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.
Deleterious germline or somatic HRRm are present in about 20% of mCRPC patients (pts). Preclinically, PARP-inhibition demonstrated synergism with AR-targeted therapy. BRCAAway is a biomarker pre-selected, multicenter, randomized, phase-2 trial which evaluated efficacy of AR-inhibitor (i) vs PARPi vs combination in first-line mCRPC pts with germline and/or somatic mutations in BRCA1/2 or ATM.
Eligibility required front-line mCRPC with no prior exposure to PARPi, ARi, or chemotherapy for mCRPC, and washout of antiandrogen, radiation, and other investigational agents. Eligible pts underwent tumor next-generation sequencing (NGS)/germline testing; pts with inactivating BRCA1/2 and/or ATM alterations were randomized 1:1:1 to Arm I abiraterone (1000 mg qd) + prednisone (5mg bid), Arm II olaparib (300 mg bid), or Arm III olaparib + abiraterone/prednisone. Primary endpoint was progression free survival (PFS) as per RECIST 1.1, PCWG3, clinical assessment, or death. Secondary endpoints included measurable disease response rate (RR), PSA RR, and toxicity. Arm I and II pts could cross over at progression.
165 eligible pts were registered and underwent NGS/germline testing; 61 pts with HRRm were randomized to Arms I-III. Median age: 67 years (range 42-85); 55 White, 6 Black; prior Docetaxel 26% for mHSPC, Darolutamide/Enzalutamide 3.3% for nmCRPC; disease sites: bone n=44, viscera n=12, lymph node n=31, other n=3; median baseline PSA: 14 ng/ml (range 0.15-4,037 ng/ml). HRRm status: BRCA1 n=3, BRCA2 n=46, ATM n=11, multiple n=1 (33 germline, 28 somatic). Median (range) time from randomization to last encounter in pts still alive n=56: 16 (0.8-60), 15 (4.1-36), and 23 (2.9-56) months (m) in Arms I, II and III, respectively. 51 pts had treatment-related AEs; most common Grade 3: fatigue n=3, anemia n=2, and ALT increases n=2. OS is not mature enough with 3 deaths in Arm I and 2 in Arm II. Efficacy results for Arms I-III are presented in the table. At progression 8/19 pts crossed over from abiraterone to olaparib and 8/21 pts vice versa. Median (95% CI) PFS from crossover to: olaparib 8.3 m (5.5, 15), abiraterone 7.2 m (2.8, NR). Median (95% CI) PFS from randomization: olaparib 16 m (7.8-25) and abiraterone 16 m (11-28). RR to crossover treatment: olaparib 38% and abiraterone 25%. PSA RR to crossover treatment: olaparib 50% and abiraterone 63%.
In mCRPC pts with BRCA1/2 or ATM alterations, abiraterone/prednisone + olaparib was well tolerated and resulted in a longer PFS vs either agent alone or sequentially.
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.
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).
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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