medwireNews: Phase 2 study data show that the PARP inhibitor talazoparib has antitumor activity in men with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC) bearing DNA damage response (DDR) alterations in genes associated with homologous recombination repair (HRR).
The TALAPRO-1 study included 127 men with alterations in one of 11 HRR genes likely to sensitize to PARP inhibitors, namely ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C. Participants had received one to two taxane-based chemotherapy regimens for metastatic disease as well as either enzalutamide or abiraterone or both for mCRPC.
After a median follow-up of 16.4 months, treatment with talazoparib 1 mg/day, or 0.75 mg/day for those with moderate renal impairment, led to an independently assessed objective response rate (ORR) of 30% among the 104 individuals with measurable disease, with complete and partial responses in 7% and 23%, respectively. The median time to response was 3.4 months and responses lasted for a median of 12.8 months.
Analysis by HRR gene type showed that the ORR was highest in patients harboring BRCA1/2 alterations (n=61), at 46%, but responses were also observed in those with PALB2 (n=4) and ATM (n=17) alterations, at rates of 25% and 12%, respectively. These findings affirm that “PARP inhibition has antitumor activity beyond the BRCA1 and BRCA2 subset,” say Johann de Bono (The Institute of Cancer Research and Royal Marsden Hospital, London, UK) and colleagues in The Lancet Oncology.
No complete or partial responses were seen in patients with mutations in other genes, but 36% had stable disease of any length and 6% had a decrease in prostate-specific antigen levels of 50% or more.
The researchers note that “[t]he safety profile observed so far in TALAPRO-1 is consistent with the established safety profile of talazoparib.”
Overall, 48% of patients had a grade 3–4 treatment-emergent adverse event (TEAE), most commonly anemia (31%), thrombocytopenia (9%), and neutropenia (8%). Twenty-six percent of participants required a dose reduction and 12% discontinued treatment due to all-cause TEAEs. Serious TEAEs occurred in 34%, but there were no treatment-related deaths.
Writing in an accompanying comment, Vincenza Conteduca and Ugo De Giorgi, both from IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori” in Meldola, Italy, say: “Overall, TALAPRO-1 provides a rationale to include talazoparib in the armamentarium to treat heavily pretreated patients presenting with potentially aggressive DDR-defective prostate cancers.
“However, we still need to learn, based on the biology, how to maximise the opportunities for its use. In this regard, the optimal approach for correlative studies or DDR biomarker development should incorporate both tissue and plasma analyses.”
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Lancet Oncol 2021; doi:10.1016/S1470-2045(21)00376-4
Lancet Oncol 2021; doi:10.1016/S1470-2045(21)00450-2