Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated efficacy in patients with metastatic castration-resistant prostate cancer (mCRPC) DNA damage repair (DDR) mutations who were previously treated with novel hormonal therapy.1 Talazoparib is one such PARP inhibitor that has shown increased objective response rate (ORR) in patients with BRCA1/2 mutations, as well as increased overall median radiographic progression-free survival (rPFS). The interim results of a phase 2 study, TALAPRO-1, on talazoparib in men with DDR mutations and mCRPC were presented at the Genitourinary Cancers Symposium (GUCS) 2020, held in San Francisco, California.
Androgen deprivation therapy (ADT) is the mainstay of therapy for metastatic prostate cancer.2 However, 10-20% of patients will progress despite ADT, leading to mCRPC, which is incurable and associated with a poor prognosis.2 Analysis of next-generation sequencing data has shown that 11.8% of metastatic prostate cancer patients carry germline deleterious mutations in DDR genes, with BRCA2 being the most commonly mutated gene.3 Cells compensate for deleterious mutations in BRCA1 or BRCA2 by upregulating the PARP enzyme complex to continue the cell cycle.3 Treatment with PARP inhibitors will eventually lead to cell death in these cells.3
Talazoparib is an oral PARP inhibitor that is already approved in the US for the treatment of adults with deleterious or suspected deleterious germline BRCA mutated, human epidermal growth factor receptor 2 (HER2) negative, locally advanced or metastatic breast cancer.4
TALAPRO-1 is an international phase 2 study evaluating patients with measurable soft tissue disease, progressive mCRPC and DDR mutations likely to be sensitive to PARP inhibitors who have received 1-2 chemotherapy regimens (≥1 taxane-based), and progressed on 1 or more neoadjuvant hormonal therapies (enzalutamide or abiraterone acetate).1 DDR mutations included ATM, BRCA1, BRACA2, CHECK2, FANCA, MLH1, and RAD51C.1 81 patients received oral talazoparib 1mg per day until radiographic progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was ORR by blinded independent review.1 Secondary endpoints were time to ORR, duration of response, prostate-specific antigen (PSA) decrease ≥50%, circulating tumor cell (CTC) count conversion, time to PSA progression, rPFS, overall survival, safety, patient-reported outcomes, and pharmacokinetics.1
Overall ORR at the interim efficacy analysis was 25.6% (95% CI: 13.5-41.2). In patients with BRCA1/2 mutations, ORR was 50.0% (95% CI: 27.2-72.8), and 7.1% (95% CI: 0.2-33.9) in patients with ATM mutations.1 Median rPFS was 5.6 months (95% CI: 3.5-8.2) in the overall population, 8.2 months (95% CI: 5.6-NE) in the BRCA1/2 population, and 3.5 months (95% CI: 1.7-8.1) in the ATM population.1 The most common treatment-emergent adverse events (≥20%) were anemia, nausea, asthenia, decreased appetite, constipation, and decreased platelet count.1
This interim analysis of TALAPRO-1 demonstrated that talazoparib is capable of anti-tumor activity in mCRPC patients with DDR mutations who have previously received taxane chemotherapy and neoadjuvant hormonal therapies. Efficacy was most remarkable in patients harbouring BRCA1/2 mutations, and the therapy was generally well tolerated.1
1. de Bono JS et al. TALAPRO-1: A phase II study of talazoparib (TALA) in men with DNA damage repair mutations (DDRmut) and metastatic castration-resistant prostate cancer (mCRPC)—First interim analysis (IA). In: ASCO GU 2020. San Francisco; 2020. https://meetinglibrary.asco.org/record/183432/abstract. Accessed March 5, 2020.
2. Taghizadeh H et al. Immune checkpoint inhibitors in mCRPC – rationales, challenges and perspectives. Oncoimmunology. 2019;8(11). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791446/. Accessed March 5, 2020.
3. Adashek JJ et al. Clinical Development of PARP Inhibitors in Treating Metastatic Castration-Resistant Prostate Cancer. Cells. 2019;8(8). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721701/. Accessed March 5, 2020.
4. Hoy SM. Talazoparib: First Global Approval. Drugs. 2018;78(18):1939-1946.