ASCO GU 2019: Biologic Basis for Sequencing Novel Treatments for Metastatic Prostate Cancer

San Francisco, CA (UroToday.com) Dr. Beltran presented a summary of the biologic basis for sequencing novel treatments for metastatic prostate cancer.

There is an increasing need for biomarkers in advanced prostate cancer management – as there is a plethora of treatment options without much guidance about selection or sequencing. Some of the areas that require work are:
  • Choice of Androgen receptor (AR) pathway inhibitor vs. docetaxel for castration-sensitive prostate cancer (CSPC)
  • Optimal sequencing of approved drugs for castration-resistant prostate cancer (CRPC)
  • Patient selection for targeted therapy or immunotherapy
  • Early detection of treatment resistance
  • Design of rational combination therapies
She then touched upon the fact that metastatic biopsies are increasingly being utilized (either biopsy of the met directly or liquid biopsies) to look for actionable targets OR to identify treatment resistance.

  • Overall increased genomic testing has led to the identification of numerous molecular alterations in advanced prostate cancer – which has led to more biomarker-driven trials but also off label use of current drugs
UroToday ASCOGU2019 molecular alterations in advanced prostate cancer
  • International Stand Up to Cancer (SU2C) Dream Team work – have been focusing on 150 metastatic CRPC biopsies
    • Found DNA repair alterations in 22% of specimens – including homologous recombination genes and mismatch repair genes
    • These have prognostic, therapeutic and family implications
  • The mutations in the homologous recombination genes have had significant implications:
    • Poor prognosis for germline carriers (PROREPAIR-B trial)
    • Response to PARP inhibitors
    • Response to platinum chemotherapy
    • A possible response to Radium-223?
    • A possible response to AR-targeted therapies (depends on the study)
    • A possible response to checkpoint inhibitors?
    • A possible response to PSMA radionucleotide therapy?

But,

    • Are all HR mutations the same? Do somatic or germline mutations have different outcomes?
      • In PROREPAIR 2, germline BRCA2 mutations had worse prognosis than other mutations
    • Could similar biologic and clinical results be produced by co-targeting PARP and AR?
      • Phase 2 abiraterone + olaparib, unselected for HR mutations, the PFS was improved by 5 months (13.8 vs. 8.2 months)
      • DNA repair crosstalk with AR pathway?
      • But, who are the best responders to this combination?
  • Mismatch repair/microsatellite instability (MMR and MSI)
    • MMR loss results in hypermutations while MSI results in neoantigens and PDL-1 expression
    • 3-5% of mCRPC patients have these – maybe more, depending on testing
    • Pembrolizumab has been pan-approved for all histologies for patients with MSI-high tumors
    • However, as seen in Abida et al. (JAMA Onc 2018), only 6/11 patients with MSI-high tumors responded to Pembo – why don’t they all respond? What is the optimal approach to capturing this population?
The technique of assessing these matters – and will be discussed more by Mark Rubin in his talk to follow.

She then addressed tumor evolutionary biology and theories of clonal evolution to underscore the difficulties with treating metastatic disease. There are two possible clonal pathways:

  • 1) Monoclonal – where all metastases are derived from one clone from the original multifocal tumor. Therefore, they likely share some mutations with the founding lesion/primary tumor. This model is easier to treat broadly, as a single mutation may be shared by all lesions.
  • 2) Polyclonal – where the original founding tumor/primary has multiple clones with different founder mutations. As these each metastasizes and the mets cross-talk, there is a much broader array of mutations. It becomes harder to
Next, she addressed the role of biomarkers to identify treatment resistance.

The androgen receptor (AR) is still the main driver of CRPC in the majority of patients – there is a small subset of patients who are androgen-independent.

Yet, despite it still being the major driving, all our current AR-targeted therapies eventually fail. So, what is the clinical significance of this?

  • When would we NOT choose an AR-targeted therapy?
  • Germline HSD3B1 (1245C) – steroid biosynthesis enzyme – is associated with decreased response to primary ADT – may be useful as a marker for therapy intensification?
  • AR ligand binding domain mutation – useful to select an AR-targeted agent vs taxane in mCRPC?
  • AR splice variants and amplification - useful to select an AR-targeted agent vs taxane in mCRPC?
How do we better target the AR? Do we hit it harder? Combine therapies? Or switch to taxanes?

Some of her suggested strategies are as follows:

  • Not effective: sequencing abiraterone/enzalutamide in CRPC
  • Not effective: adding abiraterone to enzalutamide at the time of enza resistance
  • Combination strategies and targeting cross-talk pathways
    • Combining abi/enza up front
    • Targeting AR + chemotherapy, AR + PARP targeting, etc.
  • Newer AR targeting agents with different mechanisms
  • Bipolar androgen / high dose T (rapid cycling on androgen)
  • Earlier targeting before resistance develops – but we need to determine which patients benefit from this strategy!
On the flip-side, is there a way to better identify non-AR driven tumors early on? Are there tumors that are more resistant to AR pathway inhibition?

  • Small cell / neuroendocrine tumors – due to histologic transformation
  • Loss of AR expression / AR signaling (ie low PSA)
  • Clinical features such as visceral metastases, lytic bone metastases, low PSA, short ADT response
  • Molecular features such as combined TP53, RB1 and PTEN loss? (Hamid et al. EU 2018)
  • Can we use any of these to better identify patients for platinum chemotherapy vs. AR pathway inhibitor? Identify new therapies? Co-target AR and other susceptible foci?
In this slide, she highlights the current biomarker needs for advanced prostate cancer – and notates those currently being assessed in red:
UroToday ASCOGU2019 BiomarkerNeeds

Unfortunately, at this time, multiple barriers still exist to the effective use of biomarkers in patients with advanced prostate cancer – including patient, disease, assay and drug factors. Collaborative efforts will be required to help overcome these barriers.

Her take-home slide is very thorough:

  • There is a growing need for biomarkers to inform the optimal choice and sequencing of systemic therapies
  • Certain “targetable” genomic alterations are enriched in CRPC – ie BRCA2, AKT, CDK12, MMR
  • Resistance pathways are primarily AR-driven – has led to more potent AR-targeted approaches
  • Detection of non-AR driven disease – identifies patients with poor prognosis
  • Challenges for precision medicine include tumor evolution, heterogeneity, pathway cross-talk, non-genomic factors, many clinical factors
The future will likely be a combination of patient and molecular features to define subgroups of patients for tailored treatment approaches.


Presented by: Himisha Beltran, MD, Medical Oncologist, Dana Farber Cancer Institute, Harvard Medical School

Written by: Thenappan Chandrasekar, MD (Clinical Instructor, Thomas Jefferson University) (twitter: @tchandra_uromd, @JEFFUrology) at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA
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