Olaparib Shows Activity in Castration-Resistant Prostate Cancer With DDR Gene Defects

CHICAGO-The PARP inhibitor olaparib has antitumor activity in heavily pretreated patients with metastatic castration-resistant prostate cancer (CRPC) with DNA damage repair gene defects, according to the results of the TOPARP-B study (abstract 5005) presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, held May 31–June 4 in Chicago.

“Some 20% to 25% of all metastatic CRPCS present germline or somatic inactivation of key DNA repair genes,” said Joaquin Mateo, MD, PhD, of the Institute of Cancer Research and the Royal Marsden in London, who presented the results.

Mateo and colleagues previously reported the antitumor activity of olaparib in unselected metastatic CRPC patients in the first part of the TOPARP study, TOPARP-A. TOPARP-B is the second part of the larger phase II trial to assess olaparib in patients with metastatic CRPC selected for DNA damage repair (DDR) gene alterations, which were presumed to be pathogenic. 

Patients with metastatic CRPC that progressed after taxane chemotherapy were eligible if tumor biopsy followed by targeted DNA sequencing revealed mutations in any DDR gene.

A total of 98 patients, with a median age of 67.6 years, were randomized to receive 400 mg or 300 mg of olaparib twice daily. TOPARP-A had assessed 400 mg; however, after olaparib was approved in breast and ovarian cancer at the lower dose of 300 mg, the investigators adapted their study design to assess both doses, using a randomized, pick-the-winner design.

The primary endpoint was a composite response of radiological response, prostate-specific antigen decline of ≥ 50%, and/or circulating tumor cell count conversion from ≥ 5 to < 5, any of which had to be confirmed at least 4 weeks apart. Endpoint analyses were conducted on gene alteration subgroups. The secondary endpoints were progression-free survival (PFS) and tolerability. 

Of the 98 randomized patients, 92 were treated and evaluable. Patient progression per treatment was 100% on androgen deprivation therapy; 99% post-docetaxel, 90% post-abiraterone/enzalutamide, and 38% post-cabazitaxel. The median follow-up duration was 17.6 months. The overall response rate was 54% (95% CI, 39%–69%) in the 400-mg olaparib cohort and 39% (95% CI, 25%–55%) in the 300-mg olaparib cohort. The median PFS was 5.4 months, 5.5 months, and 5.6 months in the overall, 400-mg, and 300-mg cohorts, respectively.

When the investigators performed gene-based subgroup analyses, they revealed that BRCA1/2 had the highest response rate at 83% (25/30; median PFS, 8.1 months). The group with PALB2 alterations had the next highest response rate at 57% (4/7; median PFS, 5.3 months). The ATM and CDK groups showed response rates of 37% (7/19; median PFS, 6.1 months) and 25% (5/20; median PFS, 2.9 months), respectively. Patients with alterations in other genes (ATRX, CHEK1, CHEK2, FANCA, FANCF, FANCG, FANCI, FANCM, RAD50, and WRN) collectively had a response rate of 20% (4/20; median PFS, 2.8 months). Similarly, the BRCA1/2 (22/30; 73%) and PALB2 (4/6; 67%) subgroups had the highest PSA 50% response rates.

“Seven hundred and eleven men were screened to obtain 98 for randomization,” highlighted Mary-Ellen Taplin, MD, of Dana-Farber Cancer Institute in Boston, who was the discussant for the study. “While this is not a prevalence study, the prevalence was 27%, which is what would be expected from the published literature. There was a 13% sample failure rate due to poor sample quality, even with this very expert team. This experience provides a warning that identifying the appropriate patient in routine clinical practice may be challenging and may require repeated testing of blood and tissue samples to accurately identify genomically selected patients.”

The dose reduction rates were 36.7% in the 400-mg group and 12.2% in the 300-mg group. Treatment discontinuation rates due to adverse effects were 10.4% in the 400-mg group and 26.7% in the 300-mg group. Anemia was the most common adverse event in both groups.  

“In my opinion, the data are not yet mature enough to not recommend a PARP inhibitor in the non-BRCA1/2 group, given the lack of effective treatment options,” said Taplin.