Many trials tried to evaluate the activity and efficacy of PARP inhibitors in prostate cancer, mainly in metastatic castration-resistant prostate cancer (mCRPC). To date, mature results in this field were provided by PROFOUND trial, which enrolled mCRPC patients progressing after, at least, one androgen-receptor signaling inhibitor (ARSI), enzalutamide or abiraterone.1 The patients were randomized to receive olaparib or the ARSI not previously administered. The beneficial effect of olaparib [in terms of radiographic progression free survival (rPFS), response rate (RR), and overall survival (OS)] was limited to the patients with mutated BRCA1, BRCA2, and ATM.1,2 A following exploratory gene-by-gene analysis found that olaparib was superior to a control agent in the presence of BRCA1/2, but not in the presence of ATM alterations.3 Accordingly, olaparib was approved by the European Medicine Agency (EMA) only for BRCAmut mCRPC patients who has been previously treated with one ARSI and it is currently the only reimbursed PARP inhibitor in Europe.
The availability of this agent has raised a number of questions concerning the management of prostate cancer in everyday clinical practice. When and how BRCA mutations should be sought? What are the technical challenges related to their screening? What are the therapeutic implications of their detection? Should members of the mutation-positive patients’ families be screened?
The Italian Society for Uro-Oncology (SIUrO) tried to clarify these and other challenging issues by organising a Consensus Project aimed at generating suggestions capable of supporting prostate cancer clinicians.4 SIUrO is a scientific society founded in 1990 which promotes the multidisciplinary approach of urological cancers. It promotes several educational activities by involving all representatives of disciplines involved in the management of urological cancers: urologists, radiation oncologists, medical oncologists, pathologists, nuclear medicine physicians, geneticists, pharmacologists, and others. It also explores those grey areas where the evidences are not so robust to clearly drive and support the clinical choices. Consequently, in 2018, SIUrO organized a multidisciplinary consensus project which produced practical suggestions on monitoring procedures for patients with either metastatic hormone-sensitive prostate cancer or mCRPC.5
These SIUrO consensuses have a clear methodological basis that reinforces the value of the final suggestions provided. Formal group consensus methods allow for inclusion of a wide range of knowledge and experience, and interaction between members, while stimulating constructive debate and preventing influential behaviour of one opinion to formulate suggestions about a specific question. Since perfect agreement is seldom reached, the objective of the consensus methodology is to identify a central tendency among the group and grade the level of agreement reached. SIUrO has chosen the Estimate-Talk-Estimate method (a formal means of reaching consensus that was developed in an attempt to overcome some of the negative aspects of group dynamics) and the UCLA-RAND technique to facilitate group decision making by combining activities that restrict verbal interactions with face to-face meetings.6,7
The Consensus on the issues raised by the availability of olaparib in the daily clinical practice produced a final shared formulation of 23 statements, covering 13 themes:
- Tumour material for BRCA1/2 testing
- Disease setting for BRCA1/2 testing and treatment
- Variants to be tested: germinal vs somatic variants, BRCA1/2 vs other genes
- Eventual Homologous Recombination Deficiency (HRD) test extension
- Clinical significance of BRCA mutations
- Management and surveillance of patients with inherited BRCA disease and their family members
- Selectivity and potency of PARP inhibitors
- PARP inhibitor activity and efficacy against different types of mutation
- On- and off- target effects of PARP inhibitors
- Metabolic profile of PARP inhibitors and their drug-drug interactions
- PARP inhibitors and the therapeutic sequence
- Platinum-based chemotherapy in BRCA1/2 patients
- Accessibility and appropriateness of BRCA1/2 testing in diagnostic and therapeutic care
The first results of TRITON3 trial with rucaparib, recently presented at 2023 Genitourinary cancer symposium, reinforced the recommendations of the SIUrO Consensus, suggesting that the clinical benefit from PARP inhibitors use is limited to BRCA mutations alone while patients with ATM mutations did not benefit.8 Similarly, the superiority of rucaparib in terms of rPFS compared not only to ARSI but also to docetaxel supports the suggestion that PARP inhibitors should be considered the preferred treatment choice in patients harbouring BRCA1/2 mutations.
Recently, the theoretical interplay between androgen receptors and HRR machinery has led to the possibility of combining PARP inhibitors and ARSIs, which may be active in prostate cancer patients with and without mutations.9-12 However, despite the clear improvement in progression-free survival, the use of such a combination is still not considered as standard of care. Thus, the issues addressed in the SIUrO Consensus are still remaining critical in daily clinical practice and require to be clarified, waiting clear evidence able to drive the clinical choices.
Written by: Orazio Caffo, MD, Department of Medical Oncology, Santa Chiara Hospital, Trento, Italy
References:
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- Hussain M, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Roubaud G, Özgüroğlu M, Kang J, Burgents J, Gresty C, Corcoran C, Adelman CA, de Bono J; PROfound Trial Investigators. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020 Dec 10;383(24):2345-2357.
- Matsubara N, de Bono J, Olmos D, Procopio G, Kawakami S, Ürün Y, van Alphen R, Flechon A, Carducci MA, Choi YD, Hotte SJ, Korbenfeld E, Kramer G, Agarwal N, Chi KN, Dearden S, Gresty C, Kang J, Poehlein C, Harrington EA, Hussain M. Olaparib Efficacy in Patients with Metastatic Castration-resistant Prostate Cancer and BRCA1, BRCA2, or ATM Alterations Identified by Testing Circulating Tumor DNA. Clin Cancer Res. 2023 Jan 4;29(1):92-99.
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- Lapini A, Caffo O, Pappagallo G, Iacovelli R, D'Angelillo RM, Vavassori V, Ceccarelli R, Bracarda S, Jereczek-Fossa BA, Da Pozzo L, Conti GN. Monitoring Patients with Metastatic Hormone-Sensitive and Metastatic Castration-Resistant Prostate Cancer: A Multidisciplinary Consensus Document. Cancers (Basel). 2019 Dec 1;11(12):1908.
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- Chi KN, Rathkopf DE, Smith MR, Efstathiou E, Attard A, Olmos D, Lee JY, Small EJ, Gomes AJ, Roubaud G, Saad M, Zurawski B, Sakalo V, Mason G, del Corral A, Wang GC, Wu D, Diorio B, Mennicke Lopez- Gitlitz A, Sandhu SK. Phase 3 MAGNITUDE study: First results of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations. J Clin Oncol 2022; 40 (suppl 6); 12
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