REVIEW

Inhibitorii CDK şi cei PARP în practica clinică actuală

 CDK inhibitors and PARP inhibitors in current clinical practice

First published: 03 aprilie 2018

Editorial Group: MEDICHUB MEDIA

DOI: 10.26416/OnHe.42.1.2018.1552

Abstract

The therapeutic strategy in breast cancer, as well as in other types of cancer, changes quite frequently. These changes result from the publication of the results of clinical trials or meta-analyses of several trials. An important contribution in identifying the best therapeutic strategies is also made by the reviews of the publications that target the same subject. In this context, the present article describes the new therapeutic approaches in advanced (metastatic) breast cancer, after the introduction in clinical practice of CDK inhibitors and PARP inhibitors.

Keywords
CDK inhibitors, PARP inhibitors, breast cancer

Rezumat

Strategia terapeutică în cancerul de sân, ca şi în alte tipuri de cancer, se modifică destul de frecvent. Aceste modificări survin în urma publicării rezultatelor unor trialuri clinice sau a unor metaanalize a mai multor trialuri. O contribuţie importantă în identificarea celor mai bune strategii terapeutice o au şi review-urile care fac o analiză a mai multor publicaţii ce vizează acelaşi subiect. În acest context, articolul de faţă descrie noile abordări terapeutice în cancerul mamar avansat (metastatic), prin intrarea în practica clinică a inhibitorilor CDK şi a inhibitorilor PARP.

CDK inhibitors

Dysregulation of the cell cycle is a classic hallmark of cancer growth and metastatic potential. Reestablishing cell cycle control through CDK inhibition has emerged as an attractive option in the development of targeted cancer therapy(1).

Some clinical trials demonstrated the role of CDK inhibitors in the treatment of advanced breast cancer. One of this trials was PALMOA-2, which investigated the combination of palbociclib and letrozole. This combination offers similar health-related quality of life (QOL) and better response in the treatment of pain in postmenopausal women with estrogen receptor-positive/ HER2-negative metastatic breast cancer, compared to letrozole alone.

“Improving the response and prolonging the duration of response to endocrine-based therapy while maintaining or improving QOL is an important treatment goal”, wrote the authors of the study, led by Hope S. Rugo, medical doctor at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center. “The addition of agents targeted to pathways contributing to resistance may improve response and delay progression, but it is critical to understand both the safety profile and the impact of these therapies on QOL” (Geoffrey)(2).

Quality of life was measured using FACT-G, which was similar (77.7 with palbociclib and 79.1 with placebo), and the overall change from baseline was -0.39 with palbociclib and -0.53 with placebo (p=0.883). The EQ-5D showed no differences between the groups either.

There was, however, a difference in the subscale that assessed pain in body parts, with a significantly greater improvement from baseline with palbociclib, at -0.256 compared with -0.098 (p=0.018).

CDK4 and CDK6 are cyclin-dependent kinases that control the transition between the G1 and S phases of the cell cycle. The S phase is the period during which the cell synthesizes new DNA and prepares itself to divide during the process of mitosis. CDK4/6 activity is typically deregulated and overactive in cancer cells. There can be an amplification or overexpression of the genes encoding cyclins or of the genes encoding the CDKs themselves. Additionally, the loss of endogenous INK4 inhibitors, by gene deletion, mutation or promoter hypermethylation can also lead to overactivity of CDK4 and CDK6. A major target of CDK4 and CDK6 during cell-cycle progression is the retinoblastoma protein (Rb). When Rb is phosphorylated, its growth-suppressive properties are inactivated. Selective CDK4/6 inhibitors “turn off” these kinases and dephosphorylate Rb, resulting in a block of cell-cycle progression in mid-G1. This causes cell-cycle arrest and prevents the proliferation of cancer cells. Cancer cells must express wild-type Rb for a selective CDK4/6 inhibitor to be effective(2).

Acquired resistance to CDK4/6 inhibition emerges as a result of selection for alterations in core cell-cycle signaling pathways. In addition, adaptive features of mitogenic signaling can yield a degree of cell-cycle plasticity that can ultimately bypass the requirement for CDK4/6 activity in cell-cycle progression(3).

Toxicity

There will be presented the data resulting from the analyzing of the main trials with CDK inhibitors by Javier Cortés, from the Ramón y Cajal University Hospital, Madrid, Spain (data available at: http://ime.peervoice.com/v/index.html?collection=340204448&presentation=340204448-p2&MemberID=106479846&EmailID=19956596&SpecialtyID=108&CountryID=183&ProfessionID=12&CampaignID=2938613&AOMID=29&Promocode=340#screen1)(33).

A suggestive general evaluation of toxicity is obtained by analyzing the discontinuation of treatment with CDK determined by toxicity (Table 1).
 

Table 1. The discontinuation of treatment due to adverse events(4,5)
Table 1. The discontinuation of treatment due to adverse events(4,5)

Neutropenia was the most important adverse event for all three agents. Grade 3 neutropenia was observed in slightly more than half of patients receiving palbociclib or ribociclib in the first-line setting, and approximately 10% had grade 4 neutropenia. Grade 3/4 neutropenia occurred in about 22% of patients who received abemaciclib within the first-line setting, and in 27% of endocrine-resistant patients(6,7,8).

Let’s be a little bit more specific in terms of the toxicity profile regarding all these agents. I’ll start with palbociclib: basically, neutropenia is the most important adverse event, as we said before. However, grade 3 and 4 thrombocytopenia or anaemia were not very frequent(9,10).

Regarding ribociclib, reversible grade 3 or 4 transaminitis was observed in 7% to 8% of the patients. Prolonged QT intervals were noted in 2.7% of patients who received ribociclib(11).

In the MONARCH 3 trial, the addition of abemaciclib led to grade 3 diarrhea in 9% of patients in the first-line setting, and in 13% of patients in the second-line setting in MONARCH 2 trial. Furthermore, thromboembolic events were noted in some patients receiving abemaciclib. Finally, fatigue was also reported frequently in these studies(12,13).

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have become a standard treatment for estrogen receptor-positive/ human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Three CDK4/6 inhibitors – palbociclib, ribociclib and abemaciclib – have been evaluated in randomised phase 3 trials. Consistently, these trials indicated an almost doubling in the primary endpoint, median progression-free survival, when the CDK4/6 inhibitors are added to standard endocrine therapy compared with endocrine monotherapy.
This improvement in outcome is observed both in endocrine-sensitive and endocrine-resistant patient population. The relative improvement in progression-free survival expressed as hazard ratios is also very similar in all the other predefined subpopulations. Unfortunately, we don’t have any valid biomarker allowing selection of patients who benefit most, except the estrogen receptor status(14).

Palbociclib and ribociclib are taken orally once daily for 21 consecutive days, followed by seven days off treatment. Abemaciclib is administered two times per day, without periods of interruption in the absence of clinically significant side effects(15-17).

Palbociclib-associated neutropenia is usually an early event after beginning the treatment, with a median time to onset of grade 3 neutropenia of approximately two weeks. Also, grade 3 or 4 neutropenia is common; the risk of neutropenic fever is less than 2%. Asian ethnicity and lower absolute neutrophil counts at baseline are risk factors for developing grade 3/4 palbociclib-associated neutropenia. It is not recommended to adapt the treatment to the CDK4/6 inhibitors in case of grade 1 or 2 neutropenia(18).

The management of uncomplicated grade 3 neutropenia related to palbociclib depends on the time of recurrence. If grade 3 neutropenia is observed at the 15th day of a cycle, the patient should continue treatment without dose modification. A new blood cell count is performed at day 21. If grade 3 neutropenia is observed in the first day of a new cycle, treatment restart is postponed, and complete blood count monitoring is repeated within a week. When recovered to grade 2 or less, the treatment is restarted at the same dose. The routine use of G-CSF is not recommended for the management of uncomplicated grade 3/4 neutropenia(19,20).

The recommended dose modification for ribociclib and abemaciclib is somewhat different. In case of uncomplicated grade 3 neutropenia, the treatment should be interrupted and later resumed at the same dose after recovery to grade 2 or less. However, in case of recurrence of grade 3 neutropenia, the treatment should be started after recovery at the next lower dose level. The treatment has to be resolved until recovery and resumed later at the next lower dose.
One of my concerns is that, generally, our patients have more comorbidities, and they may be at an additional risk for infections. Therefore, grade 3 neutropenia can result in higher incidence of fever because of the comorbidities.
Other higher-grade haematologic toxicities such as anaemia and thrombocytopenia are not very common with all three CDK4/6 inhibitors. PALOMA-2 and MONARCH 3 trials reported grade 3/4 anaemia in approximately 5% of the patients. High-grade thrombocytopenia is even less frequent(21,22).

Liver toxicity can be noticed in some patients receiving a CDK4/6 inhibitor. Of course, first of all, it is important to differentiate between disease-related liver test abnormalities and drug-related toxicity. Nevertheless, some patients develop grade 3/4 liver test abnormalities, justifying the interruption of treatment by the CDK4/6 inhibitor. The majority of cases were asymptomatic and reversible with dose adjustment.
If ribociclib is administered, liver test should be monitored every two weeks during the first two cycles, monthly the next four cycles, and thereafter as clinically indicated. If abemaciclib is administered, liver tests should be monitored every two weeks during the first two cycles, monthly the next two cycles, and thereafter as clinically indicated. A more frequent monitoring is indicated with any CDK4/6 inhibitor if grade 2 or higher-grade toxicities observed(23,24).

Ribociclib can favour corrected QT interval (QTc) prolongation in some patients. Monitoring by an electrocardiogram is indicated at baseline, at day 14 of cycle one, and at the first day of the second cycle. QTc interval has to be below 480 ms, in order to continue the administration of ribociclib. Generally, it is unusual that ribociclib treatment has to be permanently discontinued because of QTc prolongation.
In addition, ribociclib comedications favouring QTc prolongation should absolutely be avoided. Physicians have to carefully check all potential drug-drug interactions and the impact of concomitant food intake when prescribing oral anti-cancer therapies. All details are available in the full prescribing information of these drugs(25).

Abemaciclib is associated with a higher digestive toxicity compared with the other two CDK4/6 inhibitors. Almost 10% of the patients receiving abemaciclib developed grade 3 diarrhea in the MONARCH 3 trial. The optimal management, including patient education, preventive measures, and early start of antidiarrhoeal therapy, should be further evaluated in order to try to decrease the incidence of high-grade diarrhoea.

Increased risk of thromboembolic events has been recently pointed out as a side effect related to abemaciclib. Patients should be monitored for signs and symptoms of venous thrombosis and pulmonary embolism, and treated properly(26).

In conclusion, CDK4/6 inhibitors combined with endocrine therapy are new important first-line treatment options in estrogen receptor-positive/ HER2-negative advanced breast cancer with a good safety profile. The most frequent grade 3/4 toxicity is uncomplicated neutropenia. Drug-drug interaction is an important issue in oral anti-cancer therapies administered. Particularly, it is important to evaluate the administration of potent CYP3A4 inhibitors or inducers, because it can result in increasing toxicity or decreasing efficacy. Prescribing physicians have to check co-medications carefully and to monitor the side effects, as recommended. Treatment interruption and dose modifications are sometimes needed.

PARP inhibitors in breast cancer

US Food and Drug Administration (FDA) approved the PARP inhibitor olaparib (Lynparza®) for the treatment of patients with metastatic breast cancer who have a mutated BRCA gene. The drug is now approved for use in HER2-negative breast cancer patients who have been previously treated with chemotherapy in either the neoadjuvant or adjuvant setting, or for metastatic disease(27).

BRCA 1/2 mutations affect approximately 5% of patients with breast cancer and are associated with triple-negative breast cancer (TNBC), which has a poor prognosis and is well-known for the resistance to targeted therapies.

In the open-label phase III OLYMPIAD trial (NCT02000622) lead by Robson and his associates, olaparib, an oral PARP inhibitor, was associated with a nearly 3-month improvement in median progression-free survival (PFS) compared with physician’s choice of conventional single-agent chemotherapy in patients with heavily pretreated HER2-negative metastatic breast cancer and a confirmed or suspected germline BRCA mutation. The median PFS was 7 months in the olaparib (300 mg twice daily) group and 4.2 months in the group that received 21-day cycles of either capecitabine (Xeloda®), eribulin (Halaven®), or vinorelbine (hazard ratio [HR]: 0.58; 95% CI; 0.43-0.80; p<0.001). The difference in this primary endpoint was more striking among patients with TNBC (HR: 0.43; 95% CI; 0.29-0.63).

Robson et al. stated that the “inclusion of patients with TNBC in this study is important, given the limited treatment options for these patients after anthracyclines and taxanes”(28).

The poly (ADP-ribose) polymerase (PARP) enzyme is an important enzyme in the process of repairing DNA errors.

There is a second mechanism of action in which the PARP enzyme can be trapped on the DNA, trying to repair the DNA breaks caused by the PARP inhibitors. The PARP enzyme is in the way and the DNA is not repaired, and that can cause cells to die. We think this may explain why even people who do not have a germline mutation or are not born with mutations in either BRCA1 or BRCA2 can still have tumors that are susceptible to killing by PARP inhibitors(29).

Many trials studied the PARP inhibitors in clinical practice. First quoted by Gerber is ICEBERG trial, which demonstrated that olaparib is effective for 10% of patients with BRCA 1/2 positive. The response was positive for patients with triple-negative breast cancer or those with ER positive.

Also, OlympiAD trial compared PARP inhibitor olaparib with one of three chemotherapy drugs capecitabine, eribulin or vinorelbine. All patients included were BRCA mutation carriers and had one or two prior treatments for metastatic disease. The study showed a significant progression-free survival advantage with olaparib; there was no overall survival benefit from the drug, however. The researchers looked at triple-negative and ER-positive patients and observed that the benefit was confined to the triple-negative patients. Patients who had prior platinum therapy as part of their treatment did not benefit, whereas those who did not have prior platinum treatment had more of a benefit(30).

Talazoparib was studied in ABRAZO trial and compared with other single agents choices. In this study, there was also a benefit in BRCA 1 and BRCA 2 carriers(31).

Another study was OlympiA, on patients with triple-negative breast cancer or ER-positive high-risk breast cancer with four or more positive nodes, who were carriers of BRCA 1 or BRCA 2 and had completed prior treatments. It was tested whether adjuvant olaparib for 1 year versus placebo would offer a survival advantage. This trial did not complete accrual for the moment, and should report data by 2020, so there is an exciting development for these drugs(32).

Conflict of interests: The author declares no conflict of interests.

Bibliografie

  1. Mayer EL. Targeting breast cancer with CDK inhibitors. Curr Oncol Rep. 2015; 17(5):443, doi: 10.1007/s11912-015-0443-3.
  2. Geoffrey I. Shapiro, CDK4/6 Inhibitors: Where They Are Now and Where They Are Headed in the Future, http://www.ascopost.com/issues/may-10-2017-ce-supplement-cdk46-inhibitors/cdk46-inhibitors-where-they-are-now-and-where-they-are-headed-in-the-future/
  3. Knudsen ES, Witkiewicz AK. The Strange Case of CDK4/6 Inhibitors: Mechanisms, Resistance, and Combination Strategies. Trends in cancer. 2017; Volume 3, January, Issue 1, p. 39–55. 
  4. Levitan D. Adding Palbociclib Did Not Diminish QOL in Metastatic Breast Cancer. Cancer Network, Jan 29, 2018, available at: http://www.cancernetwork.com/article/adding-palbociclib-did-not-diminish-qol-metastatic-breast-cancer
  5. www.peervoice.com/EVR910
  6. Palbociclib Summary of Product Characteristics (SmPC): European Medicines Agency (EMA). Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003853/WC500217196.pdf. Accessed January 8, 2018.
  7. Ribociclib SmPC: EMA. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004213/WC500233997.pdf. Accessed January 8, 2018. 
  8. Sledge GW Jr et al. MONARCH 2: Abemaciclib in Combination with Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. J Clin Oncol. 2017; 35:2875-2884.
  9. Finn RS et al. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med. 2016; 375:1925-1936.
  10. Cristofanilli M et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): Final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016; 17:425-439.
  11. Ribociclib SmPC: EMA. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004213/WC500233997.pdf. Accessed January 8, 2018.
  12. Goetz MP et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017; 35:3638-3646.
  13. Sledge GW Jr et al. MONARCH 2: Abemaciclib in Combination with Fulvestrant in Women with HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. J Clin Oncol. 2017; 35:2875-2884.
  14. O’Leary B et al. CDK4/6: cyclin-dependent kinases 4/6; PFS: progression-free survival. Nat Rev Clin Oncol. 2016; 13:417-430.
  15. Palbociclib Summary of Product Characteristics (SmPC): European Medicines Agency (EMA). Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003853/WC500217196.pdf. Accessed January 8, 2018. 
  16. Ribociclib SmPC: EMA. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004213/WC500233997.pdf. Accessed January 8, 2018. 
  17. Abemaciclib Label: US Food and Drug Administration (FDA). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208716s000lbl.pdf. Accessed January 8, 2018
  18. Palbociclib SmPC: EMA. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003853/WC500217196.pdf. Accessed January 8, 2018.
  19. Palbociclib SmPC: EMA. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003853/WC500217196.pdf. Accessed January 8, 2018.
  20. Spring LM et al. Clinical Management of Potential Toxicities and Drug Interactions Related to Cyclin-Dependent Kinase 4/6 Inhibitors in Breast Cancer: Practical Considerations and Recommendations. Oncologist. 2017; 22:1039-1048.
  21. Ribociclib SmPC: EMA. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004213/WC500233997.pdf. Accessed January 8, 2018. 
  22. Abemaciclib Label: US FDA. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208716s000lbl.pdf. Accessed January 8, 2018
  23. Ribociclib SmPC: EMA. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004213/WC500233997.pdf. Accessed January 8, 2018. 
  24. Abemaciclib Label: US FDA. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208716s000lbl.pdf. Accessed January 8, 2018.
  25. Ribociclib SmPC: EMA. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004213/WC500233997.pdf. Accessed January 8, 2018.
  26. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208716s000lbl.pdf. Accessed: January 8, 2018.
  27. Amy Karon. Select Ongoing Clinical Trials of PARP Inhibitors in Breast Cancer. Available at: http://www.targetedonc.com/publications/targeted-therapy-news/2017/october-2017/select-ongoing-clinical-trials-of-parp-inhibitors-in-breast-cancer
  28. Azvolinsky A. Role of PARP Inhibitors in Triple-Negative Breast Cancer. Onco Therapy Network, Oct 4, 2017. Available at: http://www.oncotherapynetwork.com/breast-cancer-targets/role-parp-inhibitors-triple-negative-breast-cancer
  29.  Garber J, Judy Garber on PARP Inhibitors for Triple-Negative Breast Cancer. Available at: , http://www.cancernetwork.com/triple-negative-breast-cancer/judy-garber-parp-inhibitors-triple-negative-breast-cancer 
  30. Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, Tung N, Armstrong A, Wu W, Goessl C, Runswick S, Conte P. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med. 2017; 377:523-533, DOI: 10.1056/NEJMoa1706450.
  31. Turner NC, Telli ML, Rugo HS, Mailliez A, Ettl J, Grischke EM. Final results of a phase 2 study of talazoparib (TALA) following platinum or multiple cytotoxic regimens in advanced breast cancer patients (pts) with germline BRCA1/2 mutations (ABRAZO). Journal of Clinical Oncology. 2017; 35, no. 15_suppl (May 2017) 1007-1007.
  32. Tutt A, Kaufman B, Garber J, Gelber R, McFadden E, Goessl C, Viale G, Geyer C, Zardavas D, Arahmani A, Fumagalli D, De Azambuja E, Ponde N, Herbolsheimer P, Wu W, Constantino J, Rastogi P. OlympiA: a randomized Phase III trial of olaparib as adjuvant therapy in patients with high-risk HER2-negative breast cancer (BC) and a germline BR. Annals of Oncology. 2017; 28 (suppl_5): v43-v67. 10.1093/annonc/mdx362.
  33. http://ime.peervoice.com/v/index.html?collection=340204448&presentation=340204448-p2&MemberID=106479846&EmailID=19956596&SpecialtyID=108&CountryID=183&ProfessionID=12&CampaignID=2938613&AOMID=29&Promocode=340#screen1

Articole din ediţiile anterioare

REVIEW | Ediţia 1 38 / 2017

Actualizări în tratamentul hormonal al cancerului de sân

Dan Ilie-Damboiu

Tratamentul hormonal este una din componentele de bază ale terapiei în cancerul de sân, find folosit la aproximativ 70% din paciente. El este aplic...

04 aprilie 2017
ORIGINAL STUDY | Ediţia 1 50 / 2020

Tendinţe privind mastectomia pentru cancerul de sân în stadii incipiente: experienţa unui centru medical

Cristian Lungulescu, Mihaela Dănciulescu, Denisa Bărbulescu, Ana Dorobanţu, Georgiana Camen

Cancerul de sân este o problemă majoră de sănătate publică în România, reprezentând prima cauză de mortalitate pentru femeile între 15 şi 49 de ani...

30 martie 2020
REVIEW | Ediţia 2 51 / 2020

Opţiuni terapeutice în cancerul de sân metastatic HER2-pozitiv

Ciprian Ciobotaru, Alexandru C. Grigorescu

Luând în considerare faptul că incidenţa şi mortalitatea prin cancer de sân sunt încă importante în lume, acest tip de neoplasm constituind o probl...

19 mai 2020
BASIC RESEARCH WITH CLINICAL IMPLICATIONS | Ediţia 3 48 / 2019

Obezitatea şi cancerul de sân

Iuliana Pantelimon, Tiberiu Tebeică

Această lucrare reprezintă o analiză a principalelor studii din literatura de specialitate privind mecanismele moleculare majore în ceea ce priveşt...

27 septembrie 2019