COMET-2 falls short in showing palliative effect of cabozantinib in mCRPC

Cabozantinib was no better than the combination of mitoxantrone and prednisone for pain relief in heavily pretreated men with metastatic castration-resistant prostate cancer (mCRPC) and symptomatic bone metastases, according to the findings of the COMET-2* trial.

Bone metastases in patients with mCRPC is often associated with debilitating pain and functional compromise. [J Clin Oncol 2008;26:2544-2549] Even with narcotic analgesics, pain related to osseous disease is often poorly controlled. [J Oncol Pract 2013;9:223-229] “[Durable] pain control [and pain relief] in men with symptomatic osseous metastases … remain critical unmet needs … in mCRPC,” said the researchers.

To establish the palliative effect of cabozantinib in mCRPC, researchers evaluated 119 men with mCRPC and narcotic-dependent pain from bone metastases who had progressed after two or more lines of life-prolonging therapy (docetaxel and either abiraterone or enzalutamide). Participants were randomized 1:1 to receive either once-daily oral cabozantinib 60 mg or mitoxantrone 12 mg/m² every 3 weeks (≤10 infusions) plus twice-daily oral prednisone 5 mg. The primary endpoint was pain response at week 6 confirmed at week 12**. Enrolment was terminated early due to the lack of survival benefit with cabozantinib in COMET-1***. [Eur Urol 2019;75:929-937]

The findings showed no significant difference in the rates of confirmed pain response between the cabozantinib and mitoxantrone-prednisone arms (15 percent vs 17 percent; p=0.8).

Compared with the mitoxantrone-prednisone arm, the cabozantinib arm had a higher incidence of grade 3/4 hypertension (22 percent vs 0 percent), fatigue (18 percent vs 8.8 percent), increased aspartate aminotransferase (10 percent vs 1.8 percent), diarrhoea (8.3 percent vs 1.8 percent), and decreased weight (5.0 percent vs 0 percent). Serious AEs were also more frequent among cabozantinib than mitoxantrone-prednisone recipients (72 percent vs 61 percent).

“Although this trial did not meet the primary endpoint, it provides valuable insights about the design and conduct of oncology trials assessing symptom control with patient-reported outcomes,” said the researchers.

The researchers underscored that the heavy pretreatment required and the presence of advanced disease, as well as the required washout and narcotic optimization periods, might have limited the findings. “[These factors] limited the pool of patients, particularly those with rapidly progressing disease who required immediate treatment.”

Therefore, patients with any level of pain should be eligible to participate in future trials with a composite endpoint assessing pain progression, palliation, and elimination, said the researchers. Moreover, washout and narcotic optimization periods should be shortened, they added.

“Future pain palliation trials should incorporate briefer timelines from enrolment to treatment initiation … Multiple lines of prior therapy should also not be required because later-stage disease is more heterogeneous and less likely to respond to treatment. Pain and narcotic use should be assessed independently as well as together in an exploratory composite endpoint,” said the researchers.