PARP Inhibitors Underscore the Need for Routine Germline Testing in Prostate Cancer

The regulatory approvals of olaparib (Lynparza) and rucaparib (Rubraca) have underscored the importance of translational research in prostate cancer, as well as the need for germline testing to be incorporated into routine care, according to Ajjai Shivaram Alva, MBBS.

In May 2020, the FDA approved the PARP inhibitor olaparib for use in adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene–mutated metastatic castration-resistant prostate cancer (CRPC) who had progressed after enzalutamide (Xtandi) or abiraterone acetate (Zytiga). The decision was based on data from the phase 3 PROfound trial, which showed that the agent resulted in a 66% reduction in the risk of disease progression or death versus abiraterone acetate or enzalutamide (HR, 0.34; 95% CI, 0.25-0.47; P <.0001) in those with BRCA1/2- or ATM-mutated disease.¹

In the same month, rucaparib was granted an accelerated approval from the FDA for use in adult patients with BRCA mutation–associated metastatic CRPC who had previously received androgen receptor–directed therapy and a taxane-based chemotherapy. The approval was based on data from the phase 2 TRITON2 study, which showed that the PARP inhibitor elicited a 44% confirmed objective response rate in this population.²

“Both of these studies have raised the bar much higher and have opened up this pathway for patient benefit. The fact that 25% of patients who harbor these defects can benefit from PARP inhibitors is a strong argument to make germline testing routine, mandatory, and covered by insurance,” said Alva. “Unfortunately, this is not always the; [coverage is] inconsistent depending on the insurance plans. Guidelines must be synchronized with this need. Many oncologists are making that push.”

In an interview with OncLive^® during the 2020 Institutional Perspectives in Cancer webinar on Precision Medicine, Alva, an associate professor at the University of Michigan, discussed the role of PARP inhibitors in prostate cancer, the importance of germline testing, and the need for personalized medicine.

OncLive: Could you speak to the key recent advances observed with PARP inhibitors in prostate cancer?

Alva: In recent years, pivotal clinical data have led to the FDA approval of 2 PARP inhibitors in metastatic castration-resistant prostate cancer (CRPC): rucaparib and olaparib.

Olaparib was first approved for advanced CRPC with next-generation sequencing (NGS) results showing any defect in DNA repair pathways; this was not specified further, so it’s a broad approval. The FoundationOne CDx test was also approved [to identify patients with HRR-mutated metastatic CRPC for potential treatment with olaparib].

Rucaparib has been more recently approved for patients with prostate cancer that harbor defects in BRCA1/2. These patients were proven to benefit from rucaparib in the TRITON2 study, for which data were recently reported and published in the Journal of Clinical Oncology.

To put this into context, about 25% of patients with prostate cancer have 1 of these defects; half of those are inherited germline [mutations], while the other half are somatic. These drugs are now approved, as in other cancer types.

How is germline testing working to guide these treatments?

Germline testing is important for patients with advanced prostate cancer. I'm grateful that I practice in an academic tertiary care center where I have excellent support from germline genetic counselors who I can refer patients to. They do the genetic counseling, as well as the testing, but the counseling is a very important aspect. It's not just about doing the genetic testing; it's also about explaining what it means to both the patients and their family members. Patients are often concerned about what [a diagnosis means] for their children and their siblings; that’s an important aspect. Due to the coronavirus disease 2019 (COVID-19) pandemic and the rise of telehealth, in some ways, this has become easier. We don’t need patients to make the physical trip for this anymore.

I believe genetic counseling is one area where video visits and telecounseling can really take off. As you can imagine, there is not as much importance in physical exams and direct patient interaction [with regard to this]. In some facilities, telehealth was being used even before the COVID-19 pandemic for genetic counseling. Perhaps this is a great opportunity to broaden [the accessibility of] genetic counseling for patients with prostate cancer, along with other cancer types.

Could you expand on some of the companion diagnostics that are being used for these agents?

The FoundationOne CDx test, developed by Roche, has been used in practice as one of the many NGS assays. At the University of Michigan, my colleagues and I have pioneered this effort in prostate cancer, leading to several other discoveries, including BRCA defects. Therefore, we have always integrated this into our treatment and workup paradigm. [Testing is] now becoming more of a norm, even outside of Michigan.

Not only does it detect these defects, but also non-DNA repair defects will be identified as actionable mutations. We are always looking for additional options beyond the FDA-approved therapies. This is especially important earlier on in prostate cancer because, after chemotherapy and other therapies, the biology of the cancer changes and performance status may decline.

At our center, we tried NGS to gain insight on the biology of the patient's tumor, to tailor our therapy. We use [this testing] very early on [in the treatment journey] and after most progressions. We try to get another fresh look into the biology of the tumor, through the tissue sequencing, FoundationOne CDx, or through circulating tumor DNA (ctDNA).

FoundationOne recently received an FDA approval for a ctDNA assay, as well. Both of these [assays] are great options for patients. It should be intrinsic to the practice of every prostate cancer oncologist to check for these [mutations] along the pathway of the course of the disease. Ideally, [these tests should be performed] when castration-resistant disease [is first developed], when the patients are their best health and they have not been excessively treated.

Could you provide some background on the TRITON2 trial? What did we learn from this research?

The TRITON2 study evaluated rucaparib in a similar population, although the eligible mutations were restricted to BRCA. This differs from the PROfound trial, which had proved olaparib was better than standard of care; this trial included patients with multiple DNA repair mutations.

Results from TRITON2 showed that several patients with BRCA2 mutations benefited from rucaparib. The safety pattern observed with rucaparib was similar to that of olaparib. Thus far, I have not seen data to suggest a huge difference between the 2 agents. Of course, the data sets differ between the trials, 1 had a longer follow-up than the other, and they were different phases.

One of the restrictions with rucaparib is the eligible aberrations in the gene, so BRCA1/2. Most [patients with] prostate cancer have BRCA2 mutations, while BRCA1 is involved in a smaller number of patients. It's difficult to say whether the gene has a profound impact on responses, although there are some cues that it may. For example, in TRITON2, CDK12 was previously considered a DNA repair defect; however, it probably is not because no responses were observed in these patients in TRITON2. CDK12 is not an intrinsic path or a major part of the DNA repair defect; it may play a bigger role in the immune response to cancer.

We still have a lot of work to do to understand the differences between the DNA repair defect genes. In the coming years, with more studies and retrospective data, we may be able fill in the knowledge gaps. Each patient is contributing to the understanding generated.

Could you speak to how this work underscores the importance of translational research?

PROfound and TRITON2 are the culmination of cutting-edge translational work, as well as basic science work that has been done in the preceding years. It is gratifying to see those efforts result in patient benefit in a rather quick timeframe. Previously, it took decades to translate clinical findings into real-world benefit for patients.

I want to point out the critical importance of translational research funding and research work that is being done at academic universities. Unless we invest in those types of fundamental discoveries and the translational impacts of them, we will not realize the full potential of all these actionable mutations. Because of this research, we saw the FDA approval of 2 drugs in the same pathway; that’s amazing.

Where should future efforts focus?

One of my major areas of interest has been to personalize medicine in oncology, especially for patients with prostate cancer. Notably, the NCI-MATCH trial has the same goal of directing therapy to each patient's specific tumor profile. Although it has not yet been fully recognized in every tumor type, in prostate cancer, several trials are targeting specific genes. For example, some are looking at targeting CDK12 with immunotherapy, whereas a better approach for targeting a BRCA2 mutation may be with a PARP inhibitor. Compartmentalizing these approaches into the different lanes, with different therapies matched to different patients, can potentially result in better outcomes.

What is your take-home message to your colleagues?

We need to analyze the genomic profile of each patient's prostate cancer as part of routine care, not just as a fancy test. I believe this must become part of the armamentarium and has to be known for every patient.

My dream has always been to have a precision medicine oncology clinic where, not only would I have the patient's temperature and blood pressure before entering the room, but I would also have their genomic profile ready and analyzed. As such, I could tailor my discussion with the patient according to their tumor’s biology. We are getting closer to reaching this goal. In other words, I'm getting closer to waking up from that dream, to real-world results. However, more work is needed.

This will require collaborative efforts by multiple academic institutions, government support, as well as participation of pharmaceutical companies. This will truly require team effort, all around the globe. We all need to pitch in and pool our resources to achieve this. The National Institutes of Health and The National Cancer Institute are currently leading some of these efforts and we are participating in them, so I’m very optimistic.

References

1. Lynparza. Prescribing Information. FDA; 2020. Accessed September 29, 2020. https://bit.ly/2WLJt7u.
2. Rubraca (rucaparib) approved in the US as monotherapy treatment for patients with BRCA1/2-mutant, metastatic castration-resistant prostate cancer (MCRPC) who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy. News release. Clovis Oncology. May 15, 2020. Accessed September 29, 2020. https://bit.ly/2z0rMrK.