ASCO GU 2020: Additional Mechanism of Action of PARP Inhibitor Talazoparib Attacks Prostate Cancer Cells, Spares Normal Cells

[Balsam01]

PARP Inhibitor and BRCA2.

February 13, 2020—San Francisco, California—Talazoparib monotherapy has demonstrated encouraging antitumor activity in docetaxel-pretreated patients with metastatic, castration-resistant prostate cancer, especially those harboring BRCA1/2 mutations, and was generally well tolerated.

This result of a planned interim analysis of the phase II TALAPRO-1 trial was reported at the 2020 Genitourinary Cancers Symposium, from February 13 – 15.

Johann S. De Bono, MD, PhD, of the Royal Marsden National Health Service Foundation Trust, London, UK, reported the first interim analysis of TALAPRO-1, which is evaluating talazoparib, a potent inhibitor of poly (ADP-ribose) polymerase (PARP).

TALAPRO-1 is enrolling approximately 100 patients with measurable soft tissue disease, progressive, metastatic, castration-resistant prostate cancer, and DNA damage repair mutations likely to sensitize to PARP inhibition.

These mutations include ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C. Participants have received one to two chemotherapy regimens (at least one taxane-based) and progressed on at least one novel hormone therapy (enzalutamide/abiraterone acetate).

They receive oral talazoparib 1 mg daily (moderate renal impairment, 0.75 mg daily) until radiographic progression, unacceptable toxicity, or consent withdrawal. The primary endpoint is objective response rate.

Secondary endpoints are time to objective response, duration of response, prostate-specific antigen (PSA) decrease ≥50%, circulating tumor cell count conversion (to CTC = 0 and fewer than five per 7.5 mL of blood), time to PSA progression, radiographic progression-free and 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 had received treatment for ≥8 weeks.

Overall, 81 patients had received talazoparib as of June 2019. A total of 43 patients enrolled by February 2019 were evaluable for assessment of the primary endpoint (n=20, BRCA1/2; n=2, PALB2; n=14, ATM; n=7, other). All had received docetaxel and 49% had received prior cabazitaxel.

The overall objective response rate was 25.6% (95% confidence interval, 13.5-41.2).

The objective response rate in BRCA1/2-positive patients was 50.0% (95% confidence interval, 27.2-72.8).

The objective response rate in ATM-positive patients was 7.1% (95% confidence interval, 0.2-33.9).

Overall median radiographic progression-free survival was 5.6 (95% confidence interval, 3.5-8.2) months.

Radiographic progression-free survival in BRCA1/2-positive patients was 8.2 (95% confidence interval, 5.6-NE) months.

Radiographic progression-free survival in ATM-positive patients was 3.5 (95% confidence interval, 1.7-8.1) months.

The most common treatment-emergent adverse events (≥20%) were anemia, nausea, asthenia, decreased appetite, constipation, and decreased platelet count.

Dr. De Bono explained that as a PARP inhibitor, talazoparib stops prostate cancer cells from repairing faulty DNA.

Phase II and III studies with PARP inhibitors have demonstrated antitumor activity in patients with metastatic, castrate-resistant prostate cancer with DNA damage repair mutations who have been treated previously with novel hormonal therapy.

Talazoparib 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.

In addition, the treatment is not linked to the side effects of chemotherapy or castration treatment. Talazoparib could exert a major impact on the treatment of this type of prostate cancer.

Dr. De Bono concluded that talazoparib monotherapy has demonstrated encouraging antitumor activity in docetaxel-pretreated patients with metastatic, castrate-resistant prostate cancer, especially those with BRCA1/2 mutations, and was generally well tolerated.

[henukit]

Interesting, that very few patients with BRCA were enrolled to this trial. PARP inhibitors generate great response rates for this mutation as proven in ovarian cancer already. If someone has one and is having recurrence - please go and join, you will benefit from it. My MO says we should expect FDA approval for PARP in PCa in a few months.

[kidclutch]

my dad was given talazoparib in a trial (combining with avelumab) and it did NOT go well for ATM patients. in fact, they were all removed (50 of them) from the trial because of how badly it was going. BRCA patients, like with most parp trials, did well and continued on the combo.