Ushering in a New Era of Personalized Treatment for Advanced Prostate Cancer

Over the last several decades, we’ve experienced a massive shift in how we approach, diagnose and treat prostate cancer. Prostate cancer remains the second leading cause of cancer-related deaths in men, behind lung cancer.¹ But progress is being made as the relative five-year survival rate for patients with distant metastatic prostate cancer is nearly 37%,² up from 28.7% in the early 2000s.³ 

The emergence of comprehensive genomic profiling (CGP) in the last 15 years has shown us that prostate cancer is an extremely diverse and complex disease.⁴ Given the complexities of the disease, it’s clear a “one-size-fits-all” approach is not beneficial. But thanks to continued progress in research, advancements in biomarker testing, and new targeted treatment options, a shift toward more personalized care is underway for how we treat and assess response in advanced prostate cancer.

Biomarker discoveries drive new targeted treatment options for advanced prostate cancer

The introduction of hormone therapy in the 1980s ushered in the first revolution in treatment for prostate cancer and quickly became the standard of care.⁵ However, most prostate cancers develop resistance to these treatments over time, necessitating new, innovative and targeted treatment options.

In the early 2000s, studies indicated that alterations in BRCA1 and BRCA2 and other homologous recombination repair (HRR) genes rendered tumors sensitive to poly-ADP ribose polymerase (PARP) inhibitors, which work by preventing cancer cells from repairing and growing.⁶ Nearly a quarter of prostate cancer patients have either germline or somatic HRR alterations,⁷ with BRCA1/2 alterations the most common, occurring in nearly 11% of metastatic prostate cancer cases.⁸ The presence of these mutations is also associated with more advanced disease at diagnosis and poorer clinical outcomes.⁹

It wasn’t until 2020 that the U.S. Food and Drug Administration (FDA) approved the first PARP inhibitors for the treatment of metastatic castration-resistant prostate cancer (mCRPC),¹⁰ ushering in a new era of targeted treatment. Since then, the FDA has approved multiple PARP inhibitors for patients with mCRPC.¹¹

Outside of PARP inhibitors, patients with prostate cancer may be eligible for PD-1 checkpoint inhibitors after progression on standard-of-care options if their cancer has genomic features such as high microsatellite instability, a defect in a mismatch repair gene, or a high tumor mutational burden.¹²

As our understanding of actionable biomarkers evolves, access to high-quality comprehensive genomic profiling (CGP), or biomarker tests, like FoundationOne®CDx and FoundationOne®Liquid CDx,¹³ is key to informing treatment options. FoundationOne CDx and FoundationOne Liquid CDx CGP tests each detect all 27 guideline-recommended biomarkers for advanced prostate cancer^14,15,16,17 and FoundationOne Liquid CDx is the only FDA-approved CGP liquid biopsy to detect all 19 HRR genes for approved therapies.¹⁸ Additionally, Foundation Medicine now has seven FDA-approved companion diagnostic indications for prostate cancer, the most of any company.¹⁹

Hear from John, who has been living with metastatic prostate cancer since 2014, on the important role biomarker testing played in his cancer care:

Emerging biomarkers to aid treatment decisions in advanced prostate cancer

With high-quality biomarker testing and more genomic data available, we’re also able to identify new biomarkers in prostate cancer that can help providers make informed treatment decisions.

To aid with decision-making around PARP inhibitors, we recently introduced our proprietary homologous recombination deficiency signature (HRDsig) biomarker²⁰ reported on FoundationOne CDx. Our HRDsig biomarker is a scar-based genomic signature that gives a functional readout of HRD using genome-wide copy number (CN) features. In prostate cancer, HRDsig positivity was associated with improved time to treatment discontinuation and real-world overall survival on PARP inhibitors compared to patients without HRDsig detected.²¹

Biallelic loss of BRCA1/2 is also an important new biomarker for PARP inhibitor use in prostate cancer. New research indicates the prevalence of BRCA1/2 loss at approximately 3% in both primary prostate tumors and metastatic prostate tumors.²¹ Unlike other types of BRCA alterations, biallelic BRCA1/2 loss is irreversible and, therefore, not susceptible to secondary reversion mutations caused by PARP inhibitor use that can cause treatment resistance.^22,23 As a result, those patients with biallelic loss of BRCA1/2 are more likely to have favorable outcomes and durable benefits from PARP inhibitors in clinical practice.²¹ Detecting biallelic copy loss for BRCA1/2 can be technically challenging,²⁴ particularly via liquid biopsy since it requires a higher level of circulating tumor DNA (ctDNA).²¹ However, our portfolio of tissue- and liquid-based tests can help detect BRCA1/2 losses, and we observe them in primary tumors and metastatic samples.²¹

Additionally, new research is emerging that indicates SPOP mutations may be a potential new biomarker for patients with de novo metastatic castration-sensitive prostate cancer. SPOP mutations occur in approximately 8-10% of prostate cancer,²⁵ and research demonstrates that patients with these mutations experience considerably more favorable outcomes on second-generation hormonal therapies compared to those without, but this effect was not seen with standard taxane chemotherapy. These observations, combined with a biological understanding of SPOP, suggest that SPOP is a predictive biomarker of extreme benefit from second-generation hormonal therapies in the hormone-sensitive setting. If physicians and patients prefer to try a chemotherapy-sparing option for initial treatment of de novo metastatic prostate cancer, SPOP serves as an emerging biomarker that can help aid in this clinical decision. With FoundationOne Liquid CDx, the only FDA-approved liquid biopsy that identifies SPOP mutations,²⁶ healthcare providers have information to make informed decisions to support an upfront non-chemotherapy option, helping to preserve quality of life.

The value of liquid biopsy to inform treatment decisions and monitor prostate cancer progression

While tissue testing remains the gold standard for identifying genomic alterations, not all patients with mCRPC have sufficient tumor tissue available for testing, especially at the point of disease progression.²⁷ That’s where a high-quality liquid biopsy like FoundationOne Liquid CDx can be particularly valuable.

One of the traditional challenges with liquid biopsy is the interpretation of a negative result. Is the negative result a lack of detectable tumor DNA in the blood sample or the lack of alterations in a sample with sufficient ctDNA? In the case of a negative liquid biopsy result, ctDNA tumor fraction can serve as a useful tool. Foundation Medicine’s ctDNA tumor fraction²⁸ is a determination of the amount of tumor DNA in the blood, and FoundationOne Liquid CDx reports ctDNA tumor fraction – for greater confidence in negative results.^28,29 When tumor fraction is low (<1%) and no drivers are detected by FoundationOne Liquid CDx, tumor tissue testing is more likely to detect alterations that can drive treatment decisions.

Outside of helping you interpret liquid biopsy results, ctDNA tumor fraction is emerging as a potentially powerful new biomarker in prostate cancer. Recent research found that ctDNA tumor fraction in prostate cancer provided complementary prognostic value to PSA testing and provided additional risk stratification for patients with clinically ambiguous results.³⁰

Finally, longitudinal ctDNA tumor fraction monitoring can provide value in tracking tumor response to treatment in metastatic prostate cancer. Traditionally, PSA and radiographic imaging have been used to monitor disease response to treatment. With FoundationOne®Monitor,³¹ a tissue-naïve ctDNA monitoring assay currently available for research use, we can evaluate quantitative changes in ctDNA levels over time to understand how tumors are responding to treatment. Changes in ctDNA tumor fraction may complement imaging and PSA-based approaches to treatment response assessment, especially in ambiguous situations where changes in PSA no longer correlate with tumor burden or in cases of bone-only disease where bone scans may exhibit flair reactions that are difficult to interpret.  In addition to quantitative changes in ctDNA tumor fraction, FoundationOne®Monitor reports genomic alterations that can occur with acquired resistance to targeted therapies or disease progression, informing early resistance to treatment and future therapy options.  Longitudinal ctDNA monitoring holds great promise for impacting treatment decisions for patients with metastatic prostate cancer.

Hope for the future of prostate cancer treatment

In a few short years, CGP has revolutionized the way we detect and treat prostate cancer, offering profound value and promise to patients. I’m optimistic that CGP testing will continue to help us improve outcomes for those with advanced prostate cancer.

As our understanding of the disease continues to evolve through the discovery of new biomarkers, we remain committed to continuing to innovate our portfolio and unlocking the promise of precision oncology so that every patient can benefit from personalized, targeted treatments.