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Targeting PARP

Curator: Larry H. Bernstein, MD, FCAP

LPBI

 

 

Targeting PARP in Prostate Cancer: Novelty, Pitfalls, and Promise    
Review ArticleMay 15, 2016Oncology Journal, Prostate Cancer

http://www.cancernetwork.com/oncology-journal/targeting-parp-prostate-cancer-novelty-pitfalls-and-promise#sthash.fjYB5ROU.dpuf

 

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© 2016 Steve Oh and Myriam Kirkman-Oh, KO Studios

Metastatic prostate cancer remains a highly lethal disease with no curative therapeutic options. A significant subset of patients with prostate cancer harbor either germline or somatic mutations in DNA repair enzyme genes such as BRCA1, BRCA2, or ATM. Emerging data suggest that drugs that target poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) enzymes may represent a novel and effective means of treating tumors with these DNA repair defects, including prostate cancers. Here we will review the molecular mechanism of action of PARP inhibitors and discuss how they target tumor cells with faulty DNA repair functions and transcriptional controls. We will review emerging data for the utility of PARP inhibition in the management of metastatic prostate cancer. Finally, we will place PARP inhibitors within the framework of precision medicine–based care of patients with prostate cancer.

Introduction
In 2016, prostate cancer is expected to be diagnosed in 180,890 men, and 26,120 will die of metastatic disease.[1] While the majority of localized prostate cancers can be controlled with surgery and/or radiation, metastatic disease remains a lethal disease with no curative options. Moreover, prostate cancer is a heterogeneous disease that can be highly lethal but also slow and indolent, as reflected by a 10-year estimated survival of 17% (S9346 trial, unpublished data). The advent of affordable and efficient techniques for profiling tumors molecularly represents an unprecedented opportunity to better characterize the molecular factors that result in indolent and/or lethal disease and to tailor therapy accordingly. Many clinical trials are already underway to examine whether molecularly targeted therapies can improve outcomes.[2] In this review, we will specifically examine the molecular rationale for one of these targeted approaches, poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibition, in prostate cancer. We will review how PARP inhibitors function as a class, review the molecular features that sensitize cancer cells to this therapy, and discuss the data supporting its potential for patients with prostate cancer. We will then outline a strategy for further development of PARP inhibitors in the prostate cancer field.
Metastatic prostate cancer is typically categorized as hormone-sensitive prostate cancer (HSPC), which responds to androgen ablation, or castration-resistant prostate cancer (CRPC), which develops resistance to gonadal suppression. Although bilateral orchiectomy is the historic gold-standard treatment for metastatic HSPC, gonadal suppression is currently accomplished with gonadotropin-releasing hormone agonists or antagonists with or without androgen receptor blockade. This approach remains the cornerstone of therapy for men with metastatic HSPC.[3] Emerging data from large phase III trials (CHAARTED and Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy [STAMPEDE]) have also revealed a large survival benefit for the combination of docetaxel and androgen deprivation in metastatic HSPC.[4,5]

Despite these initially effective treatments, the vast majority of men with metastatic HSPC will progress to CRPC, which is the lethal stage of the disease. For these patients, several additional therapies provide benefit by further suppression of androgen signaling (enzalutamide, abiraterone), disruption of the cell cycle in replicating cells (docetaxel, cabazitaxel), targeting of bone metastases (radium-223), or activation of antitumor immunologic response (sipuleucel-T).[6] While these therapies have undoubtedly extended the median survival of patients with metastatic CRPC, their impact on survival is modest and they clearly do not work for all men. In addition, we lack validated genomic markers that would allow better selection of patients for these therapies. Therefore, a better approach that leverages the individual and unique aspects of a patient’s cancer and utilizes therapy based on these factors may allow us to improve patient outcomes.

The development of high-throughput sequencing technology has made it feasible to comprehensively analyze the genetic mutations and gene expression changes in individual prostate cancers with a high degree of resolution in real time. Many institutions now routinely perform these analyses in the hope that they might uncover molecular features that predict response to certain therapies or provide guidance for clinical trial selection.[7] This approach, colloquially termed “precision” medicine, offers the potential promise of providing the right therapy for the right patient at the right time. In the context of prostate cancer, it means molecularly characterizing a tumor and then offering patients drugs that may specifically promote tumor lethality based on these molecular features. The limitation of this approach is that it requires that the target be truly biologically relevant and that there are drugs that can effectively target these molecular changes. The discovery of both somatic and germline DNA repair deficiencies in prostate cancer, together with the development of PARP inhibitors that can kill cancer cells with these defects, is a potent example of targeting therapy to molecularly defined tumor subtypes. While much early work validating this approach has occurred in breast and ovarian cancer populations, emerging data suggest that PARP inhibition is a potentially important strategy for managing a significant subset of prostate cancer patients.

 

PARP Inhibition: Targeting DNA Repair Deficiency

Molecular mechanism

PARP1 catalyzes the addition of poly(ADP)-ribose (PAR) groups to target proteins in a process termed PARylation.[8] PARP1 is part of a superfamily of proteins that consists of 18 members (including the related tankyrase enzymes), which have many functions within normal and cancer cells. PARP1, the founding member of this family, is responsible for the majority of PARylation of protein targets within cells. It is primarily present in the nucleus in association with chromatin, where it participates in DNA repair and regulation of gene expression by modulating protein localization and activity.[9]

DNA damage occurs continuously in all living cells as a result of oxidative damage or DNA replicative stress.[10] When DNA damage occurs on one strand of the DNA double helix, a single-strand break (SSB) results, but if two SSBs occur in close proximity and on opposite strands, the result is a double-strand break (DSB) and discontinuity of the chromosome (Figures 1 and 2). Even a single DSB is lethal to a human cell if unrepaired because of the risk of large-scale loss of genetic information.

PARP1 plays a critical role in restoration of genomic integrity by facilitating efficient repair of DNA SSBs and DSBs. PARP1 senses DNA damage by binding to the site of SSBs and DSBs and inducing auto-PARylation, which in turn promotes recruitment of DNA repair factors (such as DNA ligase III, polymerase β, and x-ray repair cross-complementing protein 1[XRCC1]).[11] Loss of PARP1 function by means of pharmacologic or genetic mechanisms results in impaired SSB repair and, following initiation of DNA replication, creation of a DNA DSB (see Figure 1). PARP may also play an important role in DSB repair and is known to recruit the MRE11-RAD50-NBS1 complex and to promote PARylation of BRCA1, factors required for the homologous recombination (HR) pathway of DNA DSB repair. Therefore, pharmacologic inhibition of PARP1/2 in DNA repair–defective (DRD) cells that lack efficient HR repair capabilities (such as those harboring BRCA1, BRCA2, or ATM mutations) results in failure to resolve SSBs, which are then converted to DSBs that promote cellular death.

The activity of PARP1 is not limited to DNA damage response. PARP1 is also known to regulate gene expression by modulation of transcription factor activity and regulation of chromatin.[12] PARP1 binds to RNA polymerase II, regulating gene expression, and may also affect tumor suppressor and oncogenic gene expression. PARP1 can also modulate hormone-dependent gene transcription from hormone-responsive nuclear receptors, such as estrogen receptors α and β, progesterone receptor, and androgen receptor.[9]

Furthermore, PARP1 can modulate the transcriptional activity of ETS transcription factors, which suggests that pharmacologic targeting of PARP1 may be useful in TMPRSS2:ERG fusion–positive prostate cancer cells (~50% of prostate cancers).[13] PARP1 physically interacts with the TMPRSS2:ERG gene fusion and the DNA–protein kinase complex, and these interactions are required for ERG-related gene transcription. Interestingly, PARP inhibition with olaparib inhibited prostate cancer xenograft growth if tumors harbored a TMPRSS2:ERG fusion, which suggests that PARP might represent a therapeutic option for prostate cancer patients withTMPRSS2:ERG fusions.[13] This concept is being evaluated in a recently completed clinical trial (National Cancer Institute [NCI] 9012).

PARP inhibitors

Given the biologic importance of PARP1 in the context of cancer, several pharmacologic agents that target this enzyme are currently under development (Table). Most PARP inhibitors mimic the NAD+ substrate of PARP1, competitively bind to the catalytic domain, and inhibit PAR synthesis.[14] PARP inhibitors require the expression of PARP1 and PARP2, and cells that lack expression of both genes are not sensitive to these agents. PARP inhibitors all appear to block catalytic activity and PAR synthesis in a roughly equivalent manner but may show differential ability to trap PARP1/2 at the site of DNA damage (niraparib > olaparib > veliparib), an event that blocks repair and promotes cellular lethality.[15,16] Whether these effects observed in vitro translate into clinically meaningful differences in efficacy is less clear. Furthermore, it is also now clear that the putative PARP inhibitor iniparib may not promote cytotoxicity via PARP inhibition. Several initial studies focused on iniparib, but when phase III trials failed to demonstrate the efficacy of this compound, additional mechanistic work demonstrated that iniparib may not truly be an effective PARP inhibitor.[17,18] These data illustrate the necessity of careful mechanistic characterization of any targeted agent prior to large-scale and expensive studies.

Germline DNA repair deficiency

Inherited defects in DNA repair pathways result in increased susceptibility to the development of malignancy.[19] Defects in mismatch repair proteins promote the development of tumors, including colon and uterine,[20] whereas inherited inactivating mutations in BRCA1 and BRCA2, which are required for efficient HR-based DNA DSB repair, significantly increase the risk of breast, ovarian, prostate, and other cancers.[21] Patients with these tumor types typically demonstrate homozygous inactivation of these genes, the first event occurring in the germline, with subsequent clonal somatic inactivation of the remaining allele.[21] These events presumably occur early in tumorigenesis and, by loss of robust DNA DSB repair, induce genomic instability, which causes loss of tumor suppressors, activation of oncogenes, and acceleration of tumorigenesis.

A germline mutation in BRCA1 or BRCA2 increases the risk of prostate cancer and thus may be found in 2% to 5% of prostate cancers.[22,23] The relative risk of development of prostate cancer for men ≤ age 65 with BRCA1 mutations is 1.8, but BRCA2 mutations in particular seem to increase the risk of prostate cancer formation by age 65 by about 8.6-fold. Mutations of BRCA1, BRCA2, and ATM (and perhaps other DNA repair genes) may also play a role in progression to the lethal castration-resistant state.[22,24-26] The frequency of BRCA2 germline mutations in prostate cancer alone may be as high as 2%.[22] Therefore, the development of therapies to target DNA repair is likely to benefit a relatively large and relatively young population.

Somatic DNA repair deficiency

In addition to germline defects, tumors can acquire defective DNA repair processes through somatic loss of DNA damage response genes, and these somatic mutations can also confer sensitivity to PARP inhibition.[27] This has led to the concept of “BRCAness,” which refers to somatically acquired defects in HR that, as a group, could predict tumor response to PARP inhibitors and cisplatin.[21] Somatic alterations can include either acquired mutations or epigenetic events that silence genes such as ATM; ATR; BRCA1 or –2; CHEK1 or -2; FANCA, -C, -D2, -E, -F; PALB2; MRE11 complex; or RAD51, which prevent efficient HR repair of DNA DSBs.

It is likely that a substantial proportion of men with prostate cancer may demonstrate aspects of BRCAness that could predict sensitivity to PARP inhibitors. Beltran et al performed targeted next-generation sequencing of tumors from men with advanced prostate cancer and found that 12% demonstrated BRCA2 loss and that 8% harbored ATM loss.[28] Furthermore, up to 19.3% of CRPCs demonstrate aberrations in BRCA1, BRCA2, or ATM; these events become more frequent as the disease progresses from hormone-sensitive to castration-resistant.[29] Together these data suggest that BRCAness is a reasonably frequent event in patients with advanced prostate cancer, which makes PARP inhibition an attractive target in this disease.

Synthetic lethality

The concept of promoting the killing of cancer cells by simultaneously blocking SSB repair using PARP inhibition in cells that lack efficient DSB repair is called “synthetic lethality.” In this scenario, tumor cells may harbor either germline or somatically acquired homozygous inactivation of HR. Germline defects (when present) typically affect only one allele in normal cells, and therefore normal tissues retain HR function. This difference between the DNA repair capacity of normal and cancer cells can be leveraged to produce selective cell killing of tumor cells by PARP inhibitors. Treatment of patients with PARP inhibitors will then block normal SSB repair in all cells, and these SSBs are subsequently converted to DSBs by DNA replication. In normal cells, HR restores the genome and allows survival, but in DRD cancer cells, DSBs persist, inducing cellular death selectively in the tumor cell population (see Figure 2).

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Early-phase studies

Ample data indicate that PARP inhibitors possess antitumor activity within diverse patient populations, particularly those with BRCA1 or BRCA2 mutations.[14] One of the first studies to validate the concept of clinical benefit in patients with BRCA mutations was a phase I trial that looked at pharmacokinetic and pharmacodynamic aspects of olaparib treatment.[24] In this study, 60 patients with solid tumors were treated with various doses of olaparib (10 mg daily to 600 mg twice daily) to determine maximum tolerated dose (MTD). The study population was intentionally enriched for BRCA mutation carriers, and 22 patients of the cohort harbored BRCA1 or BRCA2 mutations. Objective tumor activity was observed in the mutation carrier population in patients with breast, ovarian, and prostate cancers. Three patients with advanced prostate cancer were included in this study cohort; the one with a BRCA2 mutation had a greater than 50% response in prostate-specific antigen (PSA) level, resolution of bone metastases, and an extended treatment course. This study suggested that there was a benefit of olaparib therapy in BRCA mutation carriers and the potential for benefit in prostate cancer patients. Further validation of olaparib efficacy in patients with BRCA mutations came from parallel proof-of-concept studies demonstrating the activity of this agent in women with breast and ovarian cancers and BRCA1 or BRCA2 mutations.[30,31] These data ultimately led to US Food and Drug Administration (FDA) approval of olaparib for women with a BRCA mutation and metastatic ovarian cancer after chemotherapy.
Additional data that demonstrate a similar spectrum of activity are available for other PARP inhibitors. Phase I data on the safety and pharmacodynamics of single-agent veliparib have been reported as an abstract,[32] and additional studies of veliparib in combination with mitomycin,[33] irinotecan,[34] and other agents have been reported.[35] VanderWeele et al published a case report of a patient with metastatic CRPC and BRCA2 mutation who had a sustained complete response to veliparib and carboplatin/gemcitabine.[36] It seems likely that many of the available PARP inhibitors may have overlapping activities, and further data will be needed to clarify which agent to use in which tumor type and the relative toxicities of each agent.

emozolomide and veliparib in metastatic CRPC

Compelling data implicate PARP1 in the mediation of DNA repair responses to alkylating agents,[37] cellular survival in BRCA-deficient cells,[24,38] and androgen receptor–mediated prostate cancer cellular proliferation.[9,39] Furthermore, data suggest that prostate cancers that harbor the TMPRSS2:ERG fusion (present in up to 50% of prostate cancers) may be more sensitive to PARP inhibition.[13] Therefore, Hussain et al carried out a single-arm pilot study to assess the safety and efficacy of veliparib with the alkylator temozolomide (TMZ) in patients with metastatic CRPC following docetaxel therapy.[40] In this study, patients with a PSA level of ≥ 2 ng/mL were treated with veliparib, 40 mg twice daily, on days 1 to 7 and TMZ, 150 to 200 mg/m2, on days 1 to 5 on a 28-day cycle, based on tolerance data from a phase I study (ClinicalTrials.gov identifier: NCT00526617). The primary endpoint was PSA response rate (30% decline). Of the 25 patients who were evaluable for response, 2 had a confirmed response, 13 had stable PSA, and 10 had progression. The most frequent toxicities were thrombocytopenia, anemia, fatigue, neutropenia, nausea, and constipation. The investigators did assess frequency of TMPRSS2:ERG fusion but found it in only one of eight evaluable patients. Although this patient had stable disease, no conclusions could be drawn regarding the contribution of the fusion product to veliparib sensitivity. Overall, while the combination was considered tolerable, it had only modest activity. No preselection was done in the study, and because BRCAness exists in 20% of patients, it is perhaps not surprising that activity was modest. The lower dose of PARP inhibitor and the lack of established benefit for TMZ may also have contributed to less than robust clinical activity for this combination. Given the emerging molecular data, it seems that future studies will be more likely to identify activity if done in preselected patient populations.

TOPARP

The Trial of PARP Inhibition in Prostate Cancer (TOPARP-A) sought to determine whether patients with prostate cancers with molecularly identified defects in DNA repair benefited from full-dose olaparib therapy.[25] In this phase II study, 50 men with CRPC underwent biopsy of metastatic disease and targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase chain reaction. The primary endpoint was response rate (either objective response or reduction of 50% in PSA level or reduction in circulating tumor cells). All had previously received docetaxel, and most had been treated with abiraterone or enzalutamide (98%) and cabazitaxel (58%). Patients were grouped according to the presence or absence of a homozygous deletion of or deleterious mutation in DNA damage response genes, which predict sensitivity to PARP inhibition. Overall, 16 of 49 evaluable patients (33%) were biomarker positive (indicative of homozygous deleterious changes in BRCA1/2, ATM, Fanconi anemia genes, or CHEK2). Of these, five patients had germline and somatic events (three patients with germline BRCA2 and three patients with germline ATM deletions or mutations). Of the 16 patients with deleterious changes in DNA repair genes, 14 (88%) responded to olaparib. The median overall survival for patients with biomarker-positive DRD tumors who received olaparib was 13.8 months, compared with 7.5 months for those with biomarker-negative tumors (P = .05). Interestingly, two biomarker-negative patients also met criteria for response to olaparib. Although one was a longer-term responder still on therapy at the time of publication, this particular patient did harbor monoallelic deletions of both BRCA2 and PALB2 that did not meet criteria for the prespecified biomarker-positive category but that may have contributed to tumor sensitivity. Toxicity was as expected, with patients displaying grade 3 or 4 anemia (10/50), fatigue (6/50), leukopenia (3/50), thrombocytopenia (2/50), and neutropenia (2/50). These results illustrate the feasibility of using molecular profiling to identify prostate cancers that display molecular features suggestive of sensitivity to PARP inhibition (BRCAness).

NCI 9012

ETS gene fusions—which result from gene rearrangement and juxtaposition of an androgen-responsive gene, such as TMPRSS2, to an ETS transcription factor gene, such as ERG or ETV1—occur in 50% to 60% of prostate cancers.[41,42] ETS transcription factors may also physically interact with PARP1, and PARP1 activity may be required for ETS-mediated invasion, transcription, and metastasis.[13] Androgen receptor–mediated transcription may also promote DNA DSBs and requires PARP activity for efficient repair.[43-45] Therefore, therapeutic targeting of androgen receptor signaling and PARP1 activity using abiraterone and veliparib is an attractive strategy in the management of metastatic prostate cancer.

A randomized phase II clinical trial in patients with metastatic CRPC was recently completed; it examined whether ETS fusion is a biomarker of response to abiraterone or abiraterone plus veliparib. In this study, 148 patients with metastatic CRPC underwent biopsy followed by assessment of ETS fusion status and then random assignment to either abiraterone alone or abiraterone plus veliparib. The primary endpoint was confirmed PSA response in patients receiving either abiraterone alone or combination therapy, stratified by ETS status. Secondary endpoints included safety, objective response rate, progression-free survival, and whether DNA repair gene deficiency (homozygous deletions of or deleterious mutations in: BRCA1, BRCA2, ATM, FANCA, PALB2, RAD51B, RAD51C) predicts response. This trial has now completed enrollment, and preliminary results will be presented at the American Society of Clinical Oncology 2016 Annual Meeting. Although final results are pending, the study does illustrate the feasibility of a large-scale metastatic tissue–based, biomarker-driven trial involving PARP inhibition in patients with metastatic CRPC. This study will also begin to ascertain the role of ETS fusions in determining response to PARP inhibitor therapy and will further explore the contribution of DRD to patient outcomes in those treated with standard therapy (abiraterone arm) and those treated with PARP inhibition (abiraterone plus veliparib arm).

Future studies

Given the data from the studies discussed previously and the enthusiasm for molecularly targeted trials in oncology, there is interest in further testing of PARP inhibition in prostate cancer patients. Multiple trials have recently been completed, are actively enrolling, or are nearing activation within this space (see Table, ClinicalTrials.gov).

Olaparib. Olaparib is the agent that is farthest along in clinical development and has an FDA indication in ovarian cancer. Olaparib also has the most active or pending studies in prostate cancer patients. TOPARP continues to enroll patients with metastatic CRPC, with a target accrual of 98 patients (ClinicalTrials.gov identifier: NCT01682772). There is a randomized double-blind, placebo-controlled phase II study of abiraterone plus olaparib or placebo for patients with metastatic CRPC who received prior docetaxel therapy (ClinicalTrials.gov identifier: NCT01972217). This trial, which is similar to the NCI 9012 study, has completed enrollment, but results are pending. Another trial is examining the biologic effect of olaparib on prostate cancer specimens when given alone or in combination with degarelix prior to prostatectomy (ClinicalTrials.gov identifier: NCT02324998). Furthermore, there is an open-label phase II study to assess the efficacy and safety of olaparib in patients with BRCA1 or BRCA2 mutations (regardless of tumor type), which is ongoing but no longer enrolling patients (ClinicalTrials.gov identifier: NCT01078662).

Veliparib. NCI 9012 (discussed previously) will help determine whether veliparib has potential therapeutic activity in metastatic CRPC and may identify molecularly determined subsets of disease (ie, ETS fusion–positive, DRD-positive) that might be expected to show the most benefit. The results of this study may help determine whether additional studies of this agent within the prostate cancer space are warranted.

Niraparib. The Hoosier Cancer Research Network has a planned phase I study of the combination of enzalutamide and niraparib for patients with metastatic CRPC (ClinicalTrials.gov identifier: NCT02500901), which has not yet begun enrollment. The primary endpoint of this study will be determination of MTD and dose-limiting toxicity.

Talazoparib. Although no prostate cancer–specific trials using other PARP inhibitors are currently active, several trials for molecularly targeted patient populations or phase I trials for toxicity assessment in combination with chemotherapy are ongoing; these provide some information on prostate cancer populations, depending on the types of solid tumors enrolled. There is a phase I trial of talazoparib in combination with carboplatin and paclitaxel (ClinicalTrials.gov identifier: NCT02317874) and another for patients with solid tumors and hepatic and renal dysfunction (ClinicalTrials.gov identifier: NCT02567396).

Precision Targeting of the PARP Pathway in Prostate Cancer

PARP inhibitors are a promising therapeutic option for men with prostate cancer. There is good evidence that men with either germline or somatic mutations in DNA repair pathways can derive therapeutic benefit from inhibition of PARP1/2, which blocks repair of SSB, driving persistent DSBs that lead to cancer cell lethality. Preclinical data also suggest that PARP inhibition may produce benefits by targeting chromatin and gene transcription, which implies that clinical benefits may extend beyond patients with DRD tumors.[12] To continue to develop PARP inhibitors within the prostate cancer field, we will need to develop and refine a set of biomarkers for use in selecting the right patient populations for these agents and then incorporate these biomarkers into prospective studies. As part of a precision therapy strategy, PARP inhibitors will likely play an important role in the management of prostate cancer in the near future.

It is now feasible to comprehensively profile the mutational, epigenetic, and gene expression changes in men with prostate cancer, and we are beginning to use this information to guide treatment choices.[7] Unfortunately, the functional relevance of many of the molecular features uncovered in these profiles is not completely understood. DNA repair processes are complex and require many genes for efficient repair of various types of DNA damage. Most past and ongoing studies focused on patients with specific molecular features, such as BRCA1, BRCA2, ATM, FANCA, PALB2, RAD51B, and RAD51C mutations. While mutations of these genes are likely to affect sensitivity to PARP inhibitors, mutations in other DNA repair or transcription factor genes may as well, and identification of those genes could expand the patient population that could benefit from therapy. Determination of whether other genes are susceptible to PARP inhibitor therapy will require robust preclinical models with a wide selection of genetic changes that reflect human disease; such models can be used to determine whether additional mutations and epigenetic or gene expression changes also result in PARP inhibitor sensitivity. Given the potential infrequency of many of the individual mutations that might sensitize to PARP inhibitors, large-scale registries that catalog mutations and their responsiveness to therapies may be needed.

As we define the molecular features that suggest sensitivity to PARP inhibition, the challenge will then become understanding the best strategy for incorporating these targeted agents into our standard treatment algorithms. In the context of prostate cancer, PARP inhibitors could be considered in high-risk patient populations in an adjuvant manner, before or with androgen deprivation therapy (ADT) in patients with newly metastatic disease, or in the setting of castration-resistant disease before or after the many other therapeutic options. To date, most trials in the prostate cancer space have been in the castration-resistant setting, perhaps because mutations in DNA damage genes may become more common as the disease progresses.[25] Nonetheless, there is no reason to assume that patients who harbor mutations may not benefit earlier in the disease course. Adjuvant use of PARP inhibitors in those with high-risk or micrometastatic disease could conceivably render patients disease free. Similarly, the combination of ADT and PARP inhibitors in early metastatic disease may provoke prolonged progression-free intervals similar to the situation with early docetaxel therapy but with less toxicity.[4,5] In the context of castration-resistant disease, it is reasonable to hypothesize that the combination of PARP inhibitors with hormonal agents such as abiraterone or enzalutamide or with chemotherapies might act synergistically to promote disease control.

The trials to examine these questions may be more challenging to design and execute because patients with sensitizing molecular changes represent a limited subset of total patients with prostate cancer. This means that in order to identify the subset that will benefit, many will need to be screened.[25] Because most molecular analyses are done using biopsy tissue, screening and cost may be challenging factors. In addition, the natural history of patients with DNA damage pathway mutations may also be distinct from those without such mutations. It is conceivable that mutations in DNA damage response genes may modulate patient response to standard hormonal agents, chemotherapy, or radium because all three of these therapeutic modalities have the potential to induce DNA damage in prostate cancer cells. Given these caveats, it will be essential to design an efficient precision medicine clinical trial pipeline that can rapidly molecularly profile patient tumors, assign to a therapeutic intervention, and then assess the complex resulting data and analyze results according to molecular categories.

PARP inhibitors have the potential to be a promising addition to the therapeutic arsenal used to treat prostate cancer and other solid tumors that harbor the appropriate molecular features. The transition from a standard, one-size-fits-all approach to a targeted, precision medicine strategy in which an individual prostate cancer patient’s tumor biology will guide choice of therapy will require careful planning and thought. The inclusion of PARP-targeted therapies before, after, with, or in place of standard hormonal therapies and chemotherapies will need to be defined so as to maximize antitumor effect and patient survival. Hopefully, application of these novel combinations in those most likely to benefit will ultimately lead to longer and better lives for patients with prostate cancer.

Financial Disclosure: Dr. Hussain is the principal investigator for a clinical trial of veliparib through the Cancer Therapy Evaluation Program (for AbbVie), and is collaborating on a clinical trial of olaparib for AstraZeneca.

David B. Solit, MD
Philip W. Kantoff, MD
Memorial Sloan Kettering Cancer Center, New York, New York

How an Ovarian Cancer Drug Came to Have ‘Breakthrough Therapy Designation’ for Prostate Cancer

With the emergence of precision medicine, clinicians can now take advantage of high-throughput tumor sequencing to identify driver mutations in individuals with cancer, with the goal of matching these with effective therapies. Since driver mutations can be shared across cancer types, precision medicine has also challenged the notion that cancer types, as defined by site of origin, are completely separate entities. One such example is the use of vemurafenib in multiple BRAF V600–mutant cancers. Another example is that of poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitors and prostate cancer. It is now recognized that DNA repair abnormalities, including and most notably BRCA2 mutations, are found frequently in the germline and as somatic mutations in the tumors in men with metastatic prostate cancer. Moreover, recent studies have demonstrated promising activity for olaparib—a drug approved for use in BRCA-mutated ovarian cancer—in men with castration-resistant disease and germline or somatic DNA repair abnormalities. This has led the US Food and Drug Administration to confer “breakthrough therapy designation” on olaparib, based on the strong belief that the drug will ultimately be approved for this indication.

What Questions Should Future Research on PARP Inhibitors for Prostate Cancer Focus on?

Many questions still remain unanswered. These include:

1) Given the pleiotropic effects of PARP inhibitors, which activities are the most critical and which PARP inhibitors are best for each disease/mutation scenario?

2) Have we identified the full gamut of DNA repair abnormalities that might respond to PARP inhibition?

3) Can we extend the spectrum of patients eligible for PARP inhibitors to those who are homologous recombination–proficient, by combining PARP inhibitors with therapies such as alkylating agents or antiangiogenic agents like cediranib?

4) Can we identify patients early on in their disease course in whom PARP inhibition may contribute to a curative strategy?

 

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