Olaparib can be effective in patients with metastatic castration-resistant prostate cancer who have homologous recombination repair gene alterations. In the phase III PROfound trial, the drug extended median radiographic progression-free survival and increased objective response rate in patients with BRCA 1/2 and ATM mutations, compared with enzalutamide or abiraterone plus prednisone.
For the first time, a phase III trial has shown that a PARP inhibitor can be effective in patients with metastatic castration-resistant prostate cancer (mCRPC) who have faulty DNA-repair genes. In the PROfound trial, the drug extended median radiographic progression-free survival (rPFS) and increased the objective response rate (ORR) in patients with BRCA1/2 and ATM mutations, compared with newer hormonal agents.
Despite recent therapeutic advances, patients with mCRPC have a poor prognosis. However, up to 30% of patients have tumors with mutations in DNA-repair genes, including those involved in homologous recombination repair (HRR). “These gene alterations can confer sensitivity to PARP inhibition,” said Maha Hussain, MD, of Northwestern University in Chicago, IL, who presented the findings at the ESMO Congress 2019, September 27–October 1, in Barcelona, Spain. In a previous phase II trial, the PARP inhibitor olaparib (Lynparza; AstraZeneca) demonstrated antitumor activity in patients with mCRPC and HRR mutations—including alterations in BRCA1/2 and ATM, the most well-characterized DNA-repair genes (N Engl J Med 2015;373:1697–708).
The PROfound trial tested olaparib in patients with mCRPC and HRR alterations whose disease had progressed despite receiving either abiraterone (Zytiga; Janssen) or enzalutamide (Xtandi; Astellas/Pfizer). In cohort A, 245 patients with BRCA1/2 or ATM mutations were randomized 2:1 to receive olaparib or the physician's choice of enzalutamide or abiraterone plus prednisone; in cohort B, 142 patients with alterations in other HRR-related genes received olaparib or the physician's choice.
Patients in cohort A who were treated with olaparib had a median rPFS of about 7.4 months and an ORR of 33.3% and had not yet reached median time to pain progression, compared with about 3.6 months, 2.3%, and 9.9 months, respectively, in patients who received a physician's-choice therapy. Patients treated with olaparib in both cohorts had a combined median rPFS of about 5.8 months and an ORR of 21.7%, compared with about 3.5 months and 4.5% in patients receiving the physician's choice.
In an interim analysis, patients in cohort A treated with olaparib had a median overall survival (OS) of 18.5 months, compared with 15.1 months in the control group. When combined, patients treated with olaparib in both cohorts had a median OS of 17.5 months, compared with 14.3 months in the control group. In an exploratory analysis, Hussain and her team found that olaparib had clinical activity in patients with mutations in HRR genes other than BRCA1/2 and ATM, including CDK12 and CHEK2. “This highlights the fact that not all DNA repair–defect genes are the same,” Hussain said.
Overall, half of the patients who received olaparib experienced side effects classified as grade 3 or higher, and 16.4% discontinued treatment, compared with 37.7% and 8.5% of patients in the control group.
“This is a truly practice-changing study,” said Eleni Efstathiou, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, who discussed the findings. “In those patients with [DNA damage–repair] alterations, mainly BRCA2, we saw clinically meaningful improvements, and when it comes to prostate cancer therapy strategy … we're entering into the targeted-therapy era.”
“Disease outcome variability, we know, is largely driven by underlying molecular heterogeneity. The challenge remains to identify causal pathways of disease progression that can be targeted,” Efstathiou added. “Our goal is progress. It's not perfect yet; this trial moves the field forward.” –Catherine Caruso
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