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Applying New Evidence to Optimize Care in Advanced Prostate Cancer

Matthew R. Smith, MD, PhD
Released: October 8, 2020

Precision Medicine in Prostate Cancer

Patient With BRCA2 Mutation

The patient described in the polling question has mCRPC and disease progression on abiraterone acetate plus prednisone. He was also found to have a BRCA2 mutation. In our practice, for patients with characteristics similar to those in our case with the BRCA mutation, my treatment recommendation is olaparib, based on the evidence from the PROfound study. You could give docetaxel next, then go to a PARP inhibitor, but given that you have identified a patient with an actionable mutation, I would start with a PARP inhibitor. The recommendations from the tool are: 4 experts recommend olaparib, and 1 suggests either olaparib or rucaparib.

Let’s review the latest evidence on precision medicine in prostate cancer.

DNA Repair Gene Alterations Are Common in Metastatic Prostate Cancer

One of the surprising observations of translational work in recent years is that alterations in homologous recombination repair (HRR) genes are common in patients with metastatic prostate cancer. In an analysis of tumor specimens, 23% of patients with mCRPC have DNA repair alterations, and the frequency of DNA repair alterations increases with disease progression.[30] We also know that many of these DNA repair gene alterations are germline mutations. In a study of almost 700 men with metastatic prostate cancer, 11.8% had germline DNA repair gene defects.[31] There is now strong evidence that PARP inhibitors are effective in patients with mCRPC and alterations in 1 of the HRR genes.

Phase III PROfound: Olaparib vs Physician’s Choice in Progressing mCRPC

The phase III PROfound study evaluated olaparib in patients with mCRPC and disease progression on enzalutamide or abiraterone who had an alteration in an HRR gene. Cohort A included patients with BRCA1, BRCA2, or ATM alterations, and cohort B included patients with other HRR gene alterations. Patients were randomized to either olaparib or physician’s choice of switch to the other hormonal agent. The primary endpoint was rPFS in cohort A. Secondary endpoints included rPFS in both cohorts and OS in cohort A.[32]

PROfound: rPFS

Compared with the control group, olaparib was associated with significant improvement in rPFS in cohort A, with an HR of 0.34 and a P value of < .001.[32] Median rPFS was 7.4 months in the olaparib group vs 3.6 months in the control group.

The secondary endpoint of rPFS in the overall study population was also met, with an HR of 0.49 and a P value of < .001. Median rPFS in the olaparib group was 5.8 months compared with 3.5 months in the control group.

PROfound: OS in Cohort A

Olaparib was also associated with an improvement in OS in cohort A, with a 32% reduction in the risk of death (HR: 0.69; P = .02). Median OS was 19.1 months in the olaparib group and 14.7 months in the control group, respectively.[33]

Results from PROfound led to the regulatory approval of olaparib for adult patients with deleterious or suspected deleterious germline or somatic HRR gene–mutated mCRPC who have progressed following previous treatment with enzalutamide or abiraterone. Select patients for therapy based on an FDA-approved companion diagnostic for olaparib.

TRITON2: Rucaparib in Metastatic CRPC With HRR Gene Alterations

Rucaparib was also recently approved by the FDA based on results from the TRITON2 study, which is an international, multicenter, open-label phase II trial. The study included patients with mCRPC and somatic or germline alterations in HRR genes who progressed on an AR-targeted therapy as well as 1 previous line of taxane-based chemotherapy. Patients were treated with rucaparib daily until radiographic progression. The primary endpoints were ORR in patients with measurable disease and PSA response in those without measurable disease.[34]

TRITON2: Efficacy in BRCA1/BRCA2 Cohort

In the BRCA1/BRCA2 cohort of TRITON2, the majority of patients had a decrease in sites of measurable disease, including a substantial proportion of patients with deep responses.[34] Rucaparib was associated with an ORR of 50.8% (6.2% CR) by investigator evaluation and 43.5% (11.3% CR) by central review. The confirmed PSA response for the overall efficacy population was 54.8%.[34]

The label indication for rucaparib is for the treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated mCRPC who have been treated with AR-directed therapy and a taxane-based chemotherapy.

Genetic Testing in Prostate Cancer

The biggest takeaway from PROfound and TRITON2 is the need to do genetic testing for HRR gene alterations. In our practice, we offer germline testing to all patients with metastatic prostate cancer and in select other high-risk patients based on the guidelines, including those with young age at diagnosis and/or strong family history of cancer. [35] The current evidence suggests that, while somatic mutations accumulate over time, most of them are early events. Genetic testing can be done upfront if tissue is available, or liquid biopsy can be used for broad-based tumor genetic testing with next-generation sequencing.

Checkpoint Inhibitor Therapy in Prostate Cancer

The approvals of olaparib and rucaparib are a landmark in that they brought precision oncology to prostate cancer. But it is worth noting that there was an earlier precedent, with pembrolizumab. Pembrolizumab has tumor agnostic approval for any solid tumor with high microsatellite instability.[36] In mCRPC, high microsatellite instability is found in only 1% to 3% of patients. But with genetic testing there are now at least 2 potential actionable outcomes, and I speculate that in the future there will be additional targets.


To summarize, intensification of systemic treatment with the addition of docetaxel or an AR-targeted agent to ADT is the new standard of care for mHSPC. In nmCRPC, next-generation AR signaling inhibitors (apalutamide, enzalutamide, darolutamide) improve MFS and OS. In mCRPC, cabazitaxel improves both PFS and OS in patients with disease progression after enzalutamide or abiraterone and docetaxel. Germline and tumor genetic testing of HRR gene aberrations inform the selection of patients with mCRPC for treatment with a PARP inhibitor. For patients with high microsatellite instability/mismatch repair deficiency, pembrolizumab can be used to improve outcomes. Finally, there is room for individualizing therapy selection based on specific patient characteristics by consistently considering both the benefits and potential harms of each treatment.

Provided by the USF Health in partnership with Clinical Care Options.

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