Urologists, oncologists, and prostate cancer patients are entering a new era in prostate cancer therapy—one that is going to be genetically defined.
“Treatments are going to be targeting the genetic mutations in prostate cancer,” said Emmanuel S. Antonarakis, MD, professor of oncology and urology at Johns Hopkins Medicine, Baltimore. “And one of the most actionable genetic abnormalities are mutations in the BRCA1 and BRCA2 genes, which collectively account for about 10% of all metastatic prostate cancers.
“The reason why knowing about these BRCA1- or BRCA2-positive patients is paramount is that within about 6 months from now we expect to have at least one FDA-approved PARP inhibitor that can be used in those patients.”
Among the poly (ADP-ribose) polymerase inhibitors (PARP inhibitors) that are in phase II or III trials for advanced prostate cancer, the furthest along and the only one with phase III data is olaparib (Lynparza). AstraZeneca and Merck announced positive results in early August from the phase III PROfound trial of olaparib in men with metastatic castration-resistant prostate cancer with a homologous recombination repair gene mutation and whose cancer had progressed on hormonal anticancer treatment with enzalutamide (XTANDI) or abiraterone acetate (Zytiga). Olaparib has been granted FDA breakthrough designation for BRCA1- and BRCA2-mutated metastatic castration-resistant prostate cancer.
Among the other PARP inhibitors that researchers have evaluated as prostate cancer monotherapy are niraparib and rucaparib, both of which also have received the FDA breakthrough designation. Janssen presented positive phase II trial results with niraparib at the recent European Society for Medical Oncology annual meeting in Barcelona, Spain. Clinical trials for rucaparib include TRITON2, a phase II study looking at treatment of metastatic castration-resistant prostate cancer patients with BRCA mutations. TRITON2 is enrolling patients with deleterious mutations of other homologous recombination (HR) repair genes, including ATM. The phase III trial, TRITON3, is enrolling patients with BRCA mutations and ATM mutations who have progressed on androgen receptor-targeted therapy and who have not yet received chemo in the castrate-resistant setting.
Still other PARP inhibitors in the prostate cancer treatment pipeline are veliparib (ABT-888) and talazoparib.
The first PARP inhibitor to be approved for prostate cancer will most likely be olaparib, followed by rucaparib, Dr. Antonarakis speculated.