In the quest to develop more potent and targeted anti-cancer treatment strategies, the expanding family of PARP inhibitors (PARPi), including olaparib, continues to drive more precise and personalized therapeutic approaches. PARPi were the first approved cancer therapies to hone in on DNA damage response (DDR) in BRCA1/2 mutated breast and ovarian cancers. Driven by significant advances within the field, researchers have achieved a deeper understanding of the mechanisms behind sensitization of tumors to PARPi, leading to the extension of their use to more effectively treat several other cancer types, including prostate cancer.
Gene-targeted PARPi: delivering powerful blows against BRCA1/2 mutated prostate cancerBased on the results of the PROfound randomized phase III clinical trial (2), olaparib received regulatory approval in 2020 for the treatment of metastatic castration-resistant prostate cancer (mCRPC) with several DDR gene mutations (DDRm). Additional phase II studies of different PARPi in this patient population have also demonstrated the value of implementing mCRPC molecular stratification based on tumor sequencing in clinical practice.
One example is the phase II TOPARP-B multi-center trial (3); results of which confirmed the anti-tumor activity of single agent olaparib against mCRPC. The B-half of this adaptive, academic study drew on the results reported from TOPARP-A where the association between DDR and response to olaparib in molecularly unselected patients was first described.
“Around 20-25% of patients with advanced prostate cancer have different genomic alterations in DNA damage repair pathways, including homologous recombination repair genes. This renders some of these tumors more sensitive to treatment with PARPi such as olaparib”, commented Joaquin Mateo, Principal Investigator of VHIO’s Prostate Cancer Translational Research Group, and first author of TOPARP-B.
Investigating different doses of olaparib and correlating several genomic aberrations with anti-tumor activity, the investigators also confirmed the anti-tumor activity of this agent in this particular population secondary to either germline or somatic gene activation.
But, all is not rosy. While this two part adaptive trial certainly provided the rationale for implementing this gene-targeted approach in the clinic to help guide treatment decisions as well as match more effective therapies to the molecular make up of individual patients’ tumors, not all patients with advanced prostate cancers (APCs) with DDR derive similar benefit from PARPi. Further clinical qualification is therefore required in order to achieve a more precise understanding of PARPi sensitivity in mCRPC.
Seeking out more precise predictors of responseRecently published in Cancer Discovery (1), research led by Joaquin Mateo and Johann de Bono, Professor in Experimental Cancer Medicine, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust (London, UK), sought to identify molecular features in order to refine the predictive biomarker suite for patient stratification and more precisely identify patients achieving major benefit from PARPi treatment.
Analyzing samples from the aforementioned TOPARP-B study, the investigators pursued a deeper molecular characterization by whole-exome and genome sequencing, immunohistochemistry (IHC) and immunofluorescence (IF) assays. Not only did their findings reveal that patients with complete BRCA2 deletions responded exceptionally to PARPi with high and durable responses, they also advance insights into which patients carrying PALB or ATM mutations might also benefit from this therapy.
“These results may enable us to fine-tune the stratification of patients in clinical practice, as well as more precisely identify those who could benefit from this class of targeted therapy, based on the molecular specificities of their respective disease”, said VHIO’s Joaquin Mateo, co-Corresponding Author of this present study and Clinical Investigator at the Vall d’Hebron University Hospital, Vall d’Hebron Barcelona Hospital Campus.
RAD51predict: patient stratification based on DNA repair functionalityOver the past few years, VHIO’s Experimental Therapeutics Group directed by Violeta Serra has focused on various research projects based on the use of its RAD51predict in vitro diagnostic test to predict those patients who would be most likely to benefit from therapy with PARPi. Specifically, this assay facilitates the more precise and faster identification of patients with breast and ovarian cancer who could respond to this class of targeted treatments.
“Thanks to the support received through CaixaResearch funding programs, we have continued to develop RAD51predict to better guide the stratification of patients to clinical trials to evaluate the efficacy of PARPi across additional tumor types including prostate and endometrial cancers”, said Violeta Serra, also a co-author of this present research (1).
The study also demonstrates how the RAD51predict assay can help to complement genomic testing in clinical practice, also in prostate cancer, by identifying alterations in the BRCA gene, as well as PALB2 mutations; discriminating between biallelic and monoallelic in the latter. “This is particularly relevant since this research has shown that only those patients with biallelic PALB2 mutations benefit from treatment with olaparib”, added Violeta Serra.
Additionally, RAD51predict has been shown to identify less common genomic variants that impact homologous recombination and sensitize to PARPi. “This first study of RAD51predict for treating prostate cancer with PARPi shows promising results. So much so, that we have subsequently initiated validation studies in other patient cohorts”, she concluded.
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