembolic events occurred in 7.3% of patients taking olaparib and 3.3% on placebo. These were all incidental findings on CT that did not lead to drug discontinuation. Deaths due to adverse events occurred in about 4% of patients in each arm.
“Olaparib plus abiraterone led to a significant and, I believe, clinically meaningful improvement in radiographic PFS against an active control of abiraterone plus placebo,” concluded Dr. Saad. “This benefit led to what I think is the longest radiographic PFS we have seen to date in metastatic castration-resistant prostate cancer, beyond 2 years. This benefit was seen irrespective of HRR mutational status. Secondary and exploratory endpoints support the use of this combination therapy in the overall patient population.”
In an independent comment, Celestia S. Higano, MD, of the University of British Columbia in Canada, said that use of olaparib plus abiraterone acetate as a first-line option in this patient population should be put on hold until the OS data from PROpel are mature, given the high cost and toxicity of the regimen. More data are also needed to identify which patients are likely to benefit most from this particular combination.
The PROpel trial was sponsored by AstraZeneca in collaboration with Merck Sharp & Dohme Corp.
'Substandard' Control Arms in Clinical Trials– Practice found common in prostate cancer studies
Metformin: Preliminary Results of Trial in Advanced Prostate Cancer (MANSMED)
