PARP inhibitors (PARPi) are established treatments for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) deficiency after androgen receptor signalling inhibitor (ARSI) failure. New PARPi + ARSI combinations have been tested in all comers, although their clinical relevance in HRR-proficient tumours remains uncertain.
To quantitatively synthesise evidence from randomised trials assessing the efficacy and safety of PARPi + ARSI combinations for first-line treatment of mCRPC.
We searched the PubMed, EMBASE, SCOPUS, and Cochrane Library databases up to February 28, 2023. Randomised controlled trials (RCTs) comparing PARPi + ARSI versus placebo + ARSI for first-line treatment of mCRPC were eligible. Two reviewers independently performed screening and data extraction and assessed the risk of bias, while a third reviewer evaluated the eligibility criteria.
Overall, three phase 3 RCTs were included in the systematic review: PROPEL, MAGNITUDE, and TALAPRO-2. A total of 2601 patients with mCRPC were enrolled. Two of these trials (PROPEL and TALAPRO-2) assessed the radiographic progression-free survival benefit of PARPi + ARSI for first-line treatment of mCRPC, independent of HRR status. The pooled hazard ratio was 0.62 (95% confidence interval 0.53-0.72). The pooled hazard ratio for overall survival was 0.84 (95% confidence interval 0.72-0.98), indicating a 16% reduction in the risk of death among patients who received the combination.
Results from this meta-analysis support the use of ARSI + PARPi combinations in biomarker-unselected mCRPC. However, such combinations might be less clinically relevant in HRR-proficient cancers, especially considering the change in treatment landscape for mCRPC.
We looked at outcomes from trials testing combinations of two classes of drugs (PARP inhibitors and ARSI) in advanced prostate cancer. We found that these combinations seem to work regardless of gene mutations identified as biomarkers of response to PARP inhibitors when used on their own.
European urology oncology. 2023 Aug 11 [Epub ahead of print]
Carlo Messina, Emilio Francesco Giunta, Alessio Signori, Sara Elena Rebuzzi, Giuseppe Luigi Banna, Akash Maniam, Sebastiano Buti, Carlo Cattrini, Giuseppe Fornarini, Matteo Bauckneht, Alastair Greystoke, Ruth Plummer, Christoph Oing, Pasquale Rescigno
Oncology Unit, ARNAS Civico, Palermo, Italy., IRCCS Istituto Romagnolo per lo Studio dei Tumori Dino Amadori, Meldola, Italy., Section of Biostatistics, Department of Health Sciences, University of Genoa, Genoa, Italy., Medical Oncology Unit, Ospedale San Paolo, Savona, Italy; Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy., Department of Oncology, Portsmouth Hospitals University NHS Trust, Portsmouth, UK; Faculty of Science and Health, School of Pharmacy and Biomedical Science, University of Portsmouth, Portsmouth, UK., Department of Oncology, Portsmouth Hospitals University NHS Trust, Portsmouth, UK., Medical Oncology Unit, University Hospital of Parma, Parma, Italy; Department of Medicine and Surgery, University of Parma, Parma, Italy., SCDU Oncologia, AOU Maggiore della Carità , Novara, Italy., Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, Genoa, Italy., Section of Biostatistics, Department of Health Sciences, University of Genoa, Genoa, Italy; Nuclear Medicine, IRCCS Ospedale Policlinico San Martino, Genoa, Italy., Translational and Clinical Research Institute, Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK., Translational and Clinical Research Institute, Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK; Mildred Scheel Cancer Career Centre HaTriCS4, University Cancer Centre Hamburg, University Medical Centre Eppendorf, Hamburg, Germany., Translational and Clinical Research Institute, Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK; Candiolo Cancer Institute FPO-IRCCS, Candiolo, Italy. Electronic address: .