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Olaparib shows activity in metastatic castration-resistant prostate cancer with certain genetic alterations
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CHICAGO — Olaparib demonstrated activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DNA damage repair gene alterations, according to findings from the phase 2 TOPARP-B trial presented at ASCO Annual Meeting.
Researchers noted that the type of genetic alteration influenced outcomes, with higher responses occurring for patients with BRCA1/BRCA2 mutations (83.3%) or PALB2 mutations (57.1%).
“Clearly, patients with BRCA2 loss are the ones achieving higher response rates and longer duration of responses, even in a late-stage setting. This subgroup represents 10% of all metastatic prostate cancers — this approach could benefit a significant number of patients,” Joaquin Mateo, MD PhD, researcher in the Prostate Cancer Translational Research Group at Vall Hebron Institute of Oncology in Barcelona, Spain, told HemOnc Today. “Beyond BRCA2, we also detected responses in patients with mutations in PALB2, ATM, CDK12, FANCA and CHK2 genes, but the magnitude of sensitivity seems to differ from one mutation to another.”
The current study is a follow-up to the TOPARP-A trial, which demonstrated antitumor activity of 400 mg olaparib (Lynparza, AstraZeneca, Merck) in patients with molecularly unselected metastatic castration-resistant prostate cancer.
The current study included 92 patients (median age, 67.6 years) with metastatic castration-resistant prostate cancer that progressed after one or more prior lines of therapy who were preselected for putatively pathogenic DNA damage repair alterations, which occur in 20% to 25% of patients with metastatic castration-resistant prostate cancer.
Researchers randomly assigned patients 1:1 to receive 400 mg olaparib or 300 mg olaparib.
Response rate — defined as a composite of achieving radiological response as defined by RECIST 1.1, PSA decrease of 50% or greater, and CTC count conversion from five or more cells to fewer than five cells per 7.5 ml of blood — confirmed after 4 weeks served as the primary endpoint. Secondary endpoints included PFS and tolerability.
All patients previously received docetaxel, 89.8% received abiraterone and/or enzalutamide (Xtandi, Astellas) and 37.8% received cabazitaxel.
Prescreening for DNA damage repair alterations showed 32.7% of patients had BRCA1/BRCA2 mutations, 21.4% had ATM mutations, 21.4% had CDK12 mutations, 7.1% had PALB2 mutations and 21.4% had other mutations.
Median follow-up was 17.6 months.
The composite response rate was 54.3% (95% CI, 39-69.1) among those in the 400-mg olaparib arm and 39.1% (95% CI, 25.1-54.6) among those in the 300-mg olaparib arm.
The composite endpoint was achieved by 83.3% of patients with BRCA1/BRCA2 mutations, 57.1% of patients with PALB2 mutations, 36.8% of patients with ATM mutations, 25% of patients with CDK12 mutations and 20% of patients with other mutations, which included ATRX, CHEK1, CHEK2, FANCA, FANCF, FANCG, FANCI, FANCM, RAD50 and WRN.
“We knew that tumor responses to PARP inhibitors in BRCA2-mutated tumors are significant, but to observe an 80% response rate in the third-line setting for castration-resistant prostate cancer is remarkable. One-third of these patients were treated for more than 1 year,” Mateo said. “The high response rate among the PALB2-mutated subgroup was very encouraging. However, these mutations are extremely rare in prostate cancer, and we could only treat seven patients with PALB2 mutations. We need to continue investigating in this subset.”
Radiographic PFS was 6.5 months (95% CI, 2.8-9.5) for the 300-mg group and 5.5 months (95% CI, 2.8-13) for the 400-mg group.
When broken down by gene subgroup, median PFS was highest for patients with BRCA1/BRCA2 mutations (8.3 months; 95% CI, 5.5-13), followed by those with ATM mutations (5.8 months; 95% CI, 4.4-10.9), PALB2 mutations (5.3 months, 95% CI, 0.4-not estimable), CDK12 mutations (2.9 months; 95% CI, 2.6-5.6), and other mutations (2.8 months; 95% CI, 2.6-4.3).
Researchers noted that dose may matter for benefit — with the composite response rate for the 400-mg group fulfilling the criteria to confirm TOPARP-A study results — but CDK12 alterations were imbalanced between the arms. Also, dose reductions occurred among 36.7% of the 400-mg group and 12.2% of the 300-mg group, with 10.4% of the 400-mg group and 26.7% of the 300-mg group discontinuing due to an adverse event.
The most common adverse events included anemia (grade 1 or higher, 69.4%; grade 3 or higher, 33.7%), nausea (grade 1 or higher, 30.6%), thrombocytopenia (grade 1 or higher, 26.5%), vomiting, (grade 1 or higher, 25%) and neutropenia (grade 1 or higher, 18.4%; grade 3 or higher, 5.1%).
Additional trials of olaparib and other PARP inhibitors in patients with advanced prostate cancers are underway, according to Mateo.
“We can anticipate good results for the BRCA2-mutated population, but it is also important that we can confirm other subgroups of patients who could derive benefit, even if this benefit is more modest,” Mateo said. “Moreover, different clinical trials are currently exploring combinations of PARP inhibitors with androgen-signaling targeted drugs, such as abiraterone or enzalutamide, as well as immune checkpoint inhibitors.” – by Jennifer Southall
Reference:
Mateo J, et al. Abstract 5005. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Disclosures: Mateo reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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David I. Quinn, MBBS, PhD
This was a follow-up to the 2015 publication in The New England Journal of Medicine that looked at patients treated with olaparib. In this subsequent complimentary trial presented for the first time at ASCO 2019, researchers selected patients before they went on to have an alteration of the DNA repair enzyme. Researchers screened 700 patients to get 92 on the study, so it is a selected subset. The response rate in the BRCA1 and BRCA2 subgroups will probably lead to approval by the FDA and other agencies in Europe, while durable stable response was seen in patients with ATM mutations. This is an important study that met the primary endpoint, but we still have a lot of questions to address. Specifically, more research is needed on whether these patients were carrying the alterations only in their tumor rather than their germline. From this perspective, the work has just begun, but I think we will see this drug approved.
Reference:
Mateo J, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1506859.
Keck School of Medicine of USC
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