Earle Burgess, MD, associate professor of medicine, Levine Cancer Institute, Atrium Health, discusses the integration of PARP inhibitors in advanced prostate cancer. 

The FDA approvals of the PARP inhibitors olaparib (Lynparza) and rucaparib (Rubraca) in patients with advanced castration-resistant prostate cancer were significant additions to the armamentarium of available options for this patient population, Burgess says. Moreover, the percentage of patients that have underlying germline or somatic aberrations, or homologous recombination repair genes are particularly affected by these efficacious agents, based on the results from the phase 2 TRITON2 study (NCT02952534), Burgess explains.

In addition to efficacy, the availability of PARP inhibitors makes them a preferred choice for patients. Olaparib and rucaparib are given as oral treatments and have demonstrated improved safety compared with taxane-based chemotherapy, Burgess concludes.

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Earle Burgess, MD, discusses the integration of PARP inhibitors in advanced prostate cancer.  

Dr. Burgess on the Integration of PARP Inhibitors in Prostate Cancer 

Earle Burgess, MD, an associate professor of medicine at Levine Cancer Institute, Atrium Health, discusses the need for improved biomarkers for PARP inhibitors in prostate cancer.

Although PARP inhibitors have revolutionized the treatment landscape for some patients with prostate cancer, improved biomarkers are needed to inform which patients are likely to respond to the therapy, Burgess says.

The presence of a single pathogenic mutation is likely not an optimal way of defining homologous recombination repair (HRR) deficiency in this patient population, says Burgess. However, HRR deficiency is needed to induce synthetic lethality from PARP inhibition, Burgess explains. 

The addition of more functional biomarkers, such as genome-wide loss of heterozygosity, to future clinical trials could inform true HRR-deficient disease, concludes Burgess. 

Earle Burgess, MD, discusses the need for improved biomarkers for PARP inhibitors in prostate cancer.  



Dr. Burgess on Improving Biomarkers for PARP Inhibitors in Prostate Cancer 

Earle Burgess, MD, an associate professor of medicine at Levine Cancer Institute, Atrium Health, discusses future directions with PARP inhibitors in prostate cancer.

Currently, the PARP inhibitors olaparib (Lynparza) and rucaparib (Rubraca) are approved by the FDA for the treatment of certain men with metastatic castration-resistant prostate cancer (mCRPC). Olaparib is approved for use in men with deleterious or suspected deleterious germline or somatic homologous recombination repair gene–mutated mCRPC who have progressed following prior treatment with enzalutamide (Xtandi) or abiraterone acetate (Zytiga). Rucaparib is approved for use in men with germline or somatic 

 mutation—associated mCRPC who have been treated with androgen receptor–directed therapy and a taxane-based chemotherapy. 

Other trials of single-agent PARP inhibitors are ongoing, says Burgess. It is anticipated that the results of these studies will reflect those observed in the PROfound and TRITON2 trials, Burgess says. 

Additionally, combination regimens with PARP inhibitors plus immunotherapy or non–immune-based therapies are ongoing, Burgess explains. These combination approaches could expand upon the efficacy demonstrated with single-agent PARP inhibitors, as well as broaden the patient populations that are eligible for PARP inhibition therapy, concludes Burgess.

Earle Burgess, MD, discusses future directions with PARP inhibitors in prostate cancer.  



Dr. Burgess on Future Directions With PARP Inhibitors in Prostate Cancer 

Earle Burgess, MD, an associate professor of medicine at Levine Cancer Institute, Atrium Health, discusses the FDA accelerated approval of rucaparib (Rubraca) in 

-positive metastatic castration-resistant prostate cancer (mCRPC).

In May 2020, the FDA granted an accelerated approval to rucaparib for the treatment of adult patients with germline or somatic 

-mutant mCRPC who have received prior androgen receptor–directed therapy and taxane-based chemotherapy. 

The regulatory decision was based on findings from the phase 2 TRITON2 study, in which rucaparib induced a 43.9% overall response rate and a 52% confirmed prostate-specific antigen response rate in patients with mCRPC who harbored 

Notably, the approval of rucaparib is more restrictive in terms of eligibility compared with the FDA approval of olaparib (Lynparza), which is indicated for patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated mCRPC who have progressed following prior treatment with enzalutamide (Xtandi) or abiraterone acetate (Zytiga), Burgess says.

The confirmatory phase 3 TRITON3 trial (NCT02975934) is ongoing to further evaluate rucaparib in patients with HRR-deficient mCRPC, concludes Burgess.

Earle Burgess, MD, discusses the FDA accelerated approval of rucaparib in BRCA-positive metastatic castration-resistant prostate cancer. 



Dr. Burgess on the FDA Accelerated Approval of Rucaparib in BRCA+ mCRPC 

Earle Burgess, MD, an associate professor of medicine at Levine Cancer Institute, Atrium Health, discusses treatment considerations for PARP inhibitor use in patients with prostate cancer.

Several factors must be considered when identifying patients who may be eligible for a PARP inhibitor. For instance, molecular findings like a germline or somatic gene aberration would qualify a patient for treatment based on current labels, Burgess says. However, it is important to understand from efficacy data that individual gene mutations may not mean equal efficacy with these agents, Burgess adds.

 aberrations are more likely to benefit from a PARP inhibitor than those with 

 mutations, according to Burgess. There is likely to be variable efficacy across the different genes, which is important to consider when trying to determine when to use these agents and in which patients in practice, Burgess concludes.

Earle Burgess, MD, discusses treatment considerations for PARP inhibitor use in patients with prostate cancer.


Dr. Burgess on Treatment Considerations for PARP Inhibitors in Prostate Cancer

Earle Burgess, MD, associate professor of medicine, Levine Cancer Institute, Atrium Health, discusses the importance of understanding the molecular subtypes of prostate cancer.

When patients are first diagnosed with prostate cancer, physicians try to learn as much molecular information about the patient’s specific tumor as they can—sometimes even germline status, Burgess says. Profiling patients based on these molecular factors better allows clinicians to match them with effective therapy. For example, patients with certain defects in DNA mismatch repair have a better likelihood of benefitting from treatment with PARP inhibitors. The rare subset of patients with tumors expressing microsatellite instability high and DNA mismatch repair deficiency can derive benefit from immunotherapy, Burgess notes.

He concludes that it is important for researchers understand the underlying molecular defects that may drive treatment early in the course of a patient’s disease; this ultimately affects the sequencing of agents that will be used in the present and future.

Dr. Burgess on Understanding Molecular Subtypes of Prostate Cancer

Earle Burgess, MD, associate professor of medicine, Levine Cancer Institute, Atrium Health, discusses pivotal clinical trials in metastatic castration-sensitive prostate cancer.

Researchers learned 4 years ago that the addition of docetaxel to androgen deprivation therapy (ADT) improved overall survival in patients with newly diagnosed metastatic disease; this was reported in the pivotal phase III CHAARTED trial.

Conducted in the United Kingdom, the multi-arm STAMPEDE trial evaluated the addition of abiraterone acetate (Zytiga) plus prednisone to ADT in patients with relapsed prostate cancer. This trial confirmed the findings of CHAARTED; the addition of chemotherapy to ADT improved patient outcomes, Burgess says.

The use of abiraterone acetate in combination with ADT has also been evaluated in patients with metastatic castration-sensitive prostate cancer. The randomized phase III LATITUDE trial showed that the addition of abiraterone acetate to ADT at the time of diagnosis improved overall survival in this patient population. This study led to the February 2018 FDA approval of abiraterone in combination with prednisone for high-risk patients.

Dr. Burgess on Key Data in Metastatic Castration-Sensitive Prostate Cancer

Earle Burgess, MD, associate professor of medicine, Levine Cancer Institute, discusses the role of immunotherapy in prostate cancer.

Immunotherapy has been shown to dramatically improve outcomes for patients with genitourinary malignancies like bladder cancer and renal cell carcinoma, but now, it seems that this approach can be beneficial for those with prostate cancer as well.

New data presented at the 2018 ASCO Annual Meeting showed that a small subset of patients with advanced prostate cancer can benefit from this treatment approach, particularly those who have microsatellite instability high tumors or tumors expressing homologous recombinant deficiency and DNA mismatch repair defects, Burgess says.

Researchers are also learning more about the role of CDK12 in prostate cancer, he adds. It seems apparent that CDK12 aberrations are associated with sensitivity to immunotherapy, but this has not yet been proven in clinical trials. These characteristics are of low incidence, but Burgess concludes there may be an expanded role for checkpoint inhibitors in the treatment of 

Dr. Burgess on Immunotherapy in Prostate Cancer

Earle Burgess, MD, associate professor of medicine, Levine Cancer Institute, discusses the synergy between abiraterone acetate (Zytiga) and androgen deprivation therapy (ADT) in prostate cancer.

Abiraterone inhibits adrenal steroid agenesis, explains Burgess. In a patient with castrate-resistant or castrate-sensitive prostate cancer, testicular androgen production is slowed or stopped. The low volume of adrenal steroid agenesis becomes biologically relevant to the growth and progression of prostate cancer, notes Burgess. Abiraterone essentially turns off adrenal steroid agenesis, which has been shown to reflect an improvement in patients with castrate-resistant prostate cancer, says Burgess.

Through the LATITUDE trial and the abiraterone arm of the STAMPEDE trial, physicians showed that earlier introduction of abiraterone reflects a greater magnitude of benefit for patients. That is likely due to the additional blockade of adrenal androgen production, says Burgess. The synergy with ADT then, likely comes from the maximal androgen blockade, he concludes.

Earle Burgess, MD

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