Friday, May :15 am. PARP Is a Perp: Biology of Cancer Update. Session 10 11:15 am Room 272

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1 Session Room 272 PARP Is a Perp: Biology of Cancer Update This session has been planned in collaboration with the Cancer Genetics and Targeted and Biological Therapies Special Interest Group. Session Description: In this interactive session, you ll learn about the action of new therapies based on the PARP enzyme in relation to cancer biology, identify your role in patient education and symptom management during PARP inhibitor therapy, and apply the principles presented to a clinical scenario. You ll also have a chance to play DNA Repair Jeopardy to test your new knowledge. Level of Content: Level II Content Area: Types of Cancer and Treatment Coordinator/Speaker: Julie Eggert, RN, PhD, GNP-C, AOCN Associate Professor Clemson University Clemson, SC jaegger@clemson.edu Full Disclosure: Nothing to Disclose Speaker: Lori Williams, PhD, RN, AOCN, OCN Assistant Professor MD Anderson Cancer Center Houston, TX loriwilliams@mdanderson.org Full Disclosure: Speaker intends to discuss unapproved/investigational use of a commercial product/device during this session. At the end of this session, participants will be able to: 1. Describe the action of new therapies based on the PARP enzyme in relation to cancer biology. 2. Identify the role of the nurse in patient education and symptom management during PARP inhibitor therapy. Content Outline: I. Biology of cancer A. Genetics B. DNA repair pathways C. Proteins important in DNA repair D. Differences between normal and malignant cell DNA repair II. Therapies A. PARP inhibitors 1. Treatment 2. Prevention 3. Concerns for use B. Characteristics of PARP sensitive tumors C. Cancers sensitive to PARP inhibition 1. Breast cancer 2. Prostate cancer 3. Squamous cell lung cancer 4. Colorectal cancer 5. Ovarian cancer 6. Malignant melanoma III. Role of the nurse A. Patient education B. Symptom management IV. Scenario application Bibliography: Ashworth, A. (2008). A synthetic lethal therapeutic approach: Poly (ADP) ribose polymerase inhibitors for the treatment of cancers deficient in dna double-strand break repair. Journal of Clinical Oncology, 26(22), Audeh, M.W., Carmichael, J., Penson, R.T., Friedlander, M., Powell, B., Bell-McGuinn, K.M.,... Tutt, A. (2010). Oral poly (ADPribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-ofconcept trial. Lancet, 376(9737), Bedikian, A.Y., Papadopoulos, N.E., Kim, K.B., Hwu, W.J., Homsi, J., Glass, M.R.,... Hwu, P.A. (2009). Phase IB trial of intravenous INO-1001 plus oral temozolomide in subjects with unresectable stage-iii or IV melanoma. Cancer Investigation, 27(7), Drew, Y., & Calvert, H. (2008). The potential of PARP inhibitors in genetic breast and ovarian cancers. Annals of the New York Academy of Sciences, 1138, Elmageed, Z.Y.A., Naura, A.S., Errami, Y., & Zerfaoui, M. (2012). The poly (ADP-ribose) polymerases (PARPs): New roles in intracellular transport. Cellular Signaling, 24(1), 1 8. Fong, P.C., Boss, D.S., Yap, T.A., Tutt, A., Wu, P., Mergui-Roelvink, M.,... de Bono, J.S. (2009). Inhibition of poly(adp-ribose) polymerase in tumors from BRCA mutation carriers. New England Journal of Medicine, 361(2), Fong, P.C., Yap, T.A., Boss, D.S., Carden, C.P., Mergui-Roelvink, M., Gourley, C.,... Kaye, S.B. (2010). Poly(ADP)-ribose polymerase inhibition: Frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. Journal of Clinical Oncology, 28(15), Gelmon, K.A., Tischkowitz, M., Mackay, H., Swenerton, K., Robidoux, A., Tonkin, K.,... Oza, A. (2011). Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, mul- Oncology Nursing Society 37th Annual Congress 135

2 ticentre, open-label, non-randomised study. Lancet Oncology, 12(9), Guha, M. (2011). PARP inhibitors stumble in breast cancer. Nature Biotechnology, 29, Jayle, M., & Curtin, N.J. (2012). The potential for poly (ADP-ribose) polymerase inhibitors in cancer therapy. Ther Adv Med Oncol, 3(6), Kaye, S.B., Lubinski, J., Matulonis, U., Ang, J.E., Gourley, C., Karlan, B.Y.,... Kaufman, B. (2012). Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. Journal of Clinical Oncology, 30(4), Konstantinopoulos, P.A., & Cannistra, S.A. (2012). Comparing poly (ADP-ribose) polymerase inhibitors with standard chemotherapy in BRCA-mutated, recurrent ovarian cancer: Lessons learned from a negative trial. Journal of Clinical Oncology, 30(4), Konstantinopoulos, P.A., Spentzos, D., Karlan, B.Y., Taniguchi, T., Fountzilas, E., Francoeur, N.,... Cannistra, S.A. (2010). Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. Journal of Clinical Oncology, 28(22), Krishnakumar, R., & Kraus, W.L. (2010). The PARP side of the nucleus: Molecular actions, physiological outcomes, and clinical targets. Molecular Cell, 39(1), Kummar, S., Chen, A., Ji, J., Zhang, Y., Reid, J.M., Ames, M.,... Doroshow, J.H. (2011). Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas. Cancer Research, 71(17), Kummar, S., Ji, J., Morgan, R.J., Lenz, H.J., Puhalla, S.L., Belani, C.P.,... Doroshow, J.H. (2012). A phase I study of veliparib in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas. Clinical Cancer Research. Lord, C.J., & Ashworth, A. (2008). Targeted therapy for cancer using PARP inhibiors. Current Opinion in Pharmacology, 8(4), Mukhopadhyay, A., Elattar, A., Cerbinskaite, A., Wilkinson, S.J., Drew, Y., Kyle, S.,... Curtin, N.J. (2010). Development of a functional assay for homologous recombination status in primary cultures of epithelial ovarian tumor and correlation with sensitivity to poly(adp-ribose) polymerase inhibitors. Clinical Cancer Research, 16(8), O Shaughnessy, J., Osborne, C., Pippen, J.E., Yoffe, M., Patt, D., Rocha, C.,... Bradley, C. (2011). Iniparib plus chemotherapy in metastatic triple-negative breast cancer. New England Journal of Medicine, 364(3), Plummer, R., Jones, C., Middleton, M., Wilson, R., Evans, J., Olsen, A.,... Calvert, H. (2008). Phase I study of the poly(adpribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. Clinical Cancer Research, 14(23), Ratnam, K., & Low, J.A. (2007). Current development of clinical inhibitors of poly (ADP-ribose) polymerase in oncology. Clinical Cancer Research, 13, deruijter, T.C., Veeck, J., de Hoon, J.P.J, van Engeland, M., & Tjan-Heijnen, V.C. (2011). Characteristics of triple-negative breast cancer. Journal of Cancer Research in Clinical Oncology, 137, Sandhu, S.K., Yap, T.A., & de Bono, J.S. (2011). The emerging role of poly(adp-ribose) polymerase inhibitors in cancer treatment. Current Drug Targets, 12(14), Tutt, A., Robson, M., Garber, J.E., Domchek, S.M., Audeh, M.W., Weitzel, J.N.,... Carmichael, J. (2010). Oral poly(adp-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: A proof-of-concept trial. Lancet, 376(9737), Weberpals, J.I., Koti, M., & Squire, J.A. (2011). Targeting genetic and epigenetic alterations in the treatment of serous ovarian cancer. Cancer Genetics, 204(10), Oncology Nursing Society 37th Annual Congress

3 Biology of Cancer Genetics DNA binding Chromatin binding Nucleosomes Genomic localization Transcription machinery DNA repair pathways Proteins important in DNA repair Differences between normal and malignant cell DNA repair Krishnakumar & Kraus. Mol Cell 2010; 39:8 24. PARP: What it Does PARP 1 binds to DNA nicks and breaks activation of catalytic activity poly(adp)ribosylation (PARP)[negatively charged]of PARP 1 + other acceptor proteins (histones) signal recruitment of DNA repair pathways + modifying activity of proteins PARP [highly negatively charged] produced around site of damage serve as an anti recombinogenic factor Multiple other cellular pathways DNA Repair Deficiency Alternative repair with NHEJ or SSA gross genomic instability cell death OR survival + chromosomal deletions / exchanges Enhance the cytotoxic effects of ionizing radiation and DNA damaging chemotherapy agents, such as the methylating agents and topoisomerase I inhibitors. Drew & Calvert. Ann N Y Acad Sci 2008; 1138: PARP Inhibitor Therapies: Use in Prevention BrCa 1 or BrCa2 carriers Ratnam &Low. Clin Cancer Res 2007; 13: PARP Inhibitor Therapies: Use in Treatment BrCa1 & BrCa2 Inherited Tumors BrCa1 (phenotypic) basal like breast cancers Sporadic BrCa1 tumors Uterine Ovarian Metastatic melanoma Glioma PARP Inhibitor Therapies: Concerns for Use Reduction of cisplatin nephrotoxicity or doxorubicin cardiotoxicity Clinical trial reported exacerbation of temozolomide induced hematologic toxicity Development of markers of target effect Ashworth. JCO 2008; 26: ; Ratnam &Low. Clin Cancer Res 2007; 13: Ratnam &Low. Clin Cancer Res 2007; 13: Oncology Nursing Society 37th Annual Congress 137

4 Characteristics of PARP Sensitive Tumors BrCaI or BrCa2 tumors Triple negative breast cancer tumors Cancers Sensitive to PARP Inhibition Breast cancer Prostate cancer Squamous cell lung cancer Colorectal cancer Ovarian cancer Malignant melanoma Lord & Ashworth. Curr Opin Pharmacol 2008; 8: Phase I 23 patients with advanced solid tumors Single agent iniparib Drug active at doses from 2.8 mg/kg Maximum tolerated dose not reached at 8 mg/kg Phase Ib 66 patients Imiparib combined with either topotecan, gemcitabine, temozolomide, or carboplatin (AUC6)/paclitaxel (200mg/m 2 ) Responses in breast, ovarian, renal cell, and uterine cancer, and sarcoma Lord & Ashworth. Curr Opin Pharmacol 2008; 8: Phase II Randomized 123 patients with advanced triple negative breast cancer Carboplatin (AUC2) and gemcitibine (1000mg/m 2 ) days 1 and 8 with or without iniparib 5.6 mg/kg days 1, 4, 8, and 11 every 21 days. Clinical benefit of 62% (iniparib) vs 21% (control) O'Shaughnessy et al. NEJM 2011; 364: ; Phase III study in triple negative breast cancer ongoing Multiple other studies Combined with irinotecan, temozolomide, carboplatin /paclitaxel, and topotecan Various tumor types Single agent use in BRCA associated ovarian cancer, primary peritoneal cancer, fallopian tube cancer, and malignant gliomas mg/kg administered IV over 60 minutes twice weekly Very short half life (4 minutes) with longer acting active metabolites Potential drug drug Interactions May alter metabolism of CYP 1A2 drugs Glutathione depleting drugs may increase iniparib levels O'Shaughnessy et al. NEJM 2011; 364: ; 138 Oncology Nursing Society 37th Annual Congress

5 Side Effects Fatigue, drowsiness Nausea, vomiting, loss of appetite, dyspepsia, diarrhea Stomatitis Photosensitivity Anemia, neutropenia, lymphopenia, thrombocytopenia not as severe as other PARP inhibitors Convulsions, dizziness, and other CNS toxicities at higher doses Acute renal failure Pulmonary embolism Olaparib (AZD2281) 46 patients with advanced BRCA mutated ovarian cancer ~50% clinical benefit 54 patients with advanced BRCA mutated breast cancer ~40% response rare 33 patients with advanced BRCA mutated ovarian cancer ~33 80% response rate Antitumor activity in prostate cancer Combination studies ongoing with carboplatin and paxlitaxel, gemcitibine and/or cisplatin, topoisomerse inhibitors, liposomal doxorubicin, and bevacizumab in advanced solid tumors including colorectal cancer Audeh et al. Lancet 2010; 376: ; Gelmon et al. Lancet Oncology 2011; 12: ; Kaye et al. J Clin Oncol 2012; 30: ; Sandhu et al. Current Drug Targets 2011; 12: ; Tutt et al. Lancet 2010; 376: Olaparib (AZD2281) 400 mg orally twice a day daily as single agent or intermittently before or after chemotherapy Side Effects Fatigue, drowsiness Nausea, vomiting, loss of appetite, dyspepsia, diarrhea Stomatitis Dizziness Myelosuppression, lymphopenia, anemia Peak level 1 3 hours after dose; half life 5 7 hours Rucaparib (AG014699) Administered IV or orally either daily or intermittently Malignant melanoma Phase I Rucaparib 12 mg/m 2 and temozolimide 200 mg/m 2 IV daily for 5 days every 4 weeks Phase II ~ 60% response or stable disease Neutropenia and thrombocytopenia (up to Grade 4) Being evaluated in BRCA deficient advanced breast and ovarian cancer Plummer et al. Clin Cancer Res 2008; 14: ; Velaparib (ABT888) Phase 1 35 patients with metastatic solid tumors and low grade lymphomas Maximum tolerated dose velaparib 60 mg/day with metronomic cyclophosphamide 50 mg/day orally for 21 day cycles Short half life (5 hours) but twice daily dosing not needed Adverse events Moderate myelosuppression especially lymphopenia, respiratory failure, abdominal pain and distention Partial responses and stable disease ~ 40% of patients mostly with known BCRA mutations Patients received up to 17 cycles of therapy Kummar et al. Cancer Res, 2012; 17: ; Kummar et al. Clin Cancer Res, 2012: Epub ahead of print. Velaparib (ABT888) Phase 1b studies in progress with chemotherapies temozolomide, irinotecan, cyclophosphamide, or carboplatin Single agent in hematological malignancies Velaparib and topotecan in chronic lymphocytic leukemia, lymphoma, and refractory ovarian cancer First line treatment in ovarian cancer with carboplatin/paclitaxel/ bevacizumab combination Oncology Nursing Society 37th Annual Congress 139

6 INO 1001 Malignant melanoma INO mg twice daily with temozolimide 200 mg/m 2 IV daily for 5 days ~ 40% of patients had response or stable disease Myelosuppression (some Grade 3 4), hepatic toxicity Currently being evaluated in malignant glioma CEP 9722 Advanced solid tumors Phase I trials ongoing Bedikian et al. Cancer Investigation 2009;27: ; MK 4827 Advanced BRCA mutated ovarian cancer Castration resistant prostate cancer Phase I trials ongoing KU Combination with irinotecan, carboplatin and/or paclitaxel, dacarbazine, liposomal doxorubicin, topotecan, cisplatin and/or gemcitabine, and bevacizumab Phase I II trials ongoing Questions for Future PARP Inhibitor Usage Which PARP inhibitors are best for which cancers at what doses? Should PARP inhibitors be used in combination with chemotherapy and what are the best combinations and doses to achieve maximum effectiveness with minimum toxicities? Can PARP inhibitors be used as radiosensitizers and what would the toxicities and long term effects be? Can PARP inhibitors be combined with other targeted agents? What about PARP inhibitors as adjuvant, prophylactic, or maintenance treatments? Can PARP inhibitors be effective in sporadic tumors with homologous recombination defects and how can these tumors be identified? Roles of the Nurse Clinical Trials Patient Education Knowledgeable Practitioner Evidence Based Symptom Management Nursing Research 140 Oncology Nursing Society 37th Annual Congress

7 Clinical Trials Encouraging appropriate patient participation Clinical trials research nurse functions Participating in study design and initiation Assessing for trial eligibility Obtaining informed consent Study drug administration Assessing patients during study Collecting data and maintaining records Monitoring for safety and reporting adverse events Participating in trial audits Assisting with analysis Contributing to study outcomes reporting PARP Background PARP protein needed by cells need to repair damage PARP blocked no damage repair cell death Some cancer cells dependent on PARP BRCA or BRCA like mutations Your tumor may be dependent on PARP PARP inhibitors may be used to prevent repair of damage from chemotherapy or radiation Patient Education Why did my doctor suggest PARP inhibitor therapy? How will I take a PARP inhibitor? What will my pills look like? How should I store my pills? What if I miss a dose? Are there any special instructions for taking my medication? What side effects might occur? How should I manage these side effects? When should I contact my doctor? Should I follow any special precautions while I am taking a PARP inhibitor? Predicting Response to PARP Inhibitors BRCA1/BRCA2 mutations cause problems with cell repair PARP inhibitors are effective in patients with deficient cell repair Other patients may have tumors with changes that produce cell repair deficits like BRCA1/BRCA2 PARP inhibition could be effective in these patients Research is being done to find tests to identify these patients A PARP inhibitor would be recommended : You have a BRCA1 or BRCA 2 mutation You have a tumor that has a strong chance of being deficient in cell repair Konstantiinopoulos et al. J Clin Oncol 2012; 28: ; Mukhopadhyay et al. Clin Cancer Res 2010; 16: Konstantiinopoulos et al. J Clin Oncol 2012; 28: ; Mukhopadhyay et al. Clin Cancer Res 2010; 16: Drug Information PARP inhibitors are still investigational If your doctor thinks you might benefit from a PARP inhibitor: You must be eligible for a clinical trial You will have to consent to treatment on the clinical trial You will receive the PARP inhibitor drug free of charge PARP Inhibitor Administration PARP inhibitors may be given as pills or IV. It depends on the type of PARP inhibitor. If you take pills: You may take them once or twice a day. You may take the pills every day or you may take them intermittently on a schedule your doctor will give you. You may receive other therapy at the same time as the PARP inhibitor. If you receive a PARP inhibitor intravenously: It will be given on a schedule prescribed by your doctor. You will have an infusion about twice a week for several weeks and then have a few days off before the next cycle of therapy begins. The infusions will usually last about 1 hour. Oncology Nursing Society 37th Annual Congress 141

8 Oral PARP Inhibitor Therapy Side Effects of PARP Inhibitors Your doctor or pharmacist will explain to you how to store your PARP inhibitor pills. Your doctor or pharmacist will tell you what to do if you miss a dose of a PARP inhibitor pill, but try very hard not to miss a dose. Your therapy will be most effective if you take it exactly as your doctor tells you to. Your doctor or pharmacist will give you any special instructions about taking your PARP inhibitor pills. Symptom Management There is no evidence for the management of symptoms related to PARP inhibitor therapy. Apply general symptom management principles and recommendations. Fatigue, drowsiness Nausea, vomiting, lack of appetite, dyspepsia, diarrhea Abdominal pain and distention Stomatitis Photosensitivity Myelosuppression Convulsions, dizziness, and other CNS toxicities at higher doses Acute renal failure Pulmonary embolism Respiratory failure Sandhu et al. Current Drug Targets 2011; 12: ; O'Shaughnessy et al. NEJM 2011; 364: Symptom Management Fatigue exercise Nausea, vomiting anti emetic appropriate for the severity of the symptoms Lack of appetite frequent small meals, nutritional supplements Dyspepsia antacids, 5HT3 blockers Diarrhea low fiber diet, immodium, lomotil Sandhu et al. Current Drug Targets 2011; 12: ; O'Shaughnessy et al. NEJM 2011; 364: Symptom Management Abdominal pain and distention evaluate for bowel obstruction; NPO; gastric suction Photosensitivity avoid sun exposure, long sleeves and pants, use SPF 30 Myelosuppression monitor, dose delay or reduction, growth factors if appropriate, blood component transfusions, prevent infections and bleeding Dizziness avoid falls Sandhu et al. Current Drug Targets 2011; 12: ; O'Shaughnessy et al. NEJM 2011; 364: Nursing Research Identification of PARP inhibitor acute and long term side effects and symptoms Impact of PARP inhibitor side effects and symptoms on patient functioning Understanding of mechanisms behind PARP inhibitor side effects and symptoms Testing effectiveness of interventions to prevent and manage PARP inhibitor side effects and symptoms 142 Oncology Nursing Society 37th Annual Congress