Talazoparib, a potent poly(ADP-ribose) polymerase (PARP) inhibitor, achieved durable antitumor activity in heavily pretreated men with advanced metastatic castration-resistant prostate cancer (mCRPC) with alterations in genes involved directly or indirectly with homologous recombination repair (HRR), an international, open-label, phase II trial has shown.
In a cohort of 104 patients, the objective response rate (ORR) was 29.8% (95% CI, 21.2-39.6%), Johann S de Bono, PhD, the Institute of Cancer Research and Royal Marsden Hospital, London, the United Kingdom, and colleagues reported in The Lancet Oncology.
The median time to objective response was 3.4 months (interquartile range [IQR], 1.8-5.4 months) while the median duration of response was 12.8 months (95% CI, 6.5 months to not evaluable). Overall, median radiographic progression-free survival (PFS) was 5.6 months (95% CI, 3.7-8.8 months) while overall survival (OS) was 16.4 months (12.2-19.9 months).
The most common grade 3 to 4 treatment-emergent adverse events (AEs) were hematologic in nature, with rates being relatively low among the group overall.
“To our knowledge, this study is the first international phase 2 trial to assess the antitumor activity and tolerability of talazoparib in men with metastatic, castration-resistant prostate cancers with alterations in DDR (DNA damage response) genes involved in HRR who have been heavily pretreated,” de Bono and colleagues wrote.
“These results support further assessment of talazoparib,” the investigators concluded.
Talazoparib is currently approved for “treating germline BRCA1-mutated and BRCA-2 mutated human epidermal growth factor receptor 2 (HER2, Erb-2) negative metastatic or locally advanced breast cancer” the study authors wrote and noted that to their knowledge this is the “first international trial to assess the antitumor activity and tolerability of talazoparib monotherapy” in this patient population.
TALAPRO-1 enrolled patients at 43 hospital, cancer centers, and medical centers in 14 different countries.
Enrollment was restricted to patients with measurable disease with DNA alterations likely to be sensitive to PARP inhibition.
Out of the group of 104 patients, 4% had a BRCA1 alteration alone, 50% had a BRCA2 gene alteration alone; 14% had an ATM alteration alone; 4% had a PALB2 alteration alone, and the remaining 21% had other HRR gene alterations. Patients had received at least one taxane-based chemotherapy regimen for metastatic disease, had progressed on enzalutamide or abiraterone or both.
The study participants received oral talazoparib at a dose of either 1 mg a day or a lower dose of 0.75 mg/day for those with moderate renal impairment. Median treatment duration was approximately 6 months.
“The primary endpoint was confirmed objective response rate, defined as best overall soft-tissue response of complete or partial response per RECIST 1.1,” the authors noted.
Looking at treatment responses by HRR gene alteration group, 46% of patients with BRCA2 alterations, 50% of those with BRCA1 alterations; 25% of those with PALB2 alterations and 12% of those with ATM alterations achieved an ORR. The best responses were seen in men with BRCA1 or BRCA2 alterations, among whom median PFS was 11.2 months (95% CI, 7.5-19.2 months) while median OS was 24 months (95% CI, 16.2 months to not evaluable).
Most patients with both baseline and post-baseline assessments also showed a reduction in tumor burden, prostate specific antigen (PSA) levels, and circulating tumor cell counts with the highest rates being observed among those with either BRCA1 or BRCA2 alterations.
The most common grade 3 to 4 treatment-emergent AEs were anemia in 31% of patients, thrombocytopenia in 9% and neutropenia in 8%, all of the anemia and neutropenic events being grade 3. Serious treatment-emergent AEs occurred in approximately one-third of patients overall. All-cause treatment-emergent AEs led to dose reductions in 26% of patients and dose interruptions in 37% of the group.
The study had several limitations including the lack of a control group and potential investigator bias because of the open-label design of the study.
The phase III TALAPRO-2 trial is currently evaluating the use of talazoparib plus enzalutamide as a first-line treatment in men with mCRPC with or without HRR gene alterations.
Commenting on the study, Vincenza Conteduca, MD, and Ugo De Giorgi, MD, both from the Istituto Romagnolo per lo Studio dei Tumori (IRST), Meldola, Italy, pointed out that similar results have been observed in other studies where PARP inhibitors have been evaluated in the treatment of mCRPC in men with DDR defects.
For example, the TOPARP-A and TOPARP-B trials showed that olaparib also had activity in men with heavily pre-treated mCRPC.
The subsequent phase III Profound trial similarly showed that men with HRR-deficient mCRPC had better PFS and OS when they received the combination of olaparib plus abiraterone or enzalutamide compared with abiraterone or enzalutamide alone.
However, as the editorialists pointed out, “molecular stratification seems to be a crucial aspect for these patients.”
In the TALAPRO-1 trial itself, 1425 men were screened for gene alterations but 1297 of them did not have HRR gene alterations or did not meet other eligibility criteria, as they noted. Many patients in the other PARP inhibitor mCRPC trials also did not pass molecular screening.
“Therefore, the predictive testing for DDR mutations might not be reached up to about 30% of patients with metastatic castration-resistant prostate cancer who would not benefit from PAPR inhibitor therapy because of insufficient tissue sampling or quality or both,” Conteduca and De Giorgi said.
Overall, the editorialists noted that results from the TALAPRO-1 trial do provide a reason to include the drug as a treatment option for heavily pre-treated patients who present with aggressive DDR-defective prostate cancers.
“However, we still need to learn, based on the biology, how to maximize the opportunities for its use,” they cautioned. “In this regard, the optimal approach for correlative studies or DDR biomarker development should incorporate both tissue and plasma analyses.”
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The PARP inhibitor talazoparib has been shown to achieve durable antitumor activity in metastatic CRPC with DNA repair alterations.
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Treatment-emergent adverse event rates were relatively low with PARP inhibition and were largely hematological in nature.
Pam Harrison, Contributing Writer, BreakingMED™
The study was funded by Pfizer/Medivation.
De Bono reported receiving consulting fees from Astellas Pharma, AstraZeneca, Bayer, BioXcel Therapeutics, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eisai, Genmab, GSK, Janssen Oncology, Menarini Silicon Biosystems, Merck Serono, MSD, Orion Pharma GmbH, Pfizer, Roche/Genentech, Sanofi, Sierra Oncology, and Taiho Pharmaceutical as well as funding or support to his institution for laboratory and clinical work from Astex Pharmaceuticals, AstraZeneca, Bayer, Celgene, Cellcentric, Daiichi Sankyo, Genentech, GSK, MedImmune, Medivation, Merck Serono, MSD, Orion Pharma GmbH, Sanofi, Sierra Oncology, and Taiho Pharmaceutical; honoraria from Astellas Pharma, AstraZeneca, BioXcel Therapeutics, Daiichi Sankyo, Janssen Oncology, Menarini Silicon Biosystems, Pfizer, Roche/Genentech, Sanofi, and Sierra Oncology. He has also received travel, accommodation, and expenses from Astellas Pharma, AstraZeneca, Genmab, GSK, Orion Pharma GmbH, Qiagen, Sanofi, Taiho Pharmaceutical.
Conteduca has served as consultant or advisory board member for Janssen, Astellas, Merck, AstraZeneca, and Bayer and has received speaker honoraria or travel support from Astellas, Janssen, Ipsen, Bayer, and Sanofi.
De Giorgi reported receiving research support from AstraZeneca, Roche, and Sanofi, and consultancy fees from Astellas, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck, Pfizer, and Sanofi.
Cat ID: 25
Topic ID: 78,25,730,25,192,925
