BRCA, ATM, CHEK news: ASCO GU 2021: Talazoparib Demonstrates Durable Antitumor Activity in Metastatic Castration-Resistant Prostate Cancer

[Balsam01]

February 12, 2021—Talazoparib monotherapy has substantial antitumor activity in metastatic castration-resistant prostate cancer patients with DNA damage response (DDR) alterations who were previously treated with taxane-based and novel hormonal therapy, according to a study presented at the 2021 virtual meeting of the American Society of Clinical Oncology Genitourinary Cancers Symposium, which took place from February 11 to 13.

Poly (ADP-ribose) polymerase (PARP) inhibitors such as talazoparib have antitumor activity in metastatic castration-resistant prostate cancer patients being treated with novel hormonal therapy. PARP inhibition is fatal in cells with homozygous deletions and/or deleterious alterations in DDR genes involved in homologous recombination repair. “The PARP inhibitor talazoparib inhibits PARP catalytic activity and traps PARP on DNA, preventing DNA replication and transcription, and generating double strand breaks that lead to cell death,” said study presenter Johann S. De Bono, MB, MD, PhD, from the Institute of Cancer Research in London, United Kingdom, during his presentation of the data.

For the multinational phase II TALAPRO-1 trial, 128 patients with progressive metastatic castration-resistant prostate cancer were enrolled between June 4, 2017 and March 20, 2020. All had at least a monoallelic DDR gene deleterious alteration likely to sensitize them to PARP inhibition identified from an 11-gene panel (ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C). Positive DDR gene alteration status was defined as detection of homozygous deletions, putative deleterious genomic alterations, or a combination, in at least one gene. The patients had previously received one to two taxane-based chemotherapy regimens and at least one hormonal therapy with enzalutamide and/or abiraterone acetate given in the metastatic setting.

The patients received 1 mg oral talazoparib daily, or 0.75 mg daily if moderate renal impairment was present, until radiographic progression, unacceptable toxicity, consent withdrawal, or death. Radiographic assessments were performed every 8 weeks during the first 24 weeks, then every 12 weeks thereafter.

The primary endpoint was confirmed objective response rate (ORR) by blinded independent central review, while key secondary endpoints included time to objective response, response duration, radiographic progression-free survival (PFS), overall survival (OS), prostate-specific antigen (PSA) decrease of at least 50%, circulating tumor cell count conversion, and safety. Antitumor activity endpoints were analyzed by DDR groups, where patients were separated hierarchically by DDR gene alterations (BRCA1/2 > PALB2 > ATM > others). Dr. De Bono presented antitumor activity and tolerability results, with data cut-off on September 4, 2020.

The safety population (n = 127) included all patients who received at least one dose of talazoparib and a small number of patients with non-measurable disease who were enrolled in an earlier version of the protocol. The efficacy population (n = 104) included all patients with measurable soft tissue disease who had predefined tumor DDR gene alterations and had received at least one dose of talazoparib.

Baseline characteristics between both safety and efficacy populations were similar. Among all 127 patients, 48% had received more than one prior taxane-based regimen. Median duration of talazoparib treatment was 6.1 months in the safety population and 6.2 months in the efficacy population.

The ORR was 29.8% in the efficacy population (95% confidence interval 21.2–39.6). It was 45.6% for the BRCA2 alteration group, 50.0% for the BRCA1 group, 25.0% for the PALB2 group, and 11.8% for the ATM group. Reduction in tumor burden (79.8%), PSA (71.9%), and circulating tumor cell count (82.2%) was observed in most patients. These reductions were especially apparent in BRCA-altered cancers but were also found in PALB2- and ATM-altered cancers.

Time to objective response was 3.4 months (range 1.6–7.5 months), and median duration of response was 12.8 months in the efficacy population. The longest confirmed objective response was observed in patients with BRCA2 alterations. Twelve patients had an ongoing response at data cut-off. Median radiographic PFS was 5.6 months. It was 11.2 months for patients with BRCA1/2 alterations, 3.5 months for those with non-BRCA alterations, 5.6 months for those with PALB2 alterations, and 3.5 months for those with ATM alterations. Similar patterns were observed for OS and time to PSA progression.

The tolerability of talazoparib was consistent with previous reports. Of all 127 patients, 95.3% reported any all-causality treatment-emergent adverse events, the most common of which were anemia (48.8%), nausea (33.1%), decreased appetite (28.3%), and asthenia (23.6%). The most common grade 3/4 treatment-emergent adverse events were anemia (30.7%), thrombocytopenia (8.7%), and neutropenia (7.9%). Serious treatment-emergent adverse events were reported in 33.9%, which primarily included pulmonary embolism (6.3%), anemia (3.9%), disease progression (3.1%), urinary tract infection (2.4%), and pneumonia (2.4%). Permanent discontinuation of talazoparib due to treatment-emergent adverse events occurred in 11.8% of patients.

“Talazoparib monotherapy has important, substantial, and durable antitumor activity in DDR-mutated advanced metastatic castration-resistant prostate cancer in patients who have had prior taxane and novel hormonal therapy, most impressively in the BRCA-altered cancers, but also with antitumor activity in the PALB2- and ATM-altered cancers,” concluded Dr. De Bono.

The TALAPRO-1 trial was sponsored by Pfizer Inc.

[EdBar]

Thank you for this information, I have two of those mutations including NBN which is rather rare so I was surprised to see it on the list. I will tuck this information away for discussion with my MO.

Ed

[Cooolone]

Thanks for posting!

And again, the association of use of these Immunotherapy drugs only once surpassing other unrelated resistance or progression in my mind is really holding things back. In this example, it's use come into play at a very late stage of patient progression. I do understand the entirety of it all, just voicing an opinion that there needs to be a paradigm shift in mentality towards the use and availability of these drugs. To use them at any stage of diagnosis if those genetic markers are present! Earlier when progression isn't as advanced, and the patient is more healthy (typically).

Anyways, thanks for posting!

Best Regards

[Balsam01 in reply to Cooolone]

I was trying to get into an olaparib trial at Johns Hopkins where they re giving the drug up front to hormone sensitive non-metastic patients based on what you just wrote. I couldn't make it because my testosterone wouldn't get to 150 which was a trial requirement. My loss because the tentative results are quite impressive according to the doctor.