Wassim Abida, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses future research directions in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

Despite strong prospective studies that resulted in the approval of PARP inhibitors for this patient population, more information is needed on biomarkers of response to these agents, Abida says. For example, the response rate observed with this approach in patients with a 

 mutation is approximately 50%, which means that half of these patients do not respond to this treatment, Abida explains. As such, biomarkers need to be refined to better select patients for this treatment, according to Abida. This can potentially be done through the use of signature analysis, which is now possible with improved sequencing technologies, Abida adds.

Another area of research is focused on determining how to best target resistance, both in patients who do not respond to these agents up front, as well as those who develop resistance after initial response, Abida says. Although some data on mechanisms of resistance exist, more information is needed, Abida concludes.

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Wassim Abida, MD, PhD, discusses future research directions in the treatment of patients with metastatic castration-resistant prostate cancer.


Dr. Abida on Future Research Directions in mCRPC

Wassim Abida, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses data from the phase 3, PROfound trial (NCT02987543) in patients with metastatic castration-resistant prostate cancer (mCRPC). 

The PROfound study compared olaparib (Lynparza) with standard of care androgen receptor–directed therapy in men with mCRPC who had progressed on hormonal therapies, such as enzalutamide (Xtandi) or abiraterone acetate (Zytiga). Moreover, the patient population enrolled on the trial was varied because the inclusion criteria for PROfound did not require a prior line of taxane, Abida explains. 

The primary end point of the study was progression-free survival. Additionally, enrollment was not limited to patients with 

 mutations, Abida says. Instead, eligible patients had to harbor a 

 mutation to be included in cohort A or an alternation in any of 12 other prespecified genes to be included in cohort B, Abida concludes.

Wassim Abida, MD, PhD, discusses data from the phase 3 , PROfound trial in patients with metastatic castration-resistant prostate cancer. 


Dr. Abida on Data from the PROfound Study in mCRPC

Wassim Abida, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses the limitations of PARP inhibitors in prostate cancer.

Rucaparib (Rubraca) was granted accelerated approval by the FDA for use in men with deleterious, germline or somatic 

 mutation–associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with an androgen receptor–directed therapy and a taxane-based chemotherapy. However, findings from the pivotal, phase 2 TRITON2 trial (NCT02952534) demonstrated that patients with 

 mutations derived higher prostate-specific antigen responses with rucaparib compared with patients with 

Olaparib (Lynparza) is FDA 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). The pivotal, phase 3 PROfound trial (NCT02987543) enrolled patients with mCRPC who harbored 

 mutations in 1 cohort and patients who harbored mutations in 12 other prespecified genes in another cohort. The results revealed that not all mutated genes yielded similar sensitivity to olaparib; however, the FDA approval does not specify which patients are more likely to respond to the PARP inhibitor, Abida explains. 

As such, when selecting treatment with a PARP inhibitor for a patient with mCRPC, it is critical to understand their likelihood of response based on specific genetic markers, Abida says. Additional research is needed to understand how to better target tumors that harbor mutations associated with lower response rates, concludes Abida. 

Wassim Abida, MD, PhD, discusses the limitations of PARP inhibitors in prostate cancer.  



Dr. Abida on the Limitations of PARP Inhibitors in Prostate Cancer 

Wassim Abida, MD, PhD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses the clinical significance of the results from the phase 2 TRITON2 trial (NCT02952534) in metastatic castration-resistant prostate cancer (mCRPC).

The TRITON2 trial enrolled men with mCRPC who progressed after 1 or 2 prior lines of next-generation androgen receptor (AR)–directed therapy and 1 taxane-based chemotherapy, Abida says. Patients harbored a deleterious 

The primary end point of the trial was overall response rate (ORR) with key secondary end points including duration of response for radiographic response, rate of confirmed locally assessed prostate-specific antigen (PSA) response, time to PSA progression, radiographic progression-free survival, overall survival, and safety, Abida explains.

Findings from the trial demonstrated that treatment with the PARP inhibitor rucaparib (Rubraca) led to an ORR of 43.5% per independent radiology review and 50.8% per investigator assessment, Abida says.

Notably, these findings led the FDA to grant an accelerated approval to rucaparib on May 15, 2020, as the first PARP inhibitor available for use in men with mCRPC who harbor a deleterious, germline or somatic 

 mutation after treatment with AR-directed therapy and a taxane-based chemotherapy, Abida concludes. 

Wassim Abida, MD, PhD, discusses the clinical significance of the results from the phase 2 TRITON2 trial in metastatic castration-resistant prostate cancer. 



Dr. Abida on the Clinical Significance of the TRITON2 Study in mCRPC 

Wassim Abida, MD, PhD, medical oncologist, Developmental Therapeutics Center, Memorial Sloan Kettering Cancer Center, discusses the frequency of mutations for patients with prostate cancer.

Many patients with metastatic prostate cancer have an inherited mutation that can be identified through genetic testing, explains Abida.

Some of these mutations can predict a response to specific drugs making this an important area of study, states Abida.

Dr. Abida on the Frequency of Mutations in Prostate Cancer

Wassim Abida, MD, PhD, medical oncologist, Developmental Therapeutics Center, Memorial Sloan Kettering Cancer Center, discusses genetic testing for patients with prostate cancer.

The process of genetic testing for patients is not complicated, but the difficulty is figuring out who should be tested and what specific genes should be investigated, explains Abida.

Genetic testing is very important because it can affect decisions regarding treatment and screening for patients with prostate cancer and their families, states Abida.

Dr. Abida on Genetic Testing for Prostate Cancer

Wassim Abida, MD, PhD, Memorial Sloan Kettering Cancer Center, discusses the future of hormonal therapy in prostate cancer.

Targeting androgen receptors (AR) is a topic being explored, specifically the parts of AR that are not already being targeted. There are other targets worth attention beyond the C-terminal ligand binding domain, says Abida.

These targets include AR-V7, but new drugs need to be developed that target the protein within it. According to Abida, that is worth exploring even though it is not known whether it will yield a response.

Combination therapy is also an approach that is being looked at as the future of hormonal therapy in prostate cancer.

Dr. Abida on Future of Hormonal Therapy in Prostate Cancer

Wassim Abida, MD, PhD, assistant member and assistant attending physician in the Genitourinary Oncology Program at Memorial Sloan Kettering Cancer Center, discusses treatment options for patients with prostate cancer.  

Early chemotherapy is effective and beneficial for patients with a lot of metastatic burden. However, it less clear that it is the best option for patients with low-volume disease. Many experts believe it is, but there are still unanswered questions, says Abida.

Another question that remains is whether therapies can be selected based on tumor characteristics. That is an area of a lot of ongoing research.

A lot has been discovered about the biology of tumors recently, says Abida. There is a lot of work looking at sequencing DNA from tumors in patients with prostate cancer and researchers will have to determine how to apply these findings in the clinic.  Research is confirming the findings from the biologic studies in the lab and taking that to the clinic and learning which patients may benefit from certain therapies.

Wassim Abida, MD, PhD

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