CDK12-Altered Prostate Cancer: Clinical Features and Therapeutic Outcomes to Standard Systemic Therapies, Poly (ADP-Ribose) Polymerase Inhibitors, and PD-1 Inhibitors

Abstract

PURPOSE

In prostate cancer, inactivating CDK12 mutations lead to gene fusion–induced neoantigens and possibly sensitivity to immunotherapy. We aimed to clinically, pathologically, and molecularly characterize CDK12-aberrant prostate cancers.

METHODS

We conducted a retrospective multicenter study to identify patients with advanced prostate cancer who harbored somatic loss-of-function CDK12 mutations. We used descriptive statistics to characterize their clinical features and therapeutic outcomes (prostate-specific antigen [PSA] responses, progression-free survival [PFS]) to various systemic therapies, including sensitivity to poly (ADP-ribose) polymerase and PD-1 inhibitors.

RESULTS

Sixty men with at least monoallelic (51.7% biallelic) CDK12 alterations were identified across nine centers. Median age at diagnosis was 60.5 years; 71.7% and 28.3% were white and nonwhite, respectively; 93.3% had Gleason grade group 4-5; 15.4% had ductal/intraductal histology; 53.3% had metastases at diagnosis; and median PSA was 24.0 ng/mL. Of those who underwent primary androgen deprivation therapy for metastatic hormone-sensitive disease (n = 59), 79.7% had a PSA response, and median PFS was 12.3 months. Of those who received first-line abiraterone and enzalutamide for metastatic castration-resistant prostate cancer (mCRPC; n = 34), 41.2% had a PSA response, and median PFS was 5.3 months. Of those who received a first taxane chemotherapy for mCRPC (n = 22), 31.8% had a PSA response, and median PFS was 3.8 months. Eleven men received a PARP inhibitor (olaparib [n = 10], rucaparib [n = 1]), and none had a PSA response (median PFS, 3.6 months). Nine men received a PD-1 inhibitor as fourth- to sixth-line systemic therapy (pembrolizumab [n = 5], nivolumab [n = 4]); 33.3% had a PSA response, and median PFS was 5.4 months.

CONCLUSION

CDK12-altered prostate cancer is an aggressive subtype with poor outcomes to hormonal and taxane therapies as well as to PARP inhibitors. A proportion of these patients may respond favorably to PD-1 inhibitors, which implicates CDK12 deficiency in immunotherapy sensitivity.

INTRODUCTION

Clinically relevant genomic classifications of many cancers are increasingly aiding in the selection of optimal systemic therapies, which have heralded the era of precision oncology. In advanced prostate cancer, however, the clinical utility of germline and somatic genetic testing is limited to the detection of mismatch repair (MMR) deficiency mutations (which may predict responsiveness to PD-1 inhibitors, eg, pembrolizumab)^1,2 or the detection of homologous recombination deficiency (HRD) mutations (which may predict sensitivity to investigational poly [ADP-ribose] polymerase [PARP] inhibitors, eg, olaparib, or platinum agents).^3-5 Furthermore, while immune checkpoint blockade has resulted in unprecedented gains in a growing number of tumor types, the use of CTLA-4– and/or PD-1–targeting agents in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) has been met with limited success.^6,7 To this end, identification of additional molecular subsets of mCRPC that may benefit from immune checkpoint inhibition is paramount.⁸

CDK12 encodes cyclin-dependent kinase 12, a tumor suppressor protein with diverse functions related to genomic stability.⁹ Initially, CDK12 was believed to promote DNA repair through the regulation of homologous recombination DNA repair genes (BRCA1, FANCD2, and ATR), with a suggestion that genetic inactivation of CDK12 was associated with PARP inhibitor sensitivity in preclinical models.¹⁰ More recently, however, it was proposed that in prostate cancer, CDK12 may function primarily in DNA replication-associated repair, with biallelic inactivation of CDK12 resulting in a unique genomic signature characterized by widespread focal tandem duplications that lead to gene fusion–induced neoantigens and sensitivity to immune checkpoint inhibitors.¹¹ In that initial study, 2 of 4 patients with CDK12-altered prostate cancer demonstrated objective responses to PD-1 inhibitors,¹¹ which suggests immunotherapy sensitivity in a subset of these patients.

CONTEXT

• Key Objective

• We conducted a multicenter retrospective study to characterize the clinical, pathologic, and molecular features of prostate cancers harboring inactivating CDK12 mutations, with a particular emphasis on potential sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors and PD-1 inhibitors.

• Knowledge Generated

• We show that CDK12-altered prostate cancer is an aggressive subtype with poor outcomes to standard systemic therapies as well as to PARP inhibitors. However, a proportion of these patients respond favorably to PD-1 inhibitors.

• Relevance

• These data support the notion that CDK12-aberrant advanced prostate cancers (and perhaps other CDK12-mutated cancers) may be responsive to immunotherapy approaches, such as PD-1 inhibition.

In prostate cancer, CDK12 mutations occur in 5%-7% of patients with mCRPC,^11-13 and most are biallelic inactivations. Because little is known about the clinical characteristics and prognosis of patients with CDK12-altered prostate cancers, we aimed to describe their clinical features and therapeutic outcomes to various standard systemic therapies as well as their sensitivity to PARP inhibitors and PD-1 inhibitors. Of note, because CDK12 alterations are found in 1%-4% of many other cancer types,^12,13 the findings of this study (particularly with respect to PARP inhibitor and PD-1 inhibitor sensitivity) may have implications for a range of additional malignancies.

METHODS

We conducted a retrospective analysis that began with an interrogation of the tumor genomic databases from 9 academic medical centers. We searched for patients with recurrent or metastatic prostate cancer who had at least monoallelic loss-of-function CDK12 mutations, as detected using a clinical-grade (eg, Clinical Laboratory Improvement Amendments–certified) commercial or in-house genomic assay. Pathogenic mutations were defined a priori as those that result in a truncated protein (ie, frameshift, nonsense, splicing mutations) or genomic rearrangements that involve the CDK12 locus (eg, homozygous deletions, gene fusions, other translocations). After a pathogenic first hit was identified, a second hit was sought by examining for another pathogenic alteration as previously defined, a loss of heterozygosity (LOH) of the wild-type allele, or a missense mutation in the kinase domain (amino acids 727-1,020) of the protein. Of note, a single missense mutation in the CDK12 kinase domain alone was not considered a pathogenic alteration.

Next, we abstracted clinical data from the electronic records of patients with confirmed (at least monoallelic) CDK12 mutations. This involved collection of typical clinical characteristics, including age at diagnosis, PSA level at diagnosis, race, family history of cancer, Gleason score, presence of histologic variants, clinical and/or pathologic stage, presence of metastatic disease at diagnosis, and sites of metastatic disease. We also documented the types and number of systemic therapies received for metastatic disease. For each systemic therapy, we collected data about longitudinal PSA levels, radiographic studies, clinical symptoms, and survival status. We determined PSA response rates and progression-free survival (PFS) for each systemic therapy separately. PSA response was defined as a ≥ 50% reduction in PSA level compared with baseline values, with a confirmatory PSA value ≥ 4 weeks later. PFS was defined as the interval of time from the start of a new systemic therapy until either radiographic progression (modified Prostate Cancer Working Group 3 criteria, without requiring confirmation), clinical progression (defined as disease-related complication or clinical deterioration) or death, whichever occurred first. Overall survival (OS) was calculated as the time from initiation of systemic therapy until death as a result of any cause. This retrospective study was approved by the local institutional review boards at each institution.

Results were reported using descriptive statistics. PSA response rates are expressed as percentages with 95% CIs, and individual patient data are displayed using waterfall plots. Time-to-event outcomes (PFS, OS) were analyzed using the Kaplan-Meier product limit method, and median values (with 95% CIs) are reported. Swimmer plots are used to depict time on therapy as well as patient disposition at last follow-up. Statistical analyses were performed using R (R Foundation for Statistical Computing, Vienna, Austria).

RESULTS

A total of 60 patients (diagnosed between December 2009 and April 2019) with at least monoallelic loss-of-function CDK12 mutations were identified from 9 academic centers. The source of somatic DNA was the prostate gland in 78.3% (47 of 60), metastatic biopsy specimens in 18.3% (11 of 60), and circulating tumor DNA in 3.3% (2 of 60) of patients. The most common types of pathogenic alterations were frameshift insertions or deletions (60%; 36 of 60) followed by nonsense/stop mutations (23.3%; 14 of 60), while a smaller proportion of mutations (16.7%; 10 of 60) were due to other mechanisms (Table 1). Of these, 51.7% (31 of 60) were biallelic CDK12 mutations. A complete list of all CDK12 mutations is included in Appendix Table A1.

TABLE 1.

Baseline Demographic, Clinicopathologic, and Mutation Characteristics

We also interrogated for the presence or absence of additional concurrent genomic alterations in these patients with CDK12 mutations to explore potential mutual exclusivity with other genetic subtypes of prostate cancer by comparing against the StandUp2Cancer (SU2C) International Prostate Cancer Dream Team¹⁴ data set (Table 2). Of note, we observed a lower-than-anticipated prevalence of concurrent alterations in ERG (3.3% [2 of 60] here v 56% [84 of 150] in SU2C; P < .01), TP53 (16.7% [10 of 60] here v 53.3% [80 of 150] in SU2C; P < .01), and PTEN/PIK3CA (6.7% [4 of 60] here v 43.3% [65 of 150] in SU2C; P < .01). We also observed a relative decrease in concurrent SPOP mutations (1.7% [1 of 60] here v 8.0% [12 of 150] in SU2C; P = .13). Finally, while we did not observe any difference in the rate of concurrent HRD mutations overall, we did find a lower prevalence of BRCA2/ATM alterations (5.0% [3 of 60] here v 17.3% [26 of 150] in SU2C; P = .08) but a higher rate of non-BRCA2/ATM HRD alterations (13.3% [8 of 60] here v 2.7% [4 of 150] in SU2C; P < .01). These data suggest a relative mutual exclusivity between CDK12-altered prostate cancers and those driven by ERG, TP53, PTEN/PIK3CA, and SPOP as well as potential enrichment of CDK12-altered tumors by other non-BRCA2/ATM HRD mutations. A complete list of genomic alterations is included in Appendix Table A1.

TABLE 2.

Prevalence of Other Concurrent Genomic Alterations in CDK12-Mutated Prostate Cancer

CDK12-altered prostate cancer is characterized by aggressive disease features. In our sample, median age at diagnosis was 60.5 years, 25% (15 of 60) were black, median PSA level at diagnosis was 24 ng/mL, 93.3% (56 of 60) had Gleason grade group 4-5 (Gleason sum ≥ 4 + 4 = 8) disease, 15.4% (8 of 52 who were evaluable) had intraductal or ductal histologic features, 76.7% (46 of 60) had stage T3/T4 disease, 50% (30 of 60) had nodal involvement at diagnosis, 53.3% (32 of 60) had distant metastases at diagnosis (of whom 60% [19 of 32] had high-volume metastases by Chemo-Hormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer [CHAARTED] criteria¹⁵), and 13.3% (8 of 60) had visceral involvement at diagnosis (Table 1). We did not observe any differences in baseline clinical or pathologic characteristics when considering monoallelic and biallelic CDK12 mutations separately (Appendix Table A2).

In addition, responses to a variety of systemic therapies among CDK12-mutated prostate cancers were relatively poor (Table 3). Fifty-nine patients were evaluable for responses to first-line androgen deprivation therapy (ADT), with or without upfront docetaxel (n = 8) or abiraterone (n = 13), for recurrent or metastatic hormone-sensitive prostate cancer. In these patients, PSA response rates were 79.7% (47 of 59; 20.3% [12 of 59] demonstrated primary hormonal resistance), and median PFS was 12.3 months. OS from ADT initiation was 40.8 months (95% CI, 18.7 to 53.0 months). Thirty-four patients were evaluable for response to initial treatment with either abiraterone or enzalutamide for mCRPC. Of these, 41.2% (14 of 34) had a PSA response, and median PFS was 5.3 months. Twenty-two men were evaluable for response to a first taxane therapy for mCRPC. Of these patients, 31.8% (7 of 22) had a PSA response, and median PFS was 3.8 months.

TABLE 3.

PSA (≥ 50%) Responses Rates and Median PFS for Various Classes of Systemic Therapies

We also took a particular interest in evaluating the efficacy of PARP inhibitors as well as PD-1 inhibitors in patients with CDK12 alterations, when used as off-label therapies or in compassionate use programs. To this end, 11 patients were exposed to PARP inhibitor treatment (olaparib [n = 10], rucaparib [n = 1]). Of those, none (0%) had PSA responses, and median PFS was 3.6 months. All but 2 patients had developed progressive disease to PARP inhibitor treatment at last follow-up (Fig 1). Nine patients were exposed to PD-1 inhibitor therapy (pembrolizumab [n = 5], nivolumab [n = 4]) as fourth- to sixth-line systemic therapy for CRPC. Of those, 33.3% (3 of 9) achieved a PSA response, and median PFS was 5.4 months. All three PSA responses occurred in the first 12 weeks of PD-1 inhibitor treatment, and one was a complete response (PSA < 0.1 ng/mL); two of these patients also had objective tumor responses in soft tissue metastases, while the third had bone-only involvement. Two of these three patients remained free of disease progression for 15.1 and 7.2 months (Fig 2).

FIG 1.

(A) Prostate-specific antigen (PSA) waterfall plot and (B) Swimmer plot for patients with CDK12 alterations who received poly (ADP-ribose) polymerase inhibitor therapy (n = 11). PSA50, prostate-specific antigen reduction by ≥ 50%.

FIG 2.

(A) Prostate-specific antigen (PSA) waterfall plot and (B) Swimmer plot for patients with CDK12 alterations who received PD-1 inhibitor therapy (n = 9). PSA50, prostate-specific antigen reduction by ≥ 50%.

DISCUSSION

Loss-of-function CDK12 mutations occur in 1%-7% of multiple tumor types,^11-13 with the highest prevalence being in metastatic prostate cancer. Preclinical data and human genomic studies have suggested at least two distinct roles for CDK12, one related to homologous recombination–mediated DNA repair¹⁰ and the second related to DNA replication-associated repair.¹¹ In prostate cancer, inactivation or loss of CDK12 results in a distinct pattern of genomic instability characterized by widespread focal tandem duplications throughout the genome, some of which may occur in coding regions and result in gene fusions and potential fusion-induced neoantigens.^11,12 Indeed, CDK12-deficient prostate tumors are second only to MMR-deficient prostate cancers in expressing very high levels of total putative neoantigens and possess the highest levels of fusion-induced neoantigens.¹¹ These findings may have implications for immunotherapy sensitivity, particularly with respect to PD-1 inhibitors. The role of CDK12 in homologous recombination repair may also implicate this gene in PARP inhibitor sensitivity, as has been demonstrated in ovarian cancer.¹⁰ Here, we aimed to characterize the clinical course and responsiveness to systemic therapies of a large cohort of patients with CDK12-altered prostate cancer, with particular emphasis on PARP inhibitor and PD-1 inhibitor sensitivity.

We first focused on the genomic characterization of these 60 patients with CDK12-altered prostate cancer, who, to our knowledge, represent the largest data set of this molecular subclass to date. Most CDK12 inactivations (83%) occurred by frameshift or nonsense mutations, while a small minority was caused by other genomic mechanisms. Furthermore, more than 50% of these patients had confirmed biallelic CDK12 inactivation, although the true prevalence of biallelic alteration is likely to be higher because of our inability to assess LOH with many of the commercial genomic platforms used. Consistent with a previous report,¹¹ we observed a relative mutual exclusivity between CDK12 mutations and concurrent alterations in ERG, SPOP, TP53, and PTEN/PIK3CA, which suggests a distinct genomic subclass. However, unlike the previous report,¹¹ we did not observe a lower overall prevalence of HRD mutations in patients with CDK12 alterations, 18.3% of whom also harbored a concurrent HRD mutation. Of note, our CDK12-mutated prostate cancers seemed to have lower rates of BRCA2/ATM mutations but had higher rates of non-BRCA2/ATM HRD mutations (eg, in CHEK2, FANCA, ATR, BARD1, BRIP1). This potential co-occurrence of CDK12 and HRD alterations was also recently reported in another study, where 12.1% (24 of 199) of all CDK12-altered prostate cancers also harbored at least one concurrent HRD mutation (63% of these [15 of 24] were non-BRCA2/ATM HRD alterations).¹⁶

We then examined the clinical characteristics and outcomes associated with CDK12 mutations. We show that patients with CDK12 alterations develop aggressive prostate cancers that present at a young age with very high Gleason scores (which frequently contained variant histologies) and often present with de novo metastatic disease. Furthermore, compared with the published literature,^15,17-19 these patients with CDK12 mutations seem to have short responses to primary ADT (median PFS, 12.3 months) as well as to first-line treatment with abiraterone and enzalutamide (median PFS, 5.3 months). These patients could account for a large proportion of the innate resistance to these hormonal agents, and should prompt interrogation for CDK12 mutations in those without responses to primary or secondary hormonal therapies. Compared with the published data,^20,21 these patients also seem to have inadequate responses to initial taxane therapy (median PFS, 3.8 months). Our findings are corroborated by another recent study²² that examined clinical outcomes in 46 patients with CDK12-altered prostate cancer of whom 88% had Gleason grade group 4-5 (Gleason sum ≥ 4 + 4 = 8) disease and 44% had de novo metastases at diagnosis. In that study, responses to primary ADT were also blunted (median PFS, 24.6 months), as were responses to first-line abiraterone and enzalutamide treatment (median PFS, 3.6 months); responses to taxanes were not evaluated. Collectively, these data suggest that alternative systemic therapies are urgently needed for CDK12-deficient prostate cancers.

To this end, we next examined the clinical efficacy of two investigational therapies: PARP inhibitors and PD-1 inhibitors. Despite prior preclinical evidence that suggested that CDK12 inactivation may sensitize ovarian cancers to PARP inhibition, we did not observe any meaningful clinical activity in our prostate cancer cohort of 11 patients with CDK12 alterations who received PARP inhibitor treatment. In fact, only 2 (18%) of the 11 patients remained on PARP inhibitor treatment for more than 6 months, and none achieved a PSA response or an objective response. This observation is consistent with several reports that demonstrated that PSA/objective responses to PARP inhibitors occur in < 5% of patients with CDK12-mutated mCRPC, with PFS estimates of 3-5 months in this population.^4,23,24 However, in one of these prior studies,⁴ PFS in patients with CDK12 mutations who received olaparib was numerically greater than in those who received abiraterone and enzalutamide (5.1 v 2.2 months, respectively), which potentially suggests some benefit of using PARP inhibitors in this population. Conversely, we did observe clinical activity using PD-1 inhibitors in some patients with CDK12 alterations, despite these agents being used as fourth- to sixth-line systemic therapy for CRPC. Among 9 such patients, 5 (56%) remained on PD-1 inhibitor treatment for more than 6 months, and 3 (33%) achieved PSA and/or objective responses, including one very durable response that has lasted > 15 months thus far. Our data are in line with two other studies^11,22 that respectively reported 50% (2 of 4) and 40% (2 of 5) PSA response rates to PD-1 inhibitor agents among patients with CDK12-deficient mCRPC. Thus, the overall prevalence of PSA responses to PD-1 inhibitor treatments in the literature to date stands at 39% (7 of 18), which suggests meaningful clinical activity in this molecular subset. Collectively, these data suggest that CDK12 inactivation might be implicated in immunotherapy sensitivity, as hypothesized on the basis of the large number of gene fusion–induced neoantigens predicted to occur in these cancers.

Our study has several limitations. First, we used a number of different commercial and in-house genomic platforms to interrogate CDK12 mutational status, not all of which were able to reliably assess LOH of the second CDK12 allele. Thus, the prevalence of biallelic CDK12 alteration reported here is likely an underestimate. Second, we neither compared clinical characteristics or therapeutic outcomes between patients with CDK12-altered and CDK12 wild-type disease nor compared outcomes with other genomic subsets of prostate cancer (HRD, MMR deficient, TP53 mutated, or other). Finally, our estimates of PSA response rates and PFS were influenced by variable intervals of PSA assessments and clinical/radiographic assessments and were not uniform within or between sites. The advantages of our study include the large sample size and multicenter nature of our cohort (the largest, to our knowledge, to date) and our ability to interrogate responses to PARP inhibitor and PD-1 inhibitor therapies, which are two rational treatment strategies for these patients.

In conclusion, we demonstrate that CDK12-altered prostate cancers are associated with aggressive clinical and histologic features and respond poorly to standard systemic therapies, including ADT, novel hormonal therapies, and taxane chemotherapies. Despite showing poor responses to PARP inhibitors, some patients with CDK12-altered mCRPC may have favorable responses to PD-1 inhibitor agents, which suggests that CDK12 deficiency may be associated with immunotherapy sensitivity in prostate (and perhaps other) cancers. This also suggests that anti–PD-1 agents should be initiated earlier in the disease course. An ongoing prospective clinical trial is currently examining the combination of ipilimumab plus nivolumab in patients with any tumor type that harbors CDK12 alterations (ClinicalTrials.gov identifier: NCT03570619); other studies that aim to combine PD-1 and PARP inhibitors in these patients are also under development.

Appendix

TABLE A1.

Complete List of CDK12 Mutations and Other Concurrent Genomic Alterations

TABLE A2.

Baseline Characteristics Shown According to CDK12 Allelic Status (biallelic v monoallelic)

AUTHOR CONTRIBUTIONS

Conception and design: Emmanuel S. Antonarakis, Pedro Isaacsson Velho, Cora N. Sternberg, Alan H. Bryce, Zachery R. Reichert, Oliver Sartor, Tamara L. Lotan, Maha Hussain

Financial support: Emmanuel S. Antonarakis

Provision of study material or patients: Emmanuel S. Antonarakis, Neeraj Agarwal, Victor Sacristan Santos, Roberto Pili, Cora N. Sternberg, Panagiotis J. Vlachostergios, Scott T. Tagawa, Robert Dreicer, Oliver Sartor, Maha Hussain

Collection and assembly of data: Emmanuel S. Antonarakis, Pedro Isaacsson Velho, Neeraj Agarwal, Victor Sacristan Santos, Benjamin L. Maughan, Roberto Pili, Nabil Adra, Panagiotis J. Vlachostergios, Scott T. Tagawa, Andrea L. McNatty, Zachery R. Reichert, Robert Dreicer, Oliver Sartor, Tamara L. Lotan, Maha Hussain

Data analysis and interpretation: Emmanuel S. Antonarakis, Pedro Isaacsson Velho, Wei Fu, Hao Wang, Neeraj Agarwal, Benjamin L. Maughan, Nabil Adra, Cora N. Sternberg, Scott T. Tagawa, Zachery R. Reichert, Robert Dreicer, Oliver Sartor, Maha Hussain

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Emmanuel S. Antonarakis

Honoraria: Sanofi, Dendreon, Medivation, Janssen Biotech, ESSA, Astellas Pharma, Merck, AstraZeneca, Clovis Oncology

Consulting or Advisory Role: Sanofi, Dendreon, Janssen Biotech, ESSA, Merck, AstraZeneca, Clovis Oncology, Eli Lilly, Bayer AG

Research Funding: Janssen Biotech (Inst), Johnson & Johnson (Inst), Sanofi (Inst), Dendreon (Inst), Aragon Pharmaceuticals (Inst), Exelixis (Inst), Millennium Pharmaceuticals (Inst), Genentech (Inst), Novartis (Inst), Astellas Pharma (Inst), Tokai Pharmaceuticals (Inst), Merck (Inst), AstraZeneca (Inst), Clovis Oncology (Inst), Constellation Pharmaceuticals (Inst)

Patents, Royalties, Other Intellectual Property: Co-inventor of a biomarker technology that has been licensed to QIAGEN

Travel, Accommodations, Expenses: Sanofi, Dendreon, Medivation

Pedro Isaacsson Velho

Honoraria: Bayer AG

Speakers’ Bureau: AstraZeneca, Pfizer, Bristol-Myers Squibb

Research Funding: Bristol-Myers Squibb (Inst), Pfizer (Inst)

Expert Testimony: Bayer AG

Travel, Accommodations, Expenses: AstraZeneca, Astellas Pharma, Pfizer, Merck Serono, Merck

Neeraj Agarwal

Consulting or Advisory Role: Pfizer, Medivation, Astellas Pharma, Bristol-Myers Squibb, AstraZeneca, Nektar, Eli Lilly, Bayer AG, Foundation Medicine, Pharmacyclics, Exelixis, Janssen Oncology, Merck, Novartis

Research Funding: Bayer AG (Inst), Bristol-Myers Squibb (Inst), GlaxoSmithKline (Inst), Takeda Pharmaceuticals (Inst), Pfizer (Inst), BN ImmunoTherapeutics (Inst), Exelixis (Inst), TRACON Pharma (Inst), Rexahn Pharmaceuticals (Inst), Amgen (Inst), AstraZeneca (Inst), Active Biotech (Inst), Bavarian Nordic (Inst), Calithera Biosciences (Inst), Celldex (Inst), Eisai (Inst), Genentech (Inst), Immunomedics (Inst), Janssen Pharmaceuticals (Inst), Merck (Inst), NewLink Genetics (Inst), Prometheus (Inst), Sanofi (Inst)

Benjamin L. Maughan

Consulting or Advisory Role: Janssen Oncology, Exelixis, Tempus, Peleton, Bristol-Myers Squibb, Astellas Pharma, Medivation, Bayer AG

Research Funding: Clovis Oncology (Inst), Bristol-Myers Squibb (Inst), Bavarian Nordic (Inst)

Travel, Accommodations, Expenses: Exelixis

Roberto Pili

Consulting or Advisory Role: Exelixis

Research Funding: Pfizer, Active Biotech, Millennium Pharmaceuticals, ARIAD Pharmaceuticals, Peregrine Pharmaceuticals, Syndax, Genentech, Clinigen, Bristol-Myers Squibb

Nabil Adra

Research Funding: Merck (Inst), Genentech (Inst)

Cora N. Sternberg

Consulting or Advisory Role: Bayer AG, MSD, Pfizer, Roche, Genentech, Incyte, AstraZeneca, Merck, Medscape, UroToday, Astellas Pharma, Sanofi, Genzyme

Panagiotis J. Vlachostergios

Honoraria: DAVAOncology

Scott T. Tagawa

Consulting or Advisory Role: Medivation, Astellas Pharma, Dendreon, Janssen Pharmaceuticals, Bayer AG, Genentech, Endocyte, Immunomedics, Karyopharm Therapeutics, AbbVie, Tolmar, QED, Amgen, Sanofi, Pfizer, Clovis Oncology, Novartis, Genomic Health, POINT Biopharma

Research Funding: Eli Lilly (Inst), Sanofi (Inst), Janssen Pharmaceuticals (Inst), Astellas Pharma (Inst), Progenics (Inst), Millennium Pharmaceuticals (Inst), Amgen (Inst), Bristol-Myers Squibb (Inst), Dendreon (Inst), Rexahn Pharmaceuticals (Inst), Bayer AG (Inst), Genentech (Inst), NewLink Genetics (Inst), Inovio Pharmaceuticals (Inst), AstraZeneca (Inst), Immunomedics (Inst), Novartis (Inst), AVEO (Inst), Boehringer Ingelheim (Inst), Merck (Inst), Stem CentRx (Inst), Karyopharm Therapeutics (Inst), AbbVie (Inst), Medivation (Inst), Endocyte (Inst), Exelixis (Inst), Clovis Oncology (Inst)

Travel, Accommodations, Expenses: Sanofi, Immunomedics, Amgen

Uncompensated Relationships: Telix Pharmaceuticals, ATLAB Pharma, Phosplatin Therapeutics

Alan H. Bryce

Honoraria: Astellas Pharma

Travel, Accommodations, Expenses: Clovis Oncology, Phosplatin Therapeutics (Inst)

Andrea L. McNatty

Employment: Janssen Pharmaceuticals (I)

Stock and Other Ownership Interests: Janssen Pharmaceuticals (I)

Zachery R. Reichert

Consulting or Advisory Role: Dendreon

Research Funding: AstraZeneca (Inst)

Robert Dreicer

Consulting or Advisory Role: Astellas Pharma, AstraZeneca, Genentech, Roche, Pfizer, Eisai, Janssen Oncology, Modra Pharmaceuticals, Seattle Genetics, Astellas Pharma, Vizuri, Orion Pharma, Novartis

Research Funding: Genentech (Inst), Seattle Genetics (Inst), Janssen Oncology (Inst), Bristol-Myers Squibb (Inst)

Oliver Sartor

Stock and Other Ownership Interests: Eli Lilly, GlaxoSmithKline, AbbVie, Cardinal Health, United Health Group, Varian Medical Systems, PSMA Therapeutics

Consulting or Advisory Role: Bayer AG, Johnson & Johnson, Sanofi, AstraZeneca, Dendreon, Endocyte, Constellation Pharmaceuticals, Advanced Accelerator Applications, Pfizer, Bristol-Myers Squibb, Bavarian Nordic, EMD Serono, Astellas Pharma, Progenics, Noxo, Blue Earth Diagnostics, Myovant, Myriad Genetics, Novartis, Clovis Oncology

Research Funding: Bayer AG (Inst), Johnson & Johnson (Inst), Sanofi (Inst), Endocyte (Inst), Innocrin Pharma (Inst), Merck (Inst), InVitae (Inst), Constellation Pharmaceuticals (Inst), Advanced Accelerator Applications (Inst), AstraZeneca (Inst), Dendreon (Inst), SOTIO (Inst)

Expert Testimony: Sanofi

Travel, Accommodations, Expenses: Bayer AG, Johnson & Johnson, Sanofi, AstraZeneca, Progenics

Tamara L. Lotan

Consulting or Advisory Role: Janssen Oncology

Research Funding: Ventana Medical Systems, DeepBio

Maha Hussain

Honoraria: PER, Projects in Knowledge, Astellas Pharma, Genentech, Sanofi, Genzyme, Phillips Gilmore Oncology, Research to Practice, MLI PeerView

Consulting or Advisory Role: Pfizer, AstraZeneca, Bayer AG, Genentech

Research Funding: Genentech (Inst), Pfizer (Inst), PCCTC (Inst), AstraZeneca (Inst), Bayer AG

Patents, Royalties, Other Intellectual Property: Title: Systems and Methods for Tissue Imaging (3676 our file), serial number UM-14437/US-1/PRO 60/923,385UM-14437/US-2/ORD 12/101,753US 8,185,186 (US patent number), Systems and Methods for Tissue Imaging (issued patent) EP 08745653.9 (European patent application number), Systems and Methods for Tissue Imaging (pending) CA 2683805 (Canadian application number), Systems and Methods for Tissue Imaging (pending) US 13/362,500 (US application number), Systems and Methods for Tissue Imaging (continuation application of US 8,185,186); Title: Method of Treating Cancer docket No: serial number 224990/10-016P2/311733 61/481/671, application filed on May 2, 2011; Title: Dual Inhibition of MET and VEGF for the Treatment of Castration Resistant Prostate Cancer and Osteoblastic Bone Metastases, applicant/proprietor: Exelixis, application No./patent No. 11764665.4-1464, application No./patent No. 11764656.2-1464, application filed on September 26, 2011

Travel, Accommodations, Expenses: Genentech, Pfizer, Bayer AG, Astellas Pharma, Genentech, Roche

Open Payments Link: https://openpaymentsdata.cms.gov/physician/146932/summary

No other potential conflicts of interest were reported.