Docetaxel in combination with nivolumab in metastatic castration-resistant prostate cancer: Final analysis of cohort B of the phase II CheckMate 9KD trial
The combination of docetaxel with nivolumab is associated with an overall response rate of approximately 40% in chemotherapy-naïve mCRPC patients, irrespective of the prior use of antiandrogen therapy. Responses occurred fast and proved to be durable. As such, these findings support the further investigation of this combination in the ongoing phase III CheckMate 7DX trial.
Docetaxel (DOCE) is a well-established standard-of-care chemotherapy regimen for patients with metastatic castration-resistant prostate cancer (mCRPC). Studies have indicated the potential of docetaxel to potentiate anti-tumour immune responses which supports use in combination with immunotherapy. Conversely, the anti-PD-1 inhibitor nivolumab (NIVO) has shown minimal clinical activity as a monotherapy in unselected, advanced prostate cancer patients. The CheckMate 9KD phase II trial is a multi-arm study, investigating NIVO in combination with rucaparib, DOCE or enzalutamide in patients with mCRPC. At a previous interim analysis encouraging results were presented for the NIVO + DOCE combination.
Arm B of the CheckMate 9KD trial randomised 84 chemotherapy-naïve mCRPC patients to receive NIVO (360 mg every 3 weeks) plus DOCE (75 mg/m2 every 3 weeks) and prednisone (5mg twice daily), followed by NIVO (480 mg every 4 weeks) until disease progression, unacceptable toxicity, or up to 2 years. Eligible patients were allowed to have received maximum of 2 direct antiandrogen therapies (AAT). Patients were stratified by prior AAT use. The co-primary endpoints of this study were objective response rate (ORR) and PSA response rate (≥50% decline from baseline), with secondary objectives including radiographic progression-free survival (rPFS), overall survival (OS), time to (TTR) and duration of response (DoR), time to PSA progression and safety.
40% objective responses, irrespective of prior AAT use
The median age of this study arm was 71 years old and 27.4% of patients had visceral metastases at the start of the study. About half of the patients underwent prior cancer surgery, two thirds received prior radiotherapy and 64.3% of patients had prior AAT exposure. At the time of data cut-off, 90.5% of patients had discontinued treatment, with disease progression (59.5%) and drug toxicity (17.9%) as the most common causes. A further 9.5% remained on treatment at time of analysis. At a median follow-up of 15.2 months, patients without prior AAT exposure had an ORR of 42.9%, all partial responders. In patients who did receive a prior AATs the ORR was reported at 38.7% with 1 patient in this subgroup (3.2%) obtaining a complete response. Interestingly, the confirmed the PSA response rate was markedly higher in patients
60.7% who did not receive prior AAT therapy compared to patients who did (60.7% vs. 39.6%. Overall, the median TTR was 2.0 months, with a median DoR of 7.0 months. Overall, 79.5% of patients experienced some level of tumour reduction, with a median change from baseline of 32.1% (regardless of prior AAT exposure). Similarly, 84.0% of patients experienced a reduction in PSA from baseline, with a median change of 54.6%. Patients without prior AAT exposure had a numerically longer rPFS and OS, compared to those who had previously received NATs (median rPFS: 12 months vs. 8.5 months. Median OS: NR vs. 16.2 months).
Any-grade treatment-related adverse events (TRAEs) leading to treatment discontinuation occurred in 29.8% of patients. Any-grade TRAEs of special interest were gastrointestinal (35.7%), skin-related (26.2%), pulmonary (13.1%), endocrine (8.3%), hepatic (6.0%) and renal (2.4%). Grade ≥3 TRAEs occurred in 47.6% of patients. Overall there were 3 treatment-related deaths; 1 case of pneumonitis related to NIVO and 2 cases of pneumonia related to DOCE.
At this final analysis, NIVO plus DOCE continued to show encouraging clinical and anti-tumour activity, regardless of prior AAT exposure. With no new safety signals reported, these results support the further investigation of this combination in patients with mCRPC.
Fizazi K et al., CheckMate 9KD Arm B final analysis: Efficacy and safety of nivolumab plus docetaxel for chemotherapy-naïve metastatic castration-resistant prostate cancer. Presented at ASCO GU 2021; Abstract 12.