FormalPara Take-home message

  • Approximately 5% of localized and up to 12% of metastatic prostate cancer (PCa) patients carry pathogenic germline variants, with BRCA2 being the most prevalent alteration.

  • Different guidelines recommend germline sequencing in patients with metastatic disease, a family history of PCa or specific high-risk features in order to optimize treatment, assess personal cancer risk and prognosis and further guide family counselling for cancer predisposition syndromes.

  • In localized disease, underlying pathogenic germline variants should trigger shared decision-making when deciding on active surveillance and (intensified) curative treatment options.

  • In metastatic PCa patients with BRCA1/2 or ATM alterations, targeted treatment with poly-ADP-ribose polymerase inhibitors (PARP) inhibitors offers promising options. Additionally, a subset of metastatic PCa patients with mismatch repair (MMR) alterations could benefit from immune checkpoint inhibition.

Germline alterations in PCa

Prostate cancer (PCa) is the second most common cancer in men and significantly impacts global health as a leading cause of cancer-related deaths [1]. Recent studies have shown that a subset of PCa patients harbor pathogenic germline variants (PGVs) affecting DNA damage repair mechanisms, which play a distinct role in disease development and differentiation [2]. Detection and understanding the implications of these PGVs is crucial for improved clinical management with potentially beneficial outcomes for these patients.

In PCa, approximately 4–5% of patients with localized PCa and 12% of patients with metastasized PCa carry a PGV in genes essential for homologous DNA repair (DDR) or mismatch repair (MMR) [2,3,4]. Genes involved in DDR comprise BRCA1, BRCA2, ATM, CHEK2, and others. Among these, BRCA2 is the most frequently found PGV, with a prevalence of 44% among all PCa mutation carriers [2, 4]. BRCA1/2 germline mutations are causing hereditary breast and ovarian cancer (HBOC) syndrome, which increases the lifetime risk of developing breast and ovarian cancer to 40–70% [5]. For male BRCA2 carriers, the risk of developing PCa is approximately 15–30% compared to 10–15% in the general population, whereas the risk with a BRCA1 or other PGV may only be slightly elevated [6, 7].

Genes involved in MMR comprise MSH2, MSH6, MLH1 and PMS2 or EPCAM—an epigenetic silencer of MSH2. These genes predispose affected individuals to a high lifetime risk of developing colon, endometrial, and other cancers (Lynch syndrome [LS]) [8, 9]. Although only a subset of PCa patients harbor germline alterations in these genes (3–4% of all PGV carriers), their presence has a significant impact on the molecular alterations present in PCa tumors, as deficiencies in the DNA mismatch repair system can lead to a phenomenon called microsatellite instability (MSI) [2, 8]. Tumors with high MSI are characterized by high mutation rates and may have increased responses to immune checkpoint inhibitor (CKI) therapy, which otherwise has limited effects in unselected PCa patients [10, 11].

Indications for genetic testing

Currently, there are several guidelines regarding which PCa patients should receive genetic testing for hereditary cancer syndromes (Table 1). The testing criteria encompass personal cancer history, cancer features and pathology, family history, and precision therapy indications [12,13,14,15]. All guidelines recommend germline testing of men with metastatic PCa, as the prevalence of PGVs in this population is over 10% [2]. In addition, guidelines state that a family history of PCa or the presence of two or more cancers within the HBOC or LS spectrum in relatives on the same family side should trigger genetic testing. Furthermore, some guidelines state that patients with high-risk (T3a or ISUP 4 or PSA > 20 ng/ml) or very-high risk (T3b-T4 or primary Gleason pattern 5 or > 4 cores with ISUP 4 or 5) localized PCa, presence of intraductal, ductal or cribriform histology, an Ashkenazi Jewish ancestry, or a diagnosis of PCa < 60 years can be offered genetic testing [12, 15, 16]. There is no consensus set of genes that must be included in PCa germline testing assays, but in general, multiple genes that may be relevant to optimize targeted therapy approaches or account for the patient’s cancer and family history are analyzed. Typical panels always include BRCA1/2 but vary in coverage regarding other homologous DNA repair or DNA mismatch genes, which should be considered when ordering these tests [12, 13, 15]. It is important to note that patients undergoing germline testing need pretest and posttest genetic counseling on potential test results and their impact on further management, and conducting genetic tests and counseling is often regulated by national laws [17].

Table 1 Indications for genetic testing in prostate cancer (PCa). Summary of current guidelines and consensus statements
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Clinical management of PCa patients with germline mutations

PCa screening

PCa screening for the early detection of PCa in the population of PGV carriers is an intense subject of debate due to potentially increased rates of unnecessary biopsies and their association with overdiagnosis and overtreatment [18]. Several prospective studies have been evaluating PCa screening among PGV carriers [6, 19,20,21]. The IMPACT trial is evaluating targeted PCa screening in men with and without germline BRCA1/2 and MMR alterations [19]. In the study, men aged 40–69 underwent prostate-specific antigen (PSA) screening for 3 years, and if their PSA was higher than 3.0 ng/ml, they were offered prostate biopsy. The study reported interim results in 2019, and after 3 years of screening, BRCA2 mutation carriers had a higher incidence of PCa, were younger at diagnosis, and had more clinically significant tumors [19]. Based on this, PSA screening for men with BRCA2 mutations should start at the age of 40 or 10 years before the youngest relative was diagnosed with PCa [12, 13]. For BRCA1 carriers, no significant differences were detected compared to BRCA1 noncarriers. However, guidelines recommend that men with BRCA1 alterations should consider a screening approach similar to BRCA2 carriers [12, 13]. For carriers of MSH2 and MSH6 PGVs, a higher incidence of PCa compared with age-matched noncarriers has been reported after the first PSA screening round, indicating that PSA screening in MSH2/MSH6 carriers should start at a similar age as for BRCA2 carriers [20].

In contrast to the IMPACT study, the current practice uses imaging-based PCa examinations before definitive biopsy. This approach is tested for BRCA1/2 carriers using a combination of multiparametric magnetic resonance imaging (mpMRI)-based and PSA-based screening [21]. So far, interim results have shown that initial mpMRI-based screening may be beneficial, especially for BRCA carriers younger than 55 years, compared to PSA screening alone [21]. No data have demonstrated a benefit from prophylactic prostatectomy in PGV carriers, but clinical trials are in discussion [22]. Thus, for optimized screening approaches in this population, new biomarkers and risk calculators are urgently needed to prevent unnecessary biopsies and improve the detection of clinically significant PCa.

Active surveillance

Active surveillance (AS) intends to spare PCa patients from aggressive interventions such as surgery or radiation therapy and is indicated when the disease is low-risk after biopsy and clinical staging. However, patients with PGVs and low-risk PCa might carry a higher risk of upstaging than noncarrier patients. Indeed, a study evaluating BRCA1/2 and ATM germline mutation carriers with PCa under AS reported higher tumor grade reclassification rates than in noncarriers (hazard ratio [HR] 2.74, 95% confidence interval [CI] 1.26–5.96; p = 0.01) [23]. However, reclassification rates are similar to rates described in other AS cohorts [24]. Another study in 15 patients with low-risk PCa and DDR mutations under AS for a median of 28 months reported a PCa reclassification rate of 20%, similar to that in the general AS population [25]. Based on this limited evidence, AS is, in principle, feasible among PGV carriers and could reduce overtreatment, but given the significant reclassification rates, shared decision-making with the option of local treatment for patients with BRCA2 mutations is recommended [18].

Localized prostate cancer

After local therapy (radical prostatectomy or external-beam radiotherapy), BRCA1/2 PGV carriers have been reported to have a higher risk of metastasis and mortality with a cancer-specific survival of 61% versus 85% in noncarriers (p < 0.001) at 10 years [26]. The difference in this retrospective cohort was especially noted for patients after radiation therapy, as surgery reduced PCa-specific mortality by 48%. Patients in the radiotherapy cohort had more aggressive disease than those in the surgery cohort, which limits the direct comparison of the two groups. Among the 2019 patients enrolled in PCa screening trials, the rates of high-risk PCa, lymph node involvement (15% vs. 5%), and metastasis (18% vs. 9%) were higher in BRCA1/2 carriers than in noncarriers [4]. In addition, lower cancer-specific survival was observed in carriers than in noncarriers after standard-of-care therapy (8.6 years versus 15.7 years), and median overall survival was also decreased in carriers compared to noncarriers (8.1 years vs. 12.9 years). In a study on neoadjuvant androgen deprivation therapy followed by radical prostatectomy, a similar pathological response and no difference in the 3‑year biochemical recurrence-free survival rate was reported between DDR germline mutation carriers and noncarriers [27]. Of note, BRCA2 carriers represented only one-third of the DDR cohort. Whether a specific therapeutic approach, therapy intensification, or adjuvant therapy offers therapeutic advantages for high-risk localized PCa patients with PGVs is currently unclear, but ongoing clinical trials are addressing this pending question (NCT03432897, NCT04030559, NCT04037254).

Metastatic prostate cancer

For patients with metastatic castration-resistant (mCRPC) disease and BRCA1/2, other DDR alterations or PGVs in DNA mismatch genes, targeted therapies are available in the context of precision medicine approaches.

Several trials have shown a benefit in survival when treating DDR carriers with PARP inhibitors (PARPi), either as monotherapy or in combination with androgen receptor inhibitors (ARIs) [28,29,30,31,32]. The PARPi olaparib significantly prolonged survival compared to ARIs in mCRPC patients with somatic BRCA1/2 or ATM mutations after previous treatment with a different ARI [28]. Another PARPi, rucaparib, has been tested as monotherapy in a phase III study in patients with somatic BRCA1/2 or ATM mutations evaluating rucaparib or physician’s choice of abiraterone, enzalutamide or docetaxel after progression on ARIs. Recent results show that rucaparib significantly prolongs progression-free survival (PFS) compared to ARIs or docetaxel in this setting [30]. The PROpel trial reported that concurrent olaparib plus abiraterone versus abiraterone alone in first-line mCRPC treatment leads to improved PFS regardless of mutation status. However, subgroup analysis showed that the effect was more pronounced in patients with somatic DDR mutations [29]. Improvement of PFS was also observed in mCRPC patients receiving talazoparib plus enzalutamide versus enzalutamide in patients with and without alterations, with a noteworthy benefit especially among patients with somatic BRCA2 alterations [31]. In contrast to these unselected populations, a trial comparing niraparib and abiraterone versus abiraterone alone in first-line mCRPC observed a significant improvement in PFS solely in patients with somatic DDR alterations [32]. These trials demonstrate a significant benefit from PARPi therapy in mCRPC patients with PGVs or somatic alterations in BRCA1/2. Several other trials with PARPi in earlier-stage PCa are ongoing, i.e., the NADIR trial in high-risk localized PCa, the AMPLITUDE trial in metastatic castration-sensitive PCa, and a trial evaluating olaparib monotherapy in biochemical recurrence after radical prostatectomy in patients with and without BRCA1/2 alterations, which may lead to further indications for PARPi in PCa [33,34,35].

A subset of mCRPC patients with MMR alterations may benefit from CKI therapies. In a basket trial by Le et al., CKI therapy with pembrolizumab was tested in MMR-deficient cancers across 12 advanced cancer types, including PCa [36]. In this heavily pretreated and heterogenous cohort, CKI treatment showed an overall response rate of 53% and a complete response rate of 21%, which led to US Food and Drug Administration (FDA) approval for pembrolizumab for all solid tumors with MMR deficiency or MSI high without satisfactory alternative treatment options [37]. A case series of PCa patients with tumor and germline sequencing has shown that approximately 3% of PCa patients have MMR deficient tumors and that 25% carry a germline mutation in MMR genes. The retrospective study further showed that although these alterations were found in a small subset of PCa patients, approximately 45% of PCa MSI-high tumors clinically benefited from pembrolizumab treatment [38].

Conclusion

Management of prostate cancer (PCa) patients with germline mutations is essential in PCa screening, active surveillance, and localized or metastatic PCa treatment (Table 2). Given the recent recommendations for genetic testing and subsequent identification of mutation carriers, data on the best management of PCa patients with pathogenic germline variants (PGVs) at different stages during disease development is still scarce. In particular, experience how to manage patients with less well-studied but still rather frequently encountered alterations such as CHEK2 or ATM is limited, and further studies are needed to offer optimal clinical management for these patients.

Table 2 Selected studies with impact on clinical management of prostate cancer patients with germline mutations
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