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Monthly Oncology Tumor BoardsA Multidisciplinary Approach to Individualized Patient Care
Systemic Therapy Selection in Metastatic Castration-Resistant Prostate Cancer
Andrew J. Armstrong, MD, ScMDuke Cancer Institute
Joshua M. Lang, MD, MSUniversity of Wisconsin Carbone Cancer Center
Wednesday, July 21, 2021 | 3:00 – 4:00 PM [EDT]
Andrew J. Armstrong, MD, ScMDuke Cancer Institute
Andrew J. Armstrong, MD, ScM, is Professor of Medicine, Professor in Surgery, and Associate Professor in Pharmacology and Cancer Biology at Duke University School of Medicine. He is a medical oncologist at Duke Cancer Institute, and an internationally recognized expert in experimental therapeutics and biomarker development in genitourinary cancers, particularly prostate cancer.
Dr. Armstrong trained at Duke University as a biomedical engineer and received his medical degree at the University of Virginia School of Medicine. He completed a residency in internal medicine at the Hospital of the University of Pennsylvania and a fellowship at Johns Hopkins Hospital, followed by public health clinical investigation training at the Bloomberg School of Public Health. Dr. Armstrong joined Duke’s faculty in 2006, where he has subsequently remained.
As a clinical and translational investigator, Dr. Armstrong’s research examines experimental therapeutics for patients with advanced genitourinary malignancies, particularly with a focus on prostate cancer and the investigation of biomarkers of response and benefit. His reasearch for circulating tumor cell biology and epithelial plasticity is funded by the US Department of Defense, the Prostate Cancer Foundation and Movember, the NIH, and the American Cancer Society. He has developed a number of experimental agents in prostate and renal cell cancer, including completed or ongoing trials of mTOR inhibitors and PI3 kinase inhibitors, immunomodulatory agents, hormonal therapies, and anti-angiogenic agents. He is also heavily involoved in the leadersip of several phase 3 studies in advanced prostate cancer.
Dr. Armstrong is a member of the NCCN Prostate Cancer Panel and is co-chair of Prostate Cancer Working Group 3 which establishesguidelines for clinical investigation in men with advanced prostate cancer. He also contributes to the NCCN Oncology ResearchProgram (ORP) by serving on the Enzalutamide Scientific Review Committee and the Temsirolimus Scientific Advisory Board and Scientific Review Committee.
Joshua M. Lang, MD, MSUniversity of Wisconsin Carbone Cancer Center
Joshua M. Lang, MD, MS, is Associate Professor in the Department of Medicine at the University of Wisconsin School of Medicine and Public Health. He is the Co-Director of the internal medicine residency’s physician-scientist training program (IMPACT). He is the Director of UW Carbone Cancer Center’s circulating biomarker core and liquid biospecimen team, and co-leader of its tumor microenvironmental program, and the clinical co-chair of its precision medicine molecular tumor board.
Dr. Lang earned his medical degree from University of Illinois College of Medicine at Chicago. He completed a residency in internal medicine and fellowship in medical oncology at University of Wisconsin Hospital and Clinics.
Dr. Lang’s research interests are in developmental therapeutics for prostate cancer. He is the lead principal investigator on the multi-PI Department of Defense Prostate Cancer Research Program, and the PI of a Prostate Cancer Foundation-funded project to investigatetherapeutic targeting of AR-variant prostate cancer with a novel antibody drug conjugate. He also leads clinical trials that evaluate circulating tumor cells in solid tumor malignancies, efficacy of IMMU-132 in patients with metastatic castration-resistant prostate cancer and chemohormonal therapy in high-risk and oligo-metastatic prostate cancer.
Dr. Lang is a member of the American Society of Clinical Oncology (ASCO), the Society for Immunotherapy of Cancer, and the American Association of Cancer Research.
Dr. Lang is a Value Pathways Task Force Member of the NCCN Prostate Cancer Panel.
Case 1• 61 yo AAM presented at age 47 with a PSA of 8, found to have GG4 high
risk disease on biopsy
• After radical prostatectomy for pT3a high risk disease, PSA dropped to undetectable but rose 1 year later and he completed salvage RT and 2 years of ADT given prior + margins
• PSA rose despite ADT after 5 years, and he eventually progressed to nmCRPC and was treated with enzalutamide for 3 years
• Developed mCRPC in 2018 and progressed despite use of sipuleucel-T with pathologic adenopathy (RP, pelvic) and he was treated with docetaxel with a 6 mo response
Case 1• 61 yo AAM presented at age 47 with a PSA of 8, found to have GG4 high
risk disease on biopsy
• After radical prostatectomy for pT3a high risk disease, PSA dropped to undetectable but rose 1 year later and he completed salvage RT and 2 years of ADT given prior + margins
• PSA rose despite ADT after 5 years, and he eventually progressed to nmCRPC and was treated with enzalutamide for 3 years
• Developed mCRPC in 2018 and progressed despite use of sipuleucel-T with pathologic adenopathy (RP, pelvic) and he was treated with docetaxel with a 6 mo response
• ctDNA profiling showed a BRCA2 mutation and germline testing confirmed this BRCA2 mutation
The most appropriate next step is:
a. Olaparibb. Radium-223c. Pembrolizumabd. Abiraterone acetate
• He was treated with olaparib 300 mg bid and disease responded with a partial soft tissue response, 50% PSA decline, and lack of bone metastasis
• However, he developed disease progression 9 mo later
• ctDNA analysis at that time showed a BRCA2 reversion mutation and TP53 mutation
DNA Repair Gene Alterations (Somatic and Germline) are Common in Metastatic PCa1-3
• 23% of metastatic castration-resistant prostate cancers harbor DNA repair alterations
• The frequency of DNA repair alterations increases in metastatic disease vs. localized disease
12% of men with metastatic prostate cancer have a germline DNA repair defect
Somatic Germline
1. Robinson D, et al. Cell. 2015;161:1215-28; 2. Pritchard CC, et al. N Engl J Med. 2016;375:443-53; 3. Antonakaris ES, et al. Eur Urol. 2018;74(2):218-25.
BRCA2 Carriers With PCa Have Worse Prognosis1,2
Noncarriers
aMedian survival not reached after a median of 64-mo follow-up.1. Castro E, et al. J Clin Oncol. 2013;31:1748-57; 2. Castro E, et al. Eur Urol. 2015;68:186-93.
• Pathogenic variants are those defined as mutations or alterations known to disrupt the function of the gene and confer disease risk.
• A Variant of Uncertain Significance (VUS) is a variation in a genetic sequence for which the association with disease risk is unclear. Most of these (>90%) are benign variants and do not require specific work up or counseling or treatment.
NCCN Guidelines: Recommendations for Genetic Testing1
1. NCCN Guidelines for Prostate Cancer, V.2.2021. 2. Giri VN et al. J Clin Oncol. 2020;38(24):2798-2811.
Germline Testing Somatic Tumor Testing
• Germline genetic testing is recommended for patients with prostate cancer and any of the following:– High‐risk, very high‐risk, regional, or metastatic
prostate cancer
– Intermediate‐risk with intraductal/cribriform histology
– Ashkenazi Jewish ancestry
– Family history of high‐risk germline mutations (eg, BRCA1/2, Lynch mutation)
– A positive family history of cancer*
• Recommend evaluating tumor for alterations in homologous recombination DNA repair genes, such as BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, CHEK2, and CDK12, in patients with metastatic prostate cancer
• Can be considered in men with regional prostate cancer
• Testing for MSI‐H or dMMR is recommended in patients with metastatic CRPC, and should be considered in patients with regional or castration‐naïve metastatic prostate cancer
• The International Philadelphia Prostate Cancer Consensus Conference 2019 guidelines recommended a similar germline testing strategy2
*A strong family history of prostate cancer consists of: Brother or father or multiple family members who were diagnosed with prostate cancer (but not clinically localized Grade Group 1) at <60 years of age or who died from prostate cancerOR≥3 cancers on same side of family, especially diagnoses ≤50 years of age: bile duct, breast, colorectal, endometrial, gastric, kidney, melanoma, ovarian, pancreatic, prostate (but notclinically localized Grade Group 1), small bowel, or urothelial cancer
1. ESMO 2020, Presentation ID 610O; 2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208558s014lbl.pdf.
Olaparib(N=162)
Physician’s Choice(N=83)
Median OS, mo 19.1 14.7
HR (95% Cl)0.69 (0.61‐1.03)
P = .0175
Olaparib(N=256)
Physician’s Choice(N=131)
Median OS, mo 17.3 14.0
HR (95% Cl) 0.79 (0.61‐1.03)
aPopulation used for EMA ‘BRCA1/2 approval’ recommendation; bPopulation used for the FDA ‘deleterious germline or somatic homologous recombination repair (HRR) mutation’ approval. 66% crossed over to olaparib
COHORT A OS WITH CROSSOVER ADJUSTMENT EXPLORATORY GENE‐LEVEL ANALYSIS OF OSOlaparib 300 mg bd (N=162)Enzalutamide or abiraterone acetate (N=83)HR 0.42 (95% CI 0.19, 0.91)Crossover rate: 67%
Olaparib 300 mg bd (N=256)Enzalutamide or abiraterone acetate (N=131)HR 0.55 (95% CI 0.29, 1.06)Crossover rate: 66%
Outcomes in Chemo-naïve mCRPC
De Bono, et al ASCO 2020; abstract 134.
• Kaplan–Meier estimates of OSin patients in (A) Cohort A and (B) the overall population (Cohorts A+B) by prior taxanestatus
• 7/15 genes had alteration frequencies too low for descriptive statistics (<5 patients)1
• 97% of patients were randomized based on alterations in 8/15 single genes1
• There is evidence of clinical activity of olaparib in patients with alterations in genes other than BRCA1 or BRCA21
• Gene-level analysis is complex and exploratory, and comparisons may be confounded by multiple factors1
1. Available from: https://www.urotoday.com/conference-highlights/esmo-2019/esmo-2019-prostate-cancer/115401-esmo-2019-profound-phase-3-study-of-olaparib-vs-enzalutamide-or-abiraterone-for-metastatic-castration-resistant-prostate-cancer-with-homologous-recombination-repair-gene-alterations.html.2. Hussain M, et al. ESMO 2019. Abstract LBA12_PR.
0 2 4 6 8 10
Median rPFS, mo (95% Cl)
n =8147
6128
6224
85
57
46
14
23
BRCA2
CDK12
ATM
BRCA1
CHEK2
PPP2R2A
RAD51B
RAD54LFrequen
cy
Olaparib Physician’s choice
10.84 (9.17‐13.08)3.48 (1.74‐3.65)
5.09 (3.61‐5.52)2.20 (1.71‐4.83)
5.36 (3.61‐6.21)4.70 (1.84‐7.26)
2.07 (1.38‐5.52)1.84 (1.71‐3.71)
5.59 (1.64‐11.99)3.35 (1.38‐NR)
2.69 (1.77‐3.91)
NR
10.89 (1.61‐14.75)1.77
7.20 (3.71‐7.39)2.41 (1.81‐3.02)
PROfound (Cohorts A+B): HRQoL1
CI, confidence interval; FACT-P TS, Functional Assessment of Cancer Therapy-Prostate; FAPSI-6, FACT Advanced Prostate Symptom Index; FWB, functional wellbeing; HRQoL, health-related quality of life; PCS, prostate cancer subscale; PWB, physical wellbeing; OR, odds ratio; TOI, trial outcome index.1. Thiery-Vuillemin A, et al. ASCO 2020. Abstract 5539.
A higher proportion of patients in the olaparib arm reported improvement in HRQoL
Interruption of intervention because of adverse event 115 (45) N/A 24 (18) N/A
Dose reduction because of adverse event 57 (22) N/A 5 (4) N/A
Discontinuation of intervention because of adverse event 46 (18) N/A 11 (8) N/A
Death because of adverse event 10 (4) N/A 5 (4) N/A
FDA Full Approval: Olaparib for mCRPC
aBRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L. bSelect patients for therapy based on one of two FDA-approved companion diagnostic tests: BRACAnalysis CDx and FoundationOne CDx.1. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-hrr-gene-mutated-metastatic-castration-resistant-prostate-cancer.
In May 2020, based on data from the PROfound study, the FDA granted full approval olaparib for the treatment of patients with deleterious or suspected germline or somatic HRRa gene-mutated
mCRPC, who have progressed following prior treatment with enzalutamide or abiraterone1,b
HRR-deficiency is defined by a deleterious alteration in BRCA1, BRCA2, ATM, or 12 other HRR genes (BARD1, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD54L)
1. Ryan CJ. ASCO 2018; abstract TPS389; 2. Abida W, et al. Annals Onc. 2018:29(Suppl 8):viii271-viii302.
• 74 yo WM presents with a PSA of 424 and back pain to his local urologist, biopsy shows GG5 disease pathologic RP nodes
• Treated initially for low volume mHSPC with ADT plus abiraterone acetate with a 9 mo response, PSA drops to 0.3, and adenopathy resolves
• Over subsequent year, PSA rises to 6.0 and he presents to local ER with a seizure and brief aphasia, found to have a new left frontal lobe metastasis, enlarging RP adenopathy
• Surgical resection of CNS metastasis confirms prostate adenocarcinoma, no evidence of NEPC. Profiling of tumor shows an MSH2 splice site pathogenic mutation, MSI-high disease, and TMB of 42/MB, multiple other mutations
• Treatment with CNS radiation postop
• He has significant baseline neuropathy (grade 2) from underlying diabetes
a. Docetaxel plus ongoing ADTb. Pembrolizumab plus ongoing ADTc. Olaparib plus ongoing ADTd. Cabazitaxel plus ongoing ADTe. Enzalutamide plus ongoing ADT
• Treatment with pembrolizumab is initiated with ongoing ADT initiated 3 yrs ago
• PSA drops to 0 with resolution of all adenopathy 2 years later, no evidence of disease now off ADT for 1 year and off pembrolizumab for 1 year, no CNS recurrence.
Dung T. Le et al. Science 2017Hempelman et al, J Immunol Cancer 2018Abida et al JAMA Oncol 2018
~3-6% prevalence of MMRD/MSI high in PC
Typically involve mutations or rearrangements in MSH2 or MSH6 in PC
Mismatch Repair Deficiencies: RESPONSES to Pembrolizumab in MSI high
CRPC
Note: MSI high may be more common with more PC-specific microsatellites (MSI-Plus or MSI Sensor)
~20% of MSI high CRPC patients will have germline mutations (Lynch Syndrome)
• Differential genomic and epigenomic signatures in histologically classified adenocarcinoma and NEPC
• AR signaling activity can be dramatically distinct across
Beltran H et al. Nat Med 2016
Molecular Evaluation in CRPC
• Phase II trial of first-line carboplatin and docetaxel (CD) and second-line etoposide and cisplatin (EP)
• Aggressive disease defined by • Visceral dx or lytic bone mets• Bulky tumor masses• Low PSA relative to tumor burden• Short response to ADT
• 65.4% and 33.8% were progression free after four cycles of CD and EP, respectively
• 37 patients (50.0%) benefited from both (median OS 19.33 months) • 5 patients (6.8%) did not benefit from either (median OS 6.7 months)• 25 patients (33.8%) had a response to CD but not to EP (median OS 14.4 months)• 7 patients (9.4%) had a response to EP but not to CD (median OS 8.9 months)
• Molecular subtyping not available at the time of treatment