A phase II study evaluating single-agent olaparib in metastatic, castration-resistant prostate cancer offers the first evidence that genetic testing could be used to select patients for treatment.
The overall response rate was 86.7% in a subgroup of men (14/16) identified as harboring genomic defects in DNA repair genes and 32.7% among all evaluable patients (16/49).
Median radiological progression-free survival was estimated at 13.2 months in men with mutations and 2.7 months in those without mutations (hazard ratio, 0.21; P < .001), Dr. Joaquin Mateo of the Institute of Cancer Research and the Royal Marsden NHS Trust, London, reported at the annual meeting of the American Association for Cancer Research.
© 2015 AACR/Todd Buchanan
Dr. Joaquin Mateo
“We hope that this is a step towards molecular stratification of treatment for prostate cancer. We are a year behind breast cancer or colorectal cancer investigators,” he said during a press briefing at the meeting.
Olaparib (Lynparza), a PARP (poly ADP-ribose polymerase) inhibitor ,was approved in the United States in December 2014 for treating BRCA-positive advanced ovarian cancer.
Most of the genomic aberrations in patients with prostate cancer occurred in BRCA2 and ATM, although biallelic loss of other relevant genes, including members of the Fanconi Anemia complementation group and CHEK2, were also observed. Research presented at the meeting suggests that BRCA2 is present in about 12% of prostate tumors and ATM in about 7%, Dr. Mateo told reporters.
The first phase of the study, referred to as TOPARP-A, enrolled 50 men from 7 U.K. centers who had metastatic, castration-resistant prostate cancer after 1-2 lines of taxane chemotherapy and a circulating tumor cell (CTC) count of at least 5 cells/7.5 mL of blood at screening. All patients had received prior docetaxel (Taxotere), 58% cabazitaxel (Jevtana), 96% abiraterone (Zytiga), 28% enzalutamide (Xtandi), and 26% palliative radiotherapy. The median baseline prostate specific antigen (PSA) was 349.5 mcg/L and median age was 67.5 years.
Patients received olaparib 400 mg twice daily continuously in a 28-day cycle. Response rate, the study’s primary endpoint, was defined as objective response by RECIST 1.1 and/or PSA decline of at least 50% and/or CTC count decline from at least 5 cells to less than 5 cells/7.5 mL blood. One patient was not evaluable for response.
Genomic defects in DNA repair genes, somatic and germline, were identified via next-generation sequencing and other studies of fresh tumor samples, taken before and while on olaparib.
Among the 16 unselected patients with responses, 6 had radiological responses and 11 had biochemical responses. Four of these responses have lasted more than 1 year, Dr. Mateo said.
Among those with genomic testing results, seven patients had a BRCA2 alteration and all responded to olaparib. Four of the five men with ATM truncating mutations responded.
PTEN loss and ERG rearrangements were not associated with response, he said.
The biomarker panel had a high specificity of 94% and sensitivity of 87.5%.
Consistent with previous olaparib studies, the most common grade 3 or higher adverse events were anemia (20%) and fatigue (12%), with 13% of patients requiring a dose reduction.
The next phase of the study, TOPARP-B, will validate the biomarker panel by enrolling only patients who screen positive for the DNA repair mutations linked to response in TOPARP-A, said Dr. Mateo, noting that samples can be turned around in 7-10 days.
Press briefing moderator Dr. William Nelson, director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, said newer drugs such as abiraterone and enzalutamide have given clinicians more mileage in treating castration-resistant prostate cancer by better targeting the androgen-receptor, but that the current results with olaparib will likely prompt more drug development off the androgen receptor.
The Cancer Research UK Clinical Trials Awards and Advisory Committee, SU2C, PCF, the Experimental Cancer Medicine Center, and the U.K. National Institute for Health Research Biomedical Research Center funded the study. Dr. Mateo disclosed no financial conflicts. Two coauthors reported serving as advisors to AstraZeneca
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