Considerations on the identification and management of metastatic prostate cancer patients with DNA repair gene alterations in the Canadian context

Abstract

Olaparib is the first Health Canada-approved agent in metastatic prostate cancer to use a companion diagnostic to identify alterations in BRCA1, BRCA2, or ATM. As olaparib is introduced, clinicians must learn to access and interpret germline and somatic next-generation sequencing (NGS) results, and how to manage affected patients who appear to have distinct clinical features. The traditional model of referring patients to a hereditary cancer clinic (HCC) for germline testing is likely impractical in this disease, as the metastatic prostate cancer patient population would be overwhelming. Alternate approaches to this are clinician-ordered genetic testing (so-called “mainstreaming”), out-of-pocket payment for third-party private company genetic testing, or germline testing done in conjunction with somatic testing, particularly cell free circulating tumor DNA (ctDNA). Germline testing alone is not sufficient for identifying Olaparib-eligible patients, as less than half of BRCA1, BRCA2, or ATM alterations are germline in origin, but it is critically important to identify family members who are carriers so that risk-reduction measures can be undertaken. Somatic testing is not widely available in Canada, but some patients can access it through research protocols or by paying out-of-pocket. Somatic testing can be performed on archival or fresh solid tissue biopsy samples, or through whole blood samples to access plasma-derived circulating tumor DNA (ctDNA). Both testing approaches have relative advantages and disadvantages, but neither may be informative in all patients and, therefore, ideal somatic NGS pathways should provide options for both tissue and ctDNA testing. We advocate that clinicians begin discussions with their provincial lab formularies, HCC, and molecular pathology labs to highlight the importance of germline and somatic testing in this population and identify pathways for patient access. While olaparib has approval for use in BRCA1, BRCA2, and ATM-altered mCRPC, emerging evidence suggests that PARP inhibitors have variable activity in these three genes, with BRCA2 alterations appearing to be the most responsive. Retrospective and prospective series have reported varying outcomes to standard of care therapies, such as ARATs and taxane-based chemotherapy, in metastatic castration-resistant prostate cancer (mCRPC) patients with DNA damage repair (DDR) gene alterations, such as BRCA2. In the absence of high-level evidence showing a lack of benefit, we believe this patient population should still be considered for these treatments. In addition, platinum-based chemotherapy appears to have activity in DDR gene-altered mCRPC and should be considered another option when access to olaparib is not possible. At present, there is no evidence to support an optimal treatment sequence in this patient population, therefore, physician and patient preferences will need to be taken into consideration when selecting therapies. As olaparib and other PARP inhibitors are tested in different disease states and in combination with other therapies, we will likely see a more refined approach to use of these agents and management of this new biomarker-defined patient population.

Addressing controversial areas in the management of advanced prostate cancer in Canada

“…[24][25][26] Historically, patients were referred to genetics service or hereditary cancer clinic for genetic counselling and testing. 27,28 Mainstreaming is an alternative method for performing germline CUAJ -Special Feature Saad et al Controversial areas in the management of advanced PCa 10 © 2023 Canadian Urological Association testing and affords clinicians (oncologists, urologists, oncology surgeons) the advantage of ordering testing after pre-test counselling and taking consent from patients, rather than referring to another provider (e.g., genetic counselor, clinical geneticist). Physicians acknowledged the desire for mainstream genetic testing, however, in Canada, this approach is limited to Ontario, Quebec, and British Columbia, with the turnaround time for mainstreamed tests ranging 3-6 weeks.…”

Gene mutation profiling and clinical significances in patients with renal cell carcinoma

“… 19 , 20 In the past decades, NGS was widely used to apply diagnosis, treatment, and drug resistance to disease. 21 , 22 This study aimed to monitor gene mutation profiling and evaluate relationships between landscapes of gene mutation and the prognosis significances of renal cancer patients.…”

Genetic testing practices among specialist physicians who treat prostate cancer

“…3,4 Inevitably, patients with advanced disease will develop metastatic castration-resistant prostate cancer (mCRPC), with current standard-of-care systemic therapy options including androgen receptor pathway inhibitors (ARPIs; i.e., abiraterone acetate, enzalutamide); taxanebased chemotherapies (docetaxel, cabazitaxel); and bone-targeted therapies (radium-223). [5][6][7][8][9][10][11][12][13][14] Furthermore, alterations in genes associated with homologous recombination repair (HRR), such as BRCA1 and BRCA2, have been shown to confer sensitivity to poly adenosine diphosphateribose polymerase (PARP) inhibition in mCRPC. [15][16][17][18][19][20][21][22] Consequently, the PARP inhibitor, olaparib, was approved by Health Canada for use in patients with mCRPC harbouring a BRCA1, BRCA2-or ATM genetic alteration, who have progressed after at least one line of ARPIs, based upon the results of the Phase III PROfound trial.…”

“…[15][16][17][18][19][20][21][22] Consequently, the PARP inhibitor, olaparib, was approved by Health Canada for use in patients with mCRPC harbouring a BRCA1, BRCA2-or ATM genetic alteration, who have progressed after at least one line of ARPIs, based upon the results of the Phase III PROfound trial. 13,15,16 Genomic studies have reported that approximately 20%-30% of metastatic PCa (mPCa) patients harbour HRR pathway alterations; 13,16,17,[23][24][25][26][27] approximately 10%-15% being germline (inherited) in origin and 20%-25% somatic (acquired) 14 in origin. Response to standard-of-care therapies, such as ARPIs, also differs in mPCa patients with HRR gene alterations, in contrast to patients with wild-type HRR status.…”

“…Response to standard-of-care therapies, such as ARPIs, also differs in mPCa patients with HRR gene alterations, in contrast to patients with wild-type HRR status. 13 Since a variant in the HRR gene pathway will have prognostic and treatment implications, Ontario and international guidelines recommend germline and tissue testing in men with metastatic and high-risk localized PCa (LPCa). 17,[28][29][30] The overall objective of this crosssectional survey of a largely academic multidisciplinary (urologic oncology, medical oncology, radiation oncology) group was to: 1) evaluate current practices in genetic testing in PCa in the context of the Canadian health care system; 2) evaluate recommended genetic testing practices from Canadian healthcare providers; 3) define the patient population who should ideally be offered genetic testing; and 4) understand physician perceptions of when genetic testing should first be offered.…”