1. Fuerst, Mark L.

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SAN FRANCISCO-The unique mechanism of action of the PARP inhibitor talazoparib enhances its activity against prostate cancer cells while sparing normal cells in patients with metastatic castration-resistant prostate cancer, according to a new study.

Prostate Cancer. Pro... - Click to enlarge in new windowProstate Cancer. Prostate Cancer

Mutations in DNA repair genes are associated with aggressive forms of prostate cancer and castration resistance. Prostate cancer with DNA repair defects may be vulnerable to therapeutic targeting by poly (ADP-ribose) polymerase (PARP) inhibitors. PARP enzymes modify target proteins with ADP-ribose in a process called PARylation and are in particular involved in single strand break repair. PARP-associated DNA repair pathways are also closely connected to androgen receptor signaling, which is a key regulator of tumor growth and a central therapeutic target in prostate cancer.


"Phase II and III studies with PARP inhibitors have demonstrated antitumor activity in patients with metastatic castration-resistant prostate cancer with DNA damage response mutations who were previously treated with novel hormonal therapy," said lead author Johann S. De Bono, MD, PhD, Head of the Division of Clinical Studies at the Institute of Cancer Research at The Royal Marsden NHS Foundation Trust, London, at the 2020 Genitourinary Cancers Symposium hosted by ASCO.


The PARP inhibitor talazoparib stops prostate cancer cells from repairing faulty DNA and is unique in that it also traps PARP on DNA, interfering with cancer cell replication. This novel treatment works against prostate cancer cells, while selectively sparing normal cells in metastatic castration-resistant prostate cancer, said De Bono. In addition, the treatment does not have the side effects of chemotherapy or castration treatment, and could have a major impact on the treatment of this type of prostate cancer.


De Bono reported on the first interim analysis of a phase II study called TALAPRO-1 (Abstract 119). The trial is enrolling about 100 patients with measurable soft tissue disease, progressive metastatic castration-resistant prostate cancer, and DNA damage response mutations likely to sensitize to PARP inhibitors, including ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C. The patients received 1-2 chemotherapy regimens, one or more of them taxane-based, and progressed on one or more novel hormonal therapies, including enzalutamide or abiraterone acetate.


Patients received oral talazoparib 1 mg per day. Those with moderate renal impairment received 0.75 mg per day. They received therapy until radiographic progression, unacceptable toxicity, or withdrew their consent.


The primary endpoint of the study is objective response rate (ORR). Secondary endpoints are time to overall response, duration of response, prostate-specific antigen (PSA) decrease of 50 percent or more, circulating tumor cell count conversion, time to PSA progression, radiographic progression-free survival (PFS), overall survival, safety, patient-reported outcomes, and pharmacokinetics.


A planned interim analysis of safety and efficacy was performed after 20 patients with BRCA1/2 mutations were on treatment for 8 or more weeks.


At the ASCO meeting, De Bono reported that as of June 5, 2019, 81 patients had received talazoparib; 43 patients who were enrolled by Feb. 12, 2019, were evaluable for the primary endpoint; 20 patients had BRCA1/2, two patients had PALB2, 14 patients had ATM, and seven patients had other mutations. All patients had received docetaxel and 49 percent had received prior cabazitaxel.


The overall ORR was 25.6 percent; those patients with BRCA mutations had a higher ORR (50%) and those patients with ATM mutations a lower ORR (7.1%). Overall median radiographic PFS was 5.6 months. Again, patients with BRCA mutations had a longer PFS (8.2 months) than those with ATM mutations (3.5 months).


The most common treatment-emergent adverse events of 20 percent or more were anemia, nausea, asthenia, decreased appetite, constipation, and platelet count decrease.


In conclusion, De Bono stated: "Talazoparib monotherapy demonstrates encouraging antitumor activity in docetaxel-pretreated metastatic castration-resistant prostate cancer patients, especially those with BRCA1/2 mutations, and was generally well-tolerated."


Mark L. Fuerst is a contributing writer.


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