Talazoparib Plus Pacritinib Aims to Improve the Limitations of Second-Line Therapy in MPNs

The combination of talazoparib (Talzenna) and pacritinib (Vonjo) could provide more than symptom burden relief for patients with myeloproliferative neoplasms (MPNs) who have become unresponsive to frontline JAK2 inhibition with ruxolitinib (Jakafi), according to Peter Abdelmessieh, DO, MSC.

The regimen is under study in a phase 1 trial (NCT06218628) at Fox Chase Cancer Center and is supported by earlier work published in Blood showing the synergistic disease-modifying activity of the regimen.¹

To be eligible for enrollment, patients must have received a diagnosis of histologically or cytologically confirmed primary myelofibrosis, post-polycythemia vera-myelofibrosis, post-essential thrombocythemia-myelofibrosis, chronic myelomonocytic leukemia, polycythemia vera, or essential thrombocytosis according to the 2008 World Health Organization criteria. Patients must also have at least 2 symptoms with a score of 3 or greater or a total score of 12 or greater, according to the Myelofibrosis Symptom Assessment Form v4.0; intermediate-2 or high-risk myelofibrosis according to the Dynamic International Prognostic Scoring System Plus; and a baseline QTc less than 0.47 seconds per Bazett formula.

Additionally, patients must have prior exposure to a JAK2 inhibitor for at least 12 weeks with documented disease progression or have new, palpable splenomegaly measuring at least 5 cm below the left costal margin in patients who had no evidence of splenomegaly before the start of any frontline JAK2 inhibitor.²

“Second-line treatment for patients with this disease is an unmet need along with the need to investigate other possible pathways that might be effective in this disease. The tool shed is essentially barren for clinicians outside of JAK2 inhibitors,” Abdelmessieh said in an interview with OncLive®.

In the interview, Abdelmessieh, an assistant professor in the Department of Bone Marrow Transplant and Cellular Therapies at Fox Chase Cancer Center, in Philadelphia, Pennsylvania, discussed the basis for the phase 1 trial in patients with MPNs.

OncLive: Why is a treatment aimed at reducing symptomatic burden insufficient for patients with myelofibrosis?

Abdelmessieh: ‘Insufficient’ I feel is too hard of a term to use in this question. Treatments directed at symptom management in myelofibrosis are very effective at improving the quality of life for patients afflicted with myelofibrosis, and up until 2011, there were no real treatments directed at symptom management. However, currently, the only cure for this disease is an allogeneic stem cell transplant, which is often not a treatment most individuals afflicted with this disease can undergo.

Advancements in the field have led to the introduction of JAK2 inhibitors, which are excellent at reducing symptom burden. However [these agents] usually lose their effectiveness during the lifetime of patients with this disease because these medications are approved solely on symptom burden improvement, not the underlying biology driving these malignant cells. These advancements [served as the foundation] to our current study, which hopes to improve not only symptom burden but the biology of the disease by adding a PARP inhibitor to the current standard of care [SOC] for patients who have progressed on a JAK2 inhibitor.

What preclinical research supports the notion of adding a PARP inhibitor to a JAK2 inhibitor?

The preclinical work for this study comes from Fels Cancer Institute for Personalized Medicine, here at our center, under the guidance of Dr Tomasz Skorski. His lab published both in vivo and in vitro models in the medical journal Blood, which showed that the addition of a PARP inhibitor to a JAK2 inhibitor increased the amount of cell death in cell lines that expressed that common marker seen in patients who have myelofibrosis.

Of the approved JAK inhibitors, why was pacritinib selected?

Pacritinib was selected over the other 3 approved JAK2 inhibitors for a few reasons. The first being that it was studied and [proven] effective in patients who had lost their response to ruxolitinib [Jakafi], which is still one of the most effective and commonly used JAK2 inhibitors. Second, it’s a drug that only targets JAK2, which makes it far less myelosuppressive and which led to its indication for patients with myelofibrosis with a platelet count under 50,000[/mcL]. Myelosuppression [we also know] is a common adverse effect with talazoparib. Third, pacritinib also targets some proinflammatory pathways, which helps with disease burden, but Dr Skorki’s lab has [published] other studies showing that PARP inhibition can also enhance these effects.

Please discuss the design of the study, eligible patient population, and its objectives.

This is a phase 1 study, which means we are trying to assess the optimal safe and effective dose of talazoparib to combine with the SOC dose of pacritinib. Thus, the first dose will be what we feel would be the least toxic but effective. Once the study shows safety with one dose level, we increase to eventually what ends up being the FDA-approved dose.

Regarding eligible patients, [we’re enrolling] essentially any patient who has lost their response to frontline JAK2-directed therapy, regardless of the drug used in the frontline, and is not eligible for a stem cell transplant.

Pending positive data, what will the next steps for this research be?

The next steps would be a phase 2 study with the maximum tolerated dose of talazoparib followed by a randomized phase 3 study comparing this combination with pacritinib alone, or even a first-line study pending how positive those data turn out to be.

What could serve as a potential hindrance to the combination’s development?

Patients who lost their initial response can often be too sick to tolerate any other possible therapies due to symptom burden, so patient accruement can be difficult in this population. Clinically, my biggest concern would be patients having worsening blood counts on this therapy, which is always a concern when dealing with hematological malignancies.

What is your take-home message to your colleagues?

Aggressively assess your patient’s symptoms with the Myeloproliferative Neoplasm Symptom Assessment Form and consider referring your patient to our study if you feel your patient has started to lose their response to frontline JAK2-directed therapy.

References

1. Nieborowska-Skorska M, Maifrede S, Dasgupta Y, et al. Ruxolitinib-induced defects in DNA repair cause sensitivity to PARP inhibitors in myeloproliferative neoplasms. Blood. 2017;130(26):2848-2859. doi:10.1182/blood-2017-05-784942
2. Pacritinib w/ talazoparib in pts w/ myeloproliferative neoplasms unresponsive to JAK2 inhibition. ClinicalTrials.gov. Updated May 3, 2024. Accessed September 5, 2024. https://clinicaltrials.gov/study/NCT06218628