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Certain gene mutations linked to olaparib response in prostate cancer
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PHILADELPHIA — Men with metastatic, castration-resistant prostate cancer who harbored gene mutations associated with the repair of damaged DNA had a noticeably better response to treatment with olaparib compared with patients without those mutations, according to findings from a phase 2 trial presented at the American Association for Cancer Research Annual Meeting.
Joaquin Mateo, MD, a research fellow and doctoral candidate in the prostate targeted therapy group and drug development unit at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust in the U.K., and colleagues initiated the TOPARP trial to test the effect of the PARP inhibitor olaparib (Lynparza, AstraZeneca) in 50 men with metastatic, castration-resistant prostate cancer and to identify predictive biomarkers for treatment response. All of the men had previously received docetaxel, 96% had previously received abiraterone (Zytiga, Janssen Biotech), and 58% previously received cabazitaxel (Jevtana, Sanofi Aventis).
Joaquin Mateo
During his presentation, Mateo explained the concept of “synthetic lethality,” which was the focus of the study.
“We know that tumors lacking BRCA function are sensitive to PARP inhibition,” Mateo said during a press conference. “They’re both key elements of the DNA repair pathway. But, in prostate cancer there are other mutations of other genes that are also relevant for the DNA repair response and all of these mutations have in common that they endure sensitivity to olaparib in clinical models.”
This implies different genes have the same intimate function, also known as, “genotypic divergence with phenotypic convergence,” Mateo said.
“This trial was about proving that if you have aberrations in any of these genes, not only BRCA, the effect is the same — a good response to a PARP inhibitor,” Mateo said.
The primary endpoint of the trial was response rate — defined using RECIST 1.1 criteria, a 50% or greater PSA fall and/or a reduction in circulating tumor cells from more than 5 per 7.5 mL blood to less than 5 per 7.5 mL blood — and secondary endpoints included safety, tolerability, PFS and OS.
Forty-nine patients had evaluable data. Those whose disease progressed after one to two lines of chemotherapy received 400 mg olaparib twice daily.
Overall, 16 patients experienced a response (response rate, 32.7%; 95% CI, 20-47.5). Of those, 11 patients were assigned the treatment for more than 6 months and four patients received treatment for more than 12 months at the time of data cutoff.
Next-generation gene sequencing detected mutations associated with DNA repair in 15 patients (30.6%), of whom 13 (86.7%) achieved a response to olaparib.
Further, all seven patients with somatic (n = 4) or germline (n = 3) BRCA2 loss and four of the five patients with ATM truncating mutations achieved a response. There was no association between ERG rearrangements or PTEN loss and therapy response.
Researchers also observed the biallelic loss of other relevant genes, including members of the Fanconi Anemia complementation group and CHEK2.
Mateo and colleagues calculated a 94% specificity of the panel for DNA gene repair, suggesting 94% of patients without these mutations would be correctly identified. Clinicians can choose a different form of treatment for those patients because there would be reasonable certainty that they would not benefit from olaparib, according to the researchers.
The most common grade 3 or worse adverse events associated with olaparib were anemia (20%) and fatigue (12%). Additionally, 13 patients (26%) required a reduction in dosage of olaparib.
In the planned second portion of the trial — or TOPARP-B — researchers will enroll patients positive for these DNA mutations linked to olaparib response.
“Olaparib is active in sporadic prostate cancer with a 32% response rate,” Mateo said during the press conference. “We hope that this is a step towards molecular [application] of treatment for prostate cancer.” – by Anthony SanFilippo
Reference:
Mateo J, et al. Abstract 8311. Presented at: American Association for Cancer Research Annual Meeting; April 18-22, 2015; Philadelphia.
Disclosure: Mateo reported no relevant financial disclosures. Two other researchers reported advisory roles with AstraZeneca.
Perspective
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James L. Mohler, MD
The frequency of BRAC1/2 mutations in the tumor samples from men treated on this clinical trial appears much higher than that of the general population. The mutation must provide an advantage for growth that can be used to select a precision treatment. Further study of this exaggerated reliance on DNA repair may lead to other new treatments beyond these impressive early results for olaparib (Lynparza, AstraZeneca).
Perspective
Back to TopWilliam Nelson, MD, PhD
Synthetic lethality is a paradigm … where the loss of a gene can be tolerated, but the loss of two genes at the same time cannot be tolerated. This is a great notion of how we might target genes that are lost in cancers. We are used to targeting genes that are activated in cancers, like kinases that are oncogenes and dry cancers, but can we target genes that are lost by finding the synthetic lethal pair and target it with a drug to stop its function?
PARP is an enzyme that converts one substance to another. It actually hooks on a nucleotide sugar onto proteins in the cell and generally functions in aiding cells as they repair DNA. That’s not its only function, but one of its major ones. The drug olaparib is known to hit this target. The question is, how best to use it? It may be disproportionally active against men with a particular genome defect and one that can be tested for and serves as molecular stratification using a genome test to determine who is best to treat and who may need another kind of therapy.
This is the kind of drug that will be active against the modern castration-resistant prostate cancer. That is what the Stand Up for Cancer (SU2C) Dream Team has focused on — men who have received hormonal treatments … who are progressing.
The key to this isn’t the 30% overall response rate, but the possibility — which they are testing in the next trial — that by using a genome type of test to identify men likely to respond, they’ll get a very high response rate in that group. For the other men who didn’t respond, we’ll need to develop other treatments. There is probably a little bit of a yield from the genome sequencing from the SU2C group that there may be some other targets that can be taken out. This is the disease that’s going to appear after the current best therapies that we have, and this is a good swat at that disease.
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