The role for immunotherapy in combination with multitargeted therapy in prostate cancer, for patients who had previous docetaxol, or had visceral disease (liver) showed more benefit from the combination vs. second novel hormonal therapy.
Recall that patients who had exposure to docetaxol can be treated with pluvicto.
Genomic and genetic testing is encouraged for those patients as PARP targeted mutations can be found (homologous recombination-repair mutations).
Pts who have progressed on a prior NHT and have mCRPC with extrapelvic nodal or visceral metastasis have a poor prognosis with limited, broadly available treatment options beyond chemotherapy. C promotes an immune-permissive tumor environment and may enhance response to immune checkpoint inhibitors (ICIs).
Pts randomized 1:1 to C+A (C [40 mg PO QD] + A [1200 mg IV Q3W]) or control (ctrl) (abiraterone [1000 mg PO QD] + prednisone [5 mg PO BID] or enzalutamide [160 mg PO QD]) were stratified by liver metastasis (yes/no), prior docetaxel for mCSPC (yes/no), and prior NHT for mCSPC/M0CRPC/mCRPC. Key eligibility criteria: mCRPC with disease progression on one prior NHT, measurable extrapelvic nodal or visceral disease, ECOG PS ≤1, ongoing androgen deprivation therapy. Docetaxel was allowed for mCSPC. Dual primary endpoints are radiographic PFS (rPFS) by blinded independent radiology committee (BIRC) per RECIST 1.1 in the first 400 randomized pts (PITT) and OS in all randomized pts (ITT). Secondary endpoint is ORR by RECIST 1.1 per BIRC.
At the data cutoff (Feb 28, 2023), 507 pts (ITT) were randomized to receive C+A (n=253) or ctrl (n=254). Baseline and clinical characteristics were balanced between C+A and ctrl arms: 25% and 26% had liver metastasis, 21% and 20% received docetaxel for mCSPC, and 72% and 74% received first NHT for mCRPC. Median follow-up was 12.0 mo for ITT and 14.3 mo for PITT populations. Median rPFS was significantly longer with C+A vs ctrl (6.3 vs 4.2 mo; HR 0.65, 95% CI 0.50-0.84; P=0.0007) including in subgroups with liver metastasis (6.0 vs 2.1 mo; HR 0.47 [95% CI 0.30- 0.74]) or prior docetaxel treatment for mCSPC (8.8 vs 4.1 mo; HR 0.55 [0.32-0.96]). ORR was higher in C+A vs ctrl in pts with follow-up ≥6 mo in ITT (13.6% [23/169] vs 4.2% [7/165]). Median DOR was 9.7 mo for C+A vs not reached for ctrl, and time to response was 2.3 vs 4.6 mo. DCR was 72.8% (123/169) vs 54.5% (90/165). OS data are immature. Treatment-emergent adverse events (TEAE) occurred in 97% in C+A vs 87% in ctrl (grade 3/4 events, 48% vs 23%). Grade 5 TEAEs occurred in 9% vs 12% and no grade 5 treatment-related AEs occurred in either arm. TEAEs led to the discontinuation of all treatment components in 16% in C+A and 15% in ctrl.
C+A significantly improved rPFS vs second NHT in pts who had progressed on a prior NHT and have mCRPC with extrapelvic nodal or visceral disease, a population with high unmet medical need. These rPFS benefits were particularly notable in pts with liver metastasis and those who previously received docetaxel for mCSPC. Toxicities reported with each treatment arm were manageable. CONTACT-02 is the only phase 3 study of an ICI-based regimen to show a significant and clinically meaningful improvement in rPFS in prostate cancer with visceral metastasis. Follow-up for OS is ongoing.
We know that combination PARP and antiandrogen is better than antiandrogen alone. I have wondered if we need antiancrogen on those patients. This shows that, YES, we do. The combination also was better than PARP inhibitor monotherapy in those patients carrying HRRm.
It might be costly to get the PET scans but helps with prognosis and directing patients to palliative care since positive lesions in all predicts shorter overall survival.
SBRT improves PFS in addition to antiandrogen therapy. The question is, with oligomets, do we need systemic therapy in all patients? Or will SBRT be sufficient?
I encourage our FCS radiation oncologists to provide their input on this study, as well.
Our radiation oncologists will find this article particularly interesting – more radiation is NOT better.
Pembrolizumab plus olaparib did not significantly improve radiographic progression-free survival or overall survival versus new generation hormonal agent and was more toxic.
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