Accelerating precision medicine in metastatic prostate cancer

Abstract

Despite advances in the screening and treatment of prostate cancer, the therapy options available, particularly for later stages of the disease, remain limited, and the treatment-resistant setting represents a serious unmet medical need. Moreover, disease heterogeneity and disparities in patient access to medical advances result in considerable variability in outcomes across patients. Disease classification based on genomic sequencing is a promising approach for identifying patients whose tumors exhibit actionable targets and for making more informed treatment decisions. Here we discuss how precision oncology can be accelerated to inform broader genomically driven clinical decisions for men with advanced prostate cancer, to inform drug development and, ultimately, to contribute to new treatment paradigms.

Main

Although prostate cancer affects nearly 1.3 million men worldwide each year1, there is wide variability in outcomes across patients. Prostate cancer can be classified into clinical disease states that help guide therapy, patient counseling and goals of care (Fig. 1). Efforts in the clinically localized setting have focused on minimizing intervention for those patients with indolent prostate cancer that can be safely monitored, and escalating intervention for those with aggressive tumors at highest risk of relapse. Emerging tissue-based molecular and genomic biomarkers and imaging tools have been developed to improve clinical risk stratification and precision medicine in this disease space2,3,4,5, although data on how best to apply these clinically are still accumulating. For those men who develop metastatic disease, genomic sequencing is now more routinely applied to help guide the choice of systemic therapy, including the selection of therapy with a poly(ADP-ribose) polymerase (PARP) inhibitor or immunotherapy for those with castration-resistant disease6. In the following sections, we review the current treatment landscape and advances in the genomic classification of advanced prostate cancer, with a focus on challenges in the wider clinical adoption of the latter and potential strategies for overcoming these barriers.

Fig. 1: The unmet need of precision medicine across different clinical states of prostate cancer.
figure1

Prostate cancer encompasses a variety of diseases, ranging from indolent tumors to lethal tumors. Localized prostate cancers are managed with active surveillance or are treated with surgery, radiation and/or ADT. Metastatic prostate cancer shows enrichment for loss of genes encoding tumor suppressors and molecules involved in DNA-repair processes (left); some of these alterations may be relevant to predicting the outcome to therapies. Far right, key questions that can be addressed by precision-medicine studies across the disease spectrum to improve patient outcomes. ERG, oncogene (‘ETS-related gene’).

The clinical landscape of advanced prostate cancer

Either metastatic prostate cancer can develop after local therapy or, less commonly, men can present with metastatic disease (Fig. 2). Although it is considered incurable but highly treatable, the goals of care for patients with advanced disease have focused on systemic control, prolongation of life and improved quality of life. The most common sites of prostate-cancer metastasis are bone and lymph nodes, although some patients do develop visceral disease (e.g., liver and lungs) especially in later stages7. Over 70% of patients with prostate cancer develop bone metastases, and bone is the sole site of disease in nearly 50% of patients7,8. Bone lesions are often sclerotic, identified by bone scan and computerized tomography (CT) scan, and are challenging to evaluate in the context of response and progression on systemic therapy. Clinical criteria have been developed specifically for prostate cancer that rely on a decrease in serum prostate-specific antigen (PSA) and a change in the size of measurable, non-skeletal disease, with a definition of progressive disease that includes the emergence of new bone lesions observed on bone scans9. Research incorporating novel imaging techniques may lead to more-accurate assessments of response and progression10.

Fig. 2: Current therapeutic landscape for different clinical states of advanced forms of prostate cancer.
figure2

Summary of currently approved therapeutic strategies across advanced prostate cancer. Biochemical relapse after local therapy (top left) can evolve toward the emergence of metastasis (middle left) or, alternatively, the development of castration-resistant disease in the absence of visible metastatic disease (top right; non-metastatic CRPC). Once mCRPC ensues (bottom right), several therapies are available, but there are few tools for prioritizing them for each individual patient as subsequent lines of therapy. Tan boxes indicate drugs approved irrespective of molecular profiling; pink boxes show biomarker-driven therapies, approved only for molecularly defined subpopulations. ARSI, AR signaling inhibitor.

The mainstay of therapy for men with metastatic prostate cancer is androgen-deprivation therapy (ADT). Prostate cancer arises as a hormonally driven disease that relies on activation of the androgen receptor (AR) by endogenous ligands (e.g., testosterone and dihydrotestosterone) for growth and is initially responsive to ADT, which inhibits testosterone production by the testes11. The emergence of resistance to ADT leads to castration-resistant prostate cancer (CRPC). AR signaling represents the main driver of prostate-cancer progression12, and understanding its regulation has advanced both therapies that target this signaling axis and knowledge of the mechanisms that underlie treatment resistance. The majority of castration-resistant prostate tumors retain their dependence on the AR cistrome, mainly through genomic amplification or mutation of the AR gene and alterations in androgen synthesis, among other mechanisms13. More-potent next-generation AR-targeting agents now have a dominant role in the treatment of CRPC14,15,16,17,18,19 and hormone-naive metastatic prostate cancer in combination with ADT20,21,22,23. These drugs act through the inhibition of extra-gonadal androgen formation (i.e., abiraterone acetate) or through direct inhibition of the AR (i.e., enzalutamide, apalutamide and darolutamide). Nonetheless, resistance to these potent agents inevitably occurs, and cross-resistance limits their utility when they are used sequentially24,25. Furthermore, there remains a subset of patients with rapidly progressive, virulent disease that is unresponsive or minimally responsive to manipulation of the AR axis26,27.

Patients with metastatic CRPC (mCRPC) have multiple treatment options with varied mechanisms of action, including additional potent AR-targeted agents, taxane chemotherapies28,29,30,31, the bone-targeted radiopharmaceutical radium-223 (ref. 32), the cell-based immunotherapy sipuleucel-T (ref. 33) and, more recently, biomarker-driven therapy with the immune-checkpoint inhibitor pembrolizumab (for those with mismatch-repair deficiency (dMMR) or microsatellite instability (MSI)) and the PARP inhibitors olaparib and rucaparib (for those with homologous-recombination gene deficiency). Despite such advances, the median overall survival after the development of mCRPC remains approximately 3 years34, with wide intra-patient variability in response to therapies.

Genomic classification of metastatic prostate cancer

Although the majority of men with potentially lethal disease are not treated on the basis of molecular-biomarker selection, genomic observations combined with preclinical studies have pointed to potential predictive and prognostic biomarkers and emerging resistance mechanisms that hold promise for improving the selection of existing and developing therapies for patients (Fig. 3).

Fig. 3: Proposed workflow for the implementation of genomic testing in prostate cancer in clinical practice, from sample acquisition to clinical decision-making.
figure3

Suitable sources of tumor material for genomic testing include biopsies of the primary or metastatic tumors, or circulating tumor material (top). First, tumor DNA and RNA is isolated and sequenced (blue box); then next-generation sequencing data are processed and reported to physicians (orange boxes). These data would then be integrated into the treatment clinical decision-making (yellow boxes). The text boxes list key concepts to consider at each step of the genomic testing workflow. CNA, copy-number alterations.

Genomic sequencing studies have identified a high frequency of alterations involving cancer-related genes in metastatic prostate tumors35,36,37, including those commonly seen in localized disease and thought to be ‘early’ pathogenesis events, such as fusions of genes encoding members of the ETS family of transcription factors (approximately 40–50%) (Fig. 1 and Table 1). Other alterations for which CRPC shows enrichment include those involving AR (observed in >50% of cases); TP53, which encodes the tumor suppressor p53 (in >40% of cases); genes encoding components of the PI3K pathway, such as PTEN (in 45% of cases); BRCA2, BRCA1, ATM and other genes encoding molecules involved in homologous recombination DNA repair (in 20–25% of cases); loss of CDK12, which encodes a molecule also proposed to be involved in DNA repair (in 5–7% of cases); loss of RB1, which encodes the tumor suppressor Rb (in ~20% of cases); genes encoding components of the Wnt signaling pathway (in ~15% of cases); genes encoding epigenetic regulators (in ~20% of cases); and genes encoding components of the MAP kinase pathway (in ~5% of cases). Co-occurrence of alterations in those pathways is commonly observed. Approximately 30% of advanced prostate cancers have been reported to harbor a potentially actionable alteration beyond the AR36, defined as an alteration that may be predictive of response to an existing drug, at least on the basis of pre-clinical data, although the strength of the data needed to define clinical actionability is subject to debate.

Table 1 Prevalence of recurrent genomic alterations across prostate cancer disease states in published cohorts

Approximately 3–5% of prostate cancers harbor evidence of DNA dMMR, hyper-mutation or increased MSI (MSI-high tumors) that can be identified through DNA sequencing and/or immunohistochemistry detecting loss of MMR proteins38. Patients with such cancers may benefit from treatment with pembrolizumab, an antibody that targets the immunoinhibitory receptor PD-1 and has been approved by the US Food and Drug Administration (FDA) for all dMMR, MSI-high or tumor mutational burden–high solid tumors, and some tumors have shown durable responses to this or other immune-checkpoint inhibitors39. Despite the availability of an FDA-approved therapy, it is not clear how often patients with metastatic CRPC undergo testing for dMMR or MSI, if and/or when they are also being tested for germline aberrations, such as Lynch syndrome, and what to expect about their degree and duration of response to immunotherapy.

In addition, ~20% of men with mCRPC have germline or somatic alterations involving genes encoding molecules that mediate homologous recombination–mediated DNA repair, such as BRCA2, which may be predictive of a response to PARP inhibitors and platinum chemotherapy. The phase 3 PROfound clinical trial identified a significant benefit in radiographic evidence of progression-free survival and overall survival for olaparib in patients with DNA-repair aberrations previously treated with a potent AR-pathway inhibitor for CRPC40. This was the first phase 3 biomarker-based trial of mCRPC, and these data provide a clear rationale for molecular testing in patients with advanced disease. Although responses were observed across patients with different alterations, the benefit was especially evident for men with BRCA2 alterations. The phase 2 TRITON2 trial of the PARP inhibitor rucaparib has also demonstrated antitumor activity for patients with germline or somatic BRCA alterations41. On the basis of these studies, olaparib and rucaparib were recently approved by the FDA for the treatment of patients with mCRPC and certain homologous-recombination deficiencies. Exceptional responses to platinum chemotherapy have also been identified in patients with prostate cancer in which BRCA2 is mutated42,43. There is still much to learn about the effect of less-common genes encoding DNA-repair molecules on responsiveness to PARP inhibitors and other potential mediators of sensitivity and resistance to PARP inhibitors and platinum chemotherapy. The use of other agents that target the DNA-damage response, such as inhibitors of the DNA damage–sensing molecule ATR, may be particularly relevant for prostate cancer in which ATM is mutated44,45. Alterations CDK12, resulting in tumors characterized by focal tandem duplications, high neoantigen burden and poor prognosis, have been associated with sensitization to immune-checkpoint blockade, and clinical trials of this are ongoing46,47,48,49.

Approximately 45% of mCRPC tumors have alterations in the PI3K pathway. Rarely, these are hotspot mutations in PIK3CA (which encodes the PI3Kα catalytic subunit), which may be relevant given the FDA approval of alpelisib, an inhibitor of PI3Kα, for the treatment of breast cancer in which PIK3CA is mutated50. However, in most cases they occur as loss of function of the PTEN gene. Single-agent drugs that target the PI3K pathway have demonstrated limited efficacy for patients with mCRPC51, although preclinical data suggest benefit from concurrent inhibition of the AR52. A phase 2 study showed benefit for the combination of abiraterone with ipatasertib, which inhibits the serine-threonine kinase AKT, particularly in PTEN-deficient mCRPC53, and a phase 3 trial is ongoing (NCT03072238). Rare hotspot alterations (~1%) in AKT1 and its homologs may be potentially targetable with AKT inhibitors, which have shown activity in breast cancer and other solid tumors in which AKT is mutated54. Other less common hotspot alterations (<5%) in CRPC occur in BRAF (a proto-oncogene that encodes the serine-threonine kinase B-Raf), MAP2K1 (which encodes the kinase MEK1) and KRAS (a proto-oncogene that encodes the GTPase Ras).

In addition, a subset of CRPCs with unusually aggressive clinical behavior include those that develop histologic features of small-cell neuroendocrine carcinoma and/or have molecular characteristics typified by loss of the tumor suppressor–encoding genes RB1 and TP5326,55,56. These are particularly evident in later stages of the disease, partly as a result of tumor evolution and treatment-driven selective pressure57. RB1 loss in particular has been shown to be strongly associated with poor clinical outcomes in advanced prostate cancer39,58,59. Strategies for selectively targeting tumors with aggressive or atypical histologic, clinical or molecular findings include the use of platinum chemotherapy56,60,61 or other targeted approaches26,62,63. Insights into how these alterations might be further leveraged are particularly needed.

Challenges for precision medicine in prostate cancer

With increased understanding of the molecular landscape of advanced prostate cancer, there has been a rise in the clinical use of genomic sequencing to identify actionable targets. However, the optimal use of genomics to guide clinical decision-making in prostate cancer is not well defined, and there are no current guidelines to inform the timing, type of tissue or optimal set of clinically validated laboratory tests. With a growing number of agents being used off-label, the data reported have mostly been non-systematic. There remain substantial barriers to the implementation of precision oncology for patients (Table 2), and the development of strategies for overcoming these challenges is critical.

Table 2 Priorities for accelerating precision medicine in metastatic prostate cancer

Challenge 1: access to tumor tissue for molecular profiling

The procurement of tumor material is a vital step for molecular characterization. Over 70% of patients with metastatic prostate cancer develop bone metastases, with nearly half having bone-predominant disease7,8. Despite imaging guidance, biopsy of osteoblastic bone metastases can be technically challenging and often yields insufficient tumor tissue. Moreover, sample decalcification may affect the quantity and quality of nucleic acids. Even in high-volume academic centers that have tissue-acquisition protocols in place, the viable tumor tissue yield from bone biopsies for genomic assays is relatively low. In a whole-exome sequencing study, 43 of 76 bone biopsies (57%) were successfully sequenced64. A second study obtained adequate tissue from 76 of 110 image-guided bone biopsies (67%)65. In both series, careful patient selection led to increased yields. Lymph-node biopsies of have higher success rates; however, accessibility to pelvic and retroperitoneal lymph nodes may not be feasible in many patients.

The use of primary prostate tumor, such as biopsy cores or radical prostatectomy tissue, for the molecular stratification of advanced prostate cancer could overcome some of the challenges in acquiring metastatic biopsies for certain genomic alterations, such as those in genes encoding DNA-repair molecules. Indeed, some driver alterations show high concordance between primary tumors and metastatic tumors66. However, prostate biopsy cores may often contain insufficient tumor content, or the DNA obtained may be too low in yield or too degraded for genomic testing. In the phase 3 PROfound trial, quality-control failures accounted for 31% of all samples prospectively analyzed40. Primary localized prostate tumors are commonly multifocal67,68 and therefore the sample obtained may not always represent the clone that is driving metastatic spread. Furthermore, treatment-naive biopsies do not capture acquired alterations that may develop after progression on systemic therapies, reflective of treatment resistance and/or clonal selection.

Challenge 2: tumor heterogeneity

Multifocal prostate cancer consists of spatially and clonally distinct tumors within the primary prostate gland68. Most studies thus far support the proposal of a monoclonal origin of metastatic prostate cancer, with metastatic lesions traceable back to one founding clone within the primary tumor69,70. Tumors subsequently acquire alterations with disease progression and treatment resistance, and polyclonal metastasis-to-metastasis seeding can further lead to intra-patient heterogeneity71,72. Although autopsy studies have supported the finding of limited intra-individual heterogeneity across metastases in the context of alterations involving common oncogenes and tumor suppressor–encoding genes in late-stage disease73, more data are needed to understand how faithfully single-site metastatic biopsies represent the overall metastatic tumor burden in patients with prostate cancer and how tumor heterogeneity is affected by selective pressures from exposure to specific therapies. This is particularly relevant in the setting of oligoprogression, or cases in which differential responses are observed across sites of metastases, with some lesions progressing and others maintaining good responses due to differences between anatomical sites in their therapy response and resistance mechanisms. Greater understanding of the molecular mechanisms that promote heterogeneity and resistance is critical. For example, certain genomic or epigenomic alterations may promote plasticity or transcriptional dysregulation under therapy pressure57, and in other cases, subclonal genomic alterations emerge and/or act together to drive resistance to treatment74.

Challenge 3: detection of loss-of-function events and complex drivers

An additional layer of complexity for precision medicine in prostate cancer is intrinsic to the genomic makeup of the disease. Beyond alterations involving the AR gene, which a major driver of treatment resistance, many of the genomic alterations for which metastatic prostate cancer shows enrichment involve loss of tumor suppressor–encoding genes (such as PTEN, TP53 and RB1) rather than activating events (such as hotspot mutations in BRAF, PIK3CA or AKT). Loss of tumor suppressor–encoding genes can be the result of truncating mutations (which can occur anywhere along the gene), gene deletions (complete or partial) or complex gene rearrangements. Assessing the presence of loss-of-function events in a given gene is more challenging than is assessment of activating hotspot mutations identified through multiplexed panels. Furthermore, whereas loss of PTEN or BRCA2 may be predictive of tumors susceptible to inhibition of AKT or PARP, respectively, deletions of other genes, such as RB1, have been shown to be prognostic36,58, and their value as predictive biomarkers to guide therapy selection is not yet supported by strong data. Co-occurrence of deletion of BRCA2 and of RB1 is also frequent, given these genes’ physical proximity75. Loss of RB1 may serve a different role in facilitating lineage plasticity in the context of concurrent TP53 loss or other features75,76,77.

There is a long list of less common alterations in mCRPC for which little is known about their predictive or prognostic role or functional importance78. This ‘long tail’, which represents alterations that occur in <5% of patients, may provide unique insights into the identification of rare subsets of patients with distinct biology or therapeutic responses, alone or in combination with other events. However, traditional study designs are not geared toward investigating the clinical value of low-prevalence events.

Most clinical assays for precision medicine rely on targeted exome sequencing, either tumor-only sequencing or paired tumor and germline testing. The integration of tumor sequencing with germline sequencing offers the additional benefit of not requiring separate tests and the ability to assess loss of heterozygosity. There is also a wealth of data in non-coding regions. Whole-genome sequencing, although not clinically used today, is capable of detecting structural alterations and rearrangements that lead to the dysregulation of cancer-related genes and resistance-causing alterations48,79. An additional layer of information may be retrieved through tumor mRNA analysis to identify gene fusions and gene-expression profiles, protein expression and DNA methylation to capture epigenetic alterations, although none of these approaches are currently considered clinically actionable. Despite the potential of exploiting emerging molecular findings to learn about disease biology and discover new therapeutic targets, the gap between what is theoretically possible and what is practically feasible, especially in the clinic, remains substantial.

Challenge 4: clinical and genomic integration

Prostate cancer is unique among other cancer types due to its long natural history, the clinical use of PSA as a routine biomarker and its tendency to metastasize to bone, which makes measurements of response and resistance complex. Therefore, the relevant clinical data elements and endpoints in prostate cancer differ from those in other cancers, which is particularly pertinent in defining ‘exceptional responder’ and ‘non-responder’ classifiers that are not always based on standard RECIST criteria (Response Evaluation Criteria in Solid Tumours) and may be influenced by patterns of metastases (e.g., bone versus other sites), PSA dynamics and disease state. Identification of an ‘exceptional’ responder probably requires a definition that goes beyond the traditional complete response, assessed by radiography or PSA, but should also encompass those patients who achieve a durable benefit (e.g., lack of a need to restart or switch systemic therapy for 24 months or more) (Fig. 4).

Fig. 4: Learning from exceptional responders.
figure4

How the study of exceptional responders can lead to advances in the treatment of prostate cancer. A group of patients with prostate cancer receive treatment A (top left). The ‘swimmers’ plot (middle) shows how only some patients (in green) achieve a long-lasting response, whereas other patients are mostly resistant to drug A. Comparison of the molecular profiles of sensitive patients (in green) versus those of resistant patients may lead to the identification of putative relevant predictive biomarkers of response and resistance, to be validated in functional laboratory studies (right). Biologically validated biomarkers would then be tested back in clinical trials for clinical qualification, ideally enriched for those patients presenting the biomarker of interest (patients in green). If qualified, this enrichment would lead to an improved outcome for treatment A for patients with the putative biomarker (‘waterfall’ plot at bottom left). rPFS, radiographic progression-free survival.

In addition to integrating clinical features with genomic and other molecular alterations to identify clinically meaningful biomarkers, decision support for clinicians based on existing information is also needed. More specifically, accurate interpretation of genomic findings requires a harmonized use of terminologies. Most laboratory providers offer a clinician-oriented report as the final product from a DNA-sequencing test. However, beyond well-validated biomarkers for approved drugs, such reports often highlight gene aberrations on the basis of their functional impact rather than on the clinical actionability of the event detected, which makes the linking of patients with the most appropriate treatments or clinical trials challenging. As patients go on to receive biomarker-driven therapies, the collection of specimens to learn from responders and non-responders and those who develop acquired resistance can help catalyze future mechanistic studies.

Challenge 5: understanding the impact of genomics in diverse patient populations

Knowledge of the extent to which molecular and genomic mechanisms contribute to the progression and treatment resistance of prostate cancer in diverse patient populations is limited. Most published genomic studies were conducted at select academic institutions and were limited to patients of mainly European ancestry64,80. ETS gene fusions are less common in prostate tumors of men of Asian ancestry than in such tumors in those of European origin, and other alterations, such as loss of CHD1 (which encodes a tumor suppressor), are more common81,82. amplifications in MYC (a proto-oncogene that encodes the transcription factor c-Myc) have been reported to be more frequent in tumors from African-American men than in tumors from those of European origin, and PTEN deletion and ETS gene fusion are less common83. The question of how to address disparities in prostate cancer is of particular relevance, given the higher incidence and mortality rate in African-American men84. However, there exist reports that Black men have outcomes similar to or better than those of white men in certain settings and when access to care settings was equal85,86,87. There is also a need to expand access to genomic and genetic testing and to better understand how specific data from academic centers translate to the broader community where the majority of the population receives care. Otherwise, there is a risk that genomic testing will contribute to health disparities, if data from select population groups are incorrectly attributed to the wider society.

Challenge 6: access to matched therapies and clinical trials

Advancements in understanding prostate-tumor biology, the accelerated development of new targeted drugs and the acknowledgement of often suboptimal drug-approval timelines by traditional approaches have resulted in novel clinical-trial designs, including basket, platform and umbrella trials, intended to accelerate drug development and approval88. Umbrella trials enroll patients with the same histological cancer type and assign them to different treatment cohorts on the basis of the presence of a specific biomarker. Platform trials are an extension of umbrella trials: patients are randomly assigned to different cohorts and, by following statistical algorithms, researchers adapt new therapies or drop existing therapies from an ongoing study89. Basket trials group patients on the basis of a specific biomarker, regardless of their tumor type, which is particularly helpful for biomarkers that are present at a low frequency. Biomarker-driven strategies require validated, reproducible and scalable biomarker tests. Several multi-institutional efforts combine the umbrella and basket concepts by enrolling patients with multiple cancer types; these include the NCI-MATCH trial (National Cancer Institute Molecular Analysis for Therapy Choice); the ECOG-ACRIN (Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network) ComboMATCH, a successor to NCI-MATCH that focuses on drug combinations; the ASCO TAPUR trial (the American Society of Clinical Oncology Targeted Agent and Profiling Utilization Registry); and the iMATCH trial (Innovate Manchester Advanced Therapy Centre Hub) in the UK. Despite the available biomarker trials, including those dedicated to patients with prostate cancer, trial accessibility and effective matching to patients remain challenging, especially outside of academic institutions. The underlying factors include trial slot limitations, patient proximity to clinical-trial centers, exclusion from pan-cancer studies due to the need for concurrent ADT or a requirement of measurable non-bony disease, and insufficient familiarity of clinical practitioners with genomic biomarkers and trial-matching tools.

Strategies for overcoming barriers

In this section we propose strategies for addressing the limitations listed above and for facilitating the translation of precision oncology to the broader population of patients with prostate cancer.

Strategy 1: improving tumor tissue acquisition

Given the challenges of obtaining biopsies from metastatic sites of prostate cancer, there is clearly a need for the engagement of radiologists, pathologists and oncologists to establish guidelines that can improve biopsy yield and can be widely implemented in clinical practice. Various groups have reported their experience in optimizing bone-biopsy procedures and pathology-processing protocols to achieve the following: (1) maximize the quality of the obtained material90,91; (2) validate clinical algorithms to stratify patients on the basis of the likelihood of successful biopsy92; and (3) develop imaging assays to guide the selection of target bone lesions10. Training, experience and feedback are key to improving the skills of clinicians and biomedical professionals; thus, cross-institutional educational initiatives, such as teaching videos that show the current best practices and emerging techniques for bone biopsy and procurement, may be useful. Although protocols are not standardized at present, our review of current studies that evaluate biopsies from metastatic prostate-cancer sites has identified a number of parameters to be considered for the optimization of tumor yield for successful molecular sequencing (Box 1). The advent of next-generation imaging may also offer the opportunity for incorporating higher-resolution and functional assessments of the tumor. These techniques, including multiparameter magnetic resonance imaging (MRI) with diffusion-weighted imaging and positron-emission tomography (PET)–CT or PET–MRI fusions, could help optimize biopsy acquisition10. Moreover, the use of primary diagnostic samples may facilitate the implementation of genomic testing beyond academic institutions. Diagnostic guidelines should account for the collection of formalin-fixed paraffin-embedded blocks specifically for future genomic testing in the planning of procedures for biopsy acquisition and handling.

Strategy 2: accounting for tumor heterogeneity in clinical practice

Advanced imaging assays could also help in the selection of lesions with resistance to systemic agents for re-biopsy. Molecular imaging, such as prostate-specific membrane antigen (PSMA) PET–CT, provides insights into tumor heterogeneity across and within lesions. Nearly all hormone-naive and castration-resistant prostate-cancer cells express PSMA. PSMA PET imaging is a highly sensitive and specific imaging modality, and PSMA-directed ‘theranostics’ (therapeutics and diagnostics) are in clinical development. However, in later stages of prostate cancer, some castration-resistant prostate tumors lose PSMA expression and/or demonstrate discordance of PSMA PET versus FDG (fluorodeoxyglucose) PET, a state that has been associated with AR-independent disease and aggressive clinical activity93,94. Therefore PSMA imaging may help guide patient selection for PSMA-directed therapies and/or targeted biopsies to look for AR-independent disease or other molecular targets.

The isolation of tumor material from blood, such as circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs), also offers opportunities for non-invasive characterization of molecular features of metastatic tumors in a manner tailored to the patient. Liquid biopsies also capture intra-patient tumor heterogeneity by identifying tumor alterations across metastases whose cells have entered the bloodstream and can address temporal evolution of alterations, as repeated samples may be obtained over time without major discomfort for patients95,96,97,98. The amount of circulating DNA derived from tumor cells in the blood increases with disease progression, which makes most assays most sensitive in the setting of metastatic disease99. The detection of AR alterations (e.g., mutations or amplification) in ctDNA has been associated with inferior outcomes in men with CRPC treated with inhibitors of the AR pathway100,101. Targeted and whole-exome ctDNA sequencing has shown high concordance with matched tumor biopsies in capturing clinically relevant and recurrent prostate-cancer aberrations102,103. Nevertheless, cell-free DNA fragments are usually small, which renders copy-number estimation challenging. This is being progressively addressed by technological improvements and advanced computational pipelines100,104,105.

CTC enumeration in patients with CRPC is prognostic, and changes in CTC numbers on therapy have been identified as surrogates of overall survival at a single-patient level, which offers a promising intermediate endpoint for accelerating the development of new agents in phase 2 clinical trials106. Expression of the AR splice variant AR-V7 in CTCs has been associated with inferior response to AR-pathway inhibitors in men with mCRPC107. Single-cell CTC genomics can also capture tumor heterogeneity108,109. CTCs are amenable to various types of analyses, including DNA, mRNA and protein tests, as well morphological assessment in terms of shape, size and clustering, for the identification of specific resistance phenotypes110,111,112. However, CTC counts are variable across patients, and not all patients are amenable to all these analyses at once; interpretation of these counts is influenced by tumor burden and tumor heterogeneity. It is important to also recognize that while both ctDNA approaches and CTC approaches may be useful tools for the non-invasive detection of certain alterations, important features of the tumor (such as tumor morphology and cell-surface proteins), as well as the microenvironment, are crucially missing, and tumor biopsies will probably remain standard in the selection of patients for treatment with drugs that target these types of non-genomic features.

Strategy 3: improving the detection of clinically relevant genotypes and phenotypes

There is a pressing need for the clinical characterization not only of single-gene aberrations, including long-tail events, but also of combined or co-occurring alterations. Understanding their incidence, context and clinical importance will require detailed data capture. Functional characterization of less common alterations is also needed. Understanding their biologic importance and incorporating preclinical approaches such as genome-wide library screening may point to therapeutic vulnerabilities and provide new opportunities for target discovery (e.g., synthetic-lethal approaches).

Although whole-genome sequencing and non-genomic assays are currently limited mostly to research studies, these broader platforms will probably enter the clinic in the future, and these data should be systematically assessed in a way similar to that used for targeted panels. Beyond genomically selected trials, some therapeutic trials are targeted to non-genomic biomarkers and require specific biomarker tests available only as part of trial screening. Examples include PSMA-targeted therapies that require PSMA imaging for eligibility, AKT-inhibitor studies that require immunohistochemical detection of the loss of PTEN protein, and therapy targeting the kinase CDK4 that requires immunohistochemical assessment of Rb. Although use of the majority of these assays is considered investigational for CRPC, integration of these data with genomics may provide information on the optimal genotype and phenotype for patient selection in the future. Transcriptome analyses may be useful for identifying pathway alterations such as PI3K–AKT activation, AR activity, neuroendocrine programs or glucocorticoid receptor–driven programs, which may be useful clinically for the selection of existing or emerging drugs. Developing ways to adopt these emerging assays in clinical practice by understanding how to standardize, validate and implement them on a routine basis will be critical.

Strategy 4: integrating clinical and genomic landscapes in routine practice

Building platforms that link genomic and clinical outcome data can help uncover the importance of an individual mutation or spectrum of alterations, especially for infrequent genomic events that are unlikely to be appreciated in small data series. This framework has the potential to also inform the design of biomarker-driven clinical trials. National genomic-medicine programs provide the opportunity to promote best practices in data sharing by structuring consent processes, harmonizing clinical and genomic data collection, organizing data access, and committing to global data exchange.

The development of tools for accumulating and visualizing clinical–genomic datasets is also important. The cBioPortal for Cancer Genomics is an open-source software system that allows the visualization and analysis of large-scale cancer genomic datasets113,114. Although this portal facilitates the exploration of multidimensional cancer genomics, at present it has limited information on treatment-specific variables, including treatment types, duration and response. The American Association for Cancer Research’s project GENIE (Genomics Evidence Neoplasia Information Exchange), which utilizes cBioPortal as a strategic partner, is an international pan-cancer registry of real-world data assembled through data sharing between academic cancer centers that contribute clinical-grade genomic data and data on clinical outcomes115,116. Leveraging these existing platforms may help fast-track research in prostate cancer through data sharing between a wider scope of academic centers and may serve as a framework for the future expansion of similar efforts to community practices.

The integration of genomic data into the electronic medical record, initially designed as an ordering, billing and clinical documentation system, could also help facilitate clinical decision-making and act as a scientific discovery platform. A substantial amount of longitudinal clinical data is accessible within the electronic medical record, and having this information linked to genomic data could help unveil previously unrecognized correlations and patterns. Alternatives to human curation for large sets of clinical variables, such as machine-learning and artificial-intelligence strategies for the integration of pathology and radiology with genomic data, will be critical features for ensuring scalability117. The formulation of consistent standards for the transfer of genomic results and defining the optimal legal and ethical framework for access and use of human data are also critical.

Platforms that integrate various levels of evidence, including mutation and cancer type, and therapeutic targets, can help facilitate treatment decisions. Several pan-cancer resources, such as OncoKB (a precision oncology knowledgebase)118, PMKB (Precision Medicine Knowledgebase)119 and other knowledgebases120, and ESCAT (the European Society For Medical Oncology Scale for Clinical Actionability of Molecular Targets)121, utilize levels of evidence systems to assign clinical actionability to an individual genomic event with the goal of supporting optimal treatment decisions and providing a shared vocabulary to facilitate communication between the relevant stakeholders, including patients, physicians, healthcare systems, the pharmaceutical industry and regulatory bodies. Harmonized interpretation of these knowledgebases can improve patient matching120. As the treatment of cancer becomes increasingly driven by genomic data, molecular tumor boards or other decision support systems are essential, similar to the current model of disease-specific tumor boards today122,123. Point-of-care access to decision support through prostate cancer–specific virtual tumor boards or electronic applications could also help provide real-time guidance to practicing clinicians. Additionally, data capture for tracking the frequency of and reasons that drive clinical decisions is also needed, particularly for uncommon yet potentially actionable alterations. Understanding molecularly targeted responses not only is important for patients with confirmed MSI-high or BRCA-mutated prostate cancer but also should be explored in the context of other molecularly defined tumor subsets.

Strategy 5: incorporating diverse patient populations into genomic analyses to enable clinical decisions reflective of the real-world situation

Partnering with patients and advocacy groups is an essential step for raising awareness about personalized cancer care and ensuring that the diverse patient population is appropriately represented in the available datasets and subsequently developed analytical approaches. To that end, internet-based programs, such as the Count Me In Project (https://mpcproject.org), and social-media platforms can enhance visibility, engage patients and caregivers in research efforts and provide educational tools. The GENTleMEN study (NCT03053097) is an example of a germline genetic-testing study that is enrolling geographically distributed, diverse populations of patients with prostate cancer through internet consent and with testing kits delivered by mail. Engaging patients and other stakeholders will be important as platform costs and insurance reimbursements are considered as precision oncology expands beyond academic centers, and these considerations may differ on the basis of geography, health-delivery models and other factors.

Better understanding of variation in prostate-cancer treatment and care across diverse populations is needed, as is being addressed by the IRONMAN global population-based registry (NCT03151629). Given that disparities in healthcare are magnified in clinical research, focused efforts are also needed to engage diverse patient populations and different ancestries through the use of culturally sensitive methods. Studies that do not offer treatment, such as those focused on clinical data and specimen collection for genomic evaluation, should try to deliver substantive benefits to patients124. Discussions with patients should be comprehensive, honest and culturally sensitive and should highlight unique aspects relevant to large-scale initiatives, such as genomic data collection and sample sharing to advance discovery. Additionally, safeguards need to be in place to protect the privacy of patient information and genomic data during the process.

Partnering with community providers, local health departments and other stakeholders will be important for expanding access to genomic testing and precision medicine to diverse community patient populations. Programs such as IMPACT (Improving Access, Counseling & Treatment For Californians with Prostate Cancer), which has a mission to provide high-quality treatment for prostate cancer to Californian men with little or no health insurance, are models for expanding access to care for underserved patients with prostate cancer. The Prostate Cancer Foundation has developed a partnership with the US Veterans Administration to increase research and precision medicine studies offered to veterans with prostate cancer within the Veterans Administration healthcare system (https://www.pcf.org/va-partnership/).

Strategy 6: matching patients to appropriate therapies and clinical trials

Critical to precision medicine is an infrastructure that allows patients to identify and receive matched therapies, drugs approved either for a particular indication or in the context of therapeutic trials. Several tools are available for this, including the US National Institutes of Health ‘clinicaltrials.gov’ database, local molecular tumor boards at larger academic institutions, and increasingly detailed annotation of commercially available molecular testing reports that offer ease of access to ordering clinicians, including in non-academic settings. Matchminer (https://matchminer.org) is an open-source computational platform that aims to improve the matching of patient-specific genomic profiles with locally available trials on the basis of both genomics and curated sets of inclusion criteria. Establishment of a matching platform for prostate cancer along with a collaborative prostate-cancer tumor board across institutions may help facilitate the identification of available trials for patients. In addition to recruitment to existing trials and ensuring that patients with prostate cancer are eligible for studies, the development of new and accessible biomarker-driven trials for men with prostate cancer is also needed. This will hopefully limit the use of off-label drugs with preliminary efficacy and safety data in prostate cancer124, although reporting responses and tracking outcomes of these specific off-label situations will still be critical.

A call for action

Translational studies of the utility of next-generation sequencing technologies in the broader population and their impact are largely lacking. ‘Exceptional responders’ (‘n = 1’) to drugs identified on the basis of genomic testing have been reported in prostate cancer, including responses to both targeted therapies and immunotherapies, with little known about how often this occurs or details on those patients who do not respond62,125,126,127. In addition, there is a long list of less common alterations in metastatic prostate cancer with little data assessing their predictive or prognostic roles or functional importance. Identifying biomarker-specific trials for people with these alterations remains a considerable barrier to clinical practice. By leveraging existing infrastructures, including those developed by pan-cancer efforts, to collect and share ‘n = 1’ biomarker-driven precision-medicine experiences regardless of their level of success, precision oncology can be accelerated for patients with prostate cancer. Sharing such experiences can be used to inform broader genomically driven clinical decision-making and also facilitate drug development.

An ‘n = 1’ effort should be accessible to both academic practitioners and community practitioners and potentially other partners and would establish needed data on the clinical relevance of less prevalent but actionable alterations through pooled analyses. In addition to clinical actions, data on specific mutations or data from patients treated with off-label and single-patient ‘Investigational New Drug’ use of specific drugs could also be captured. Future directions may encompass streamlined central consent, data entry and specimen collection. By providing decision support and facilitating drug access, this would accelerate the accessibility of precision medicine for patients with prostate cancer. Select patients with rare targets or unexpected responses could be referred for expanded molecular assessment and enrollment in clinical trials.

Conclusions

A number of opportunities and challenges lie ahead for precision medicine in advanced prostate cancer. We have outlined some of them here, with specific short- and longer-term collaborative strategies (Table 2). Genomic testing (both germline and somatic) is increasingly being performed and is indicated for patients with mCRPC, with a subset of men having actionable targets (e.g., in genes encoding DNA-repair molecules) that have been confirmed through clinical trial data. Improving access to and implementation of genomic testing across diverse populations will be critical to optimizing access to better therapies. More widespread testing, based on updated guidelines128, is also now identifying alterations in patients at earlier stages of the disease, such as patients with high-risk localized or metastatic hormone-naive prostate cancer129.

If precision medicine is to make a difference for patients with prostate cancer, it is the duty of clinicians and researchers to define the optimal timing and type of genomic testing and application of test results for the treatment of patients. This will require first capturing data across diverse populations and understanding how these tests are being or could be used. Through the understanding of practice patterns, we envision a collaborative and global network for learning from both responders and non-responders and understanding the clinical impact of rare biologically important molecular alterations and response and resistance to therapies. Capturing the decision-making process and potentially expanding it to the collection of tissues from a focused group with prostate cancer across a wide network is a unique endeavor not currently addressed by pan-cancer efforts and should be prioritized. It is also important to consider that in the context of therapy response, it is not solely tumor-related contributing factors that should be considered but also barriers, including patient-specific considerations (e.g., alternative options, urgency of therapy, comorbidities, patient preference, toxicities and financial burdens), assay limitations and drug-access limitations. Addressing these challenges will help establish a framework for future genomic and non-genomic biomarkers and will help shape future guidelines for molecular profiling in prostate cancer, including who should receive it and when, and how biopsies and/or liquid biopsies should be done in patients to identify targets for precision-oncology therapy.

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Conception and design, all authors; analysis and interpretation of data, all authors; first draft of the manuscript, J.M., R.M., W.A. and H.B.; review and critical edits to the manuscript, all authors; final approval of the manuscript, all authors; study supervision, H.B.

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Correspondence to Himisha Beltran.

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Competing interests

J.M. reports advisory board participation for Amgen, AstraZeneca, Roche, Janssen, MSD and Clovis Oncology; and research funding from AstraZeneca and Pfizer Oncology. R.M. received research funding from Bayer, Pfizer and Tempus; serves on advisory board for Bayer, Bristol Myers Squib, Exelixis, Janssen, Novartis, Pfizer, Sanofi and Tempus; and is a consultant for Dendreon and Vividion. W.A. reports consulting/advisory for Clovis, Janssen, More Health, ORIC and Daiichi Sankyo; research funding from AstraZeneca, Zenith Epigenetics, Clovis, GlaxoSmithKline, ORIC and Epizyme; travel from GlaxoSmithKline, Clovis and ORIC; and honoraria from CARET. R.A. reports advisory board participation and research funding from Merck, AstraZeneca and Janssen. B.M. reports research funding from AstraZeneca, Janssen, Clovis, Astellas and Beigene. M.R. reports consulting for Amgen, Ambryx and Constellation; educational writing and consulting for Plexus; speaking for Bayer and Janssen; and funding and clinical research support from Novartis, Astellas, Medivation and Merck. D.S. has consulted for/received honoraria from Pfizer, Loxo Oncology, Lilly Oncology, BioBridge, Vivideon Therapeutics and Illumina. E.V.A. reports advisory/consulting from Tango Therapeutics, Genome Medical, Invitae, Enara Bio, Janssen, Manifold Bio and Monte Rosa; research support from Novartis and BMS; equity in Tango Therapeutics, Genome Medical, Syapse, Enara Bio, Manifold Bio, Microsoft and Monte Rosa; travel reimbursement from Roche/Genentech; and institutional patents on chromatin mutations and immunotherapy response, and methods for clinical interpretation. D.V. reports honoraria from Clovis Oncology. H.B. reports advisory/consulting from Janssen, Amgen, Astra Zeneca, Pfizer, Astellas and Sanofi Genzyme; and research funding from Janssen, Abbvie Stemcentryx, Eli Lilly, Millenium and Astellas. J.V. is employed by the Prostate Cancer Clinical Trials Consortium. H.R.S., J.W.S. and A.K.M. are employed by the Prostate Cancer Foundation.

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Mateo, J., McKay, R., Abida, W. et al. Accelerating precision medicine in metastatic prostate cancer. Nat Cancer 1, 1041–1053 (2020). https://doi.org/10.1038/s43018-020-00141-0

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