KEY TAKEAWAYS
- This phase Ib/II trial aimed to hypothesize that PARP inhibitor talazoparib, in combination with the chemotherapy temozolomide, could induce DNA damage leading to cell death and tumor response.
- The outcome was based on the composite endpoint of OR, PSA decline, and CTC conversion. Pharmacokinetics were tested using mTPI-2 for dose increase.
- The study found intermittent dosing of talazoparib + temozolomide caused hematologic toxicity in mCRPC pts but showed promising efficacy.
Poly(ADP-ribose) polymerase (PARP) inhibitors work best in cancers with DNA damage repair (DDR) alterations, but other methods are being investigated for patients without DDR defects.
Researchers aimed to hypothesize that PARP inhibitor talazoparib, in combination with the chemotherapy temozolomide, could induce DNA damage leading to cell death and tumor response.
The study used intermittent dosing of talazoparib (Days 1-6) and temozolomide (Days 2-8) in 28-day cycles for metastatic castration-resistant prostate cancer (mCRPC) patients without DDR mutations. Patients (pts) must have failed at least one androgen receptor signaling inhibitor and may have received chemotherapy in the hormone-sensitive setting. The response was measured by the overall response (OR) per RECIST v1.1, PSA50% decline, and CTC conversion from >1 to 0. Pharmacokinetic samples were collected using the mTPI-2 method in escalation.
Around 13 pts were enrolled in 4 dose levels during escalation. The most common adverse events (AE) were anemia (any grade: 31%, Gr3: 23%), thrombocytopenia (any Gr: 54%, Gr3+: 30.7%), fatigue (Gr≤2: 62%), and nausea (Gr1: 46%). One patient experienced a DLT (Gr3 neutropenic fever, Gr4 thrombocytopenia). The recommended dose for further study (RP2D) was talazoparib 1 mg (Day 1-6) and temozolomide 75mg/m2 (Day 2-8). Overall, 4 patients (30.8%) achieved the efficacy endpoint (3 CTC responses, 1 PR, 0 PSA50% decline). There were no PSA50 responses, 2 patients (15.4%) had a PSA30% decline. The median duration of the trial was 20 weeks, and 4 patients (30.8%) remained on trial for ≥6 months, with 2 of them also meeting the efficacy endpoint.
The study found that hematologic toxicity was the dose-limiting factor in this combination of intermittent talazoparib and temozolomide for mCRPC patients without DDR alterations. Reduction in CTCs to 0 was observed at different dose levels, and two patients showed PSA30% declines. Phase II study is now enrolling based on the identified RP2D.
Source: https://meetings.asco.org/abstracts-presentations/223282
Clinical Trial: https://www.clinicaltrials.gov/study/NCT04019327
Karen A. Autio, Christos Kyriakopoulos, Han Xiao, Hamid Emamekhoo, Daniel Costin Danila, Michael Edward Devitt, Elyn Riedel, Mehrin Jan, and Howard I. Scher. Journal of Clinical Oncology (2023) 41:16_suppl, e17036-e17036.
