Targeting the Unseen: Advances in Treatment of M0 CRPC

Biochemical or PSA-only recurrence of prostate cancer after initial treatment with surgery or radiation can be extremely stressful for patients and their families, particularly when the PSA rises quickly. In the last few weeks the field has been fortunate to hear reports of two practice changing studies for men with high-risk non-metastatic castration-resistant prostate cancer (M0CRPC) that make some strides in combating this issue. The Study of Apalutamide (ARN-509) in Men With Non-Metastatic Castration-Resistant Prostate Cancer (SPARTAN) and Safety and Efficacy Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer (PROSPER) studies  were discussed at GU ASCO in February 2018. Both are randomized controlled clinical trials that demonstrate that adding an androgen receptor antagonist (enzalutamide or apalutamide) to standard ADT for men with high-risk non-metastatic prostate cancer and a rising PSA prolongs metastasis free survival.These landmark discoveries provide a treatment option for men who previously had none, filling the void of a major unmet need in the field. However, as the prostate cancer community rejoices, it will be critical to consider some key points when integrating this data into clinical practice.  

  1. Patient selection remains key. As we consider using SPARTAN and PROSPER in daily clinical practice, it is important to remember that the patients included in these studies had a PSA doubling time (PSADT) ≤10 months while on ADT. This group was selected because data suggests that in untreated men with biochemical recurrence, PSADT ≤ 10 months is a cut point that represents a particularly high risk of developing metastatic disease. Other factors contributing to risk of developing metastases are Gleason ≥ 8, and recurrence ≤ 2 years after therapy for localized disease. The highest risk group with all of these features has a 3 year metastasis-free survival (MFS) of 52% when not treated with ADT (Eisenberger MA, et al. Proc ASCO 2003; 22:380a (abstract 1527). The low risk population with Gleason <8, PSADT >10 months, and recurrence > 2 years after initial therapy has a 3 year MFS of 92%, and a 7 year MFS of 84%. This data suggests 84% of men without high risk features are alive without metastatic disease without treatment with ADT 7 years after their PSA started to rise, identifying a population that may benefit most from avoiding the side effects and complications associated with ADT and AR directed therapies.
Risk stratifying patients with biochemical recurrence to identify men who may benefit from early ADT and subsequent AR antagonist treatment for M0CRPC provides us with an opportunity to improve outcomes for patients at high risk and prevent complications from therapy in low risk patients. It is the high risk group who was included in the studies, and who should be considered for treatment in the M0CRPC setting.

  1. Imaging modality matters. The SPARTAN and PROSPER studies included patients who were non-metastatic by standard imaging modalities, not men who were non-metastatic by PSMA or Axumin PET. It is highly likely that a subset of these patients would have low volume metastatic disease if assessed using advanced imaging techniques (PSMA, Axumin). Given that this data was obtained using standard imaging, and the data for subsequent therapies for mCRPC was defined using standard imaging (PREVAlL, COU-302, TAX-327, IMPACT), clinicians should use standard imaging to integrate this data into practice. As further data is presented that provides information on relevant clinical options in the setting of novel imaging modalities, we can begin to shift to utilizing these for all patients as many already do in Europe and Australia.
  1. We may not be able to make up lost time. SPARTAN introduced the concept of second PFS, defined as the time from randomization to investigator-assessed disease progression by PSA, imaging, or clinical progression by symptoms during the first subsequent treatment for mCRPC or death from any cause. This endpoint is an exploratory one that compares survival on ADT until metastasis followed by abiraterone (control arm) with apalutamide until metastasis followed by abiraterone (experimental arm). By definition, all patients had to develop metastases to get the second line drug (abiraterone for approximately 75% of patients in both arms), and the endpoint for second PFS included PSA progression in addition to progression of metastatic disease and survival.
It is hard to know exactly what to make of the comparison given that although both arms were predominantly treated with abiraterone on progression, the timing of treatment initiation was very different across the groups (median MFS was 40.5 mo in the apalutamide group vs 16.2 mo in the ADT alone group). Comparing curves with such different denominators due to different times of initiating treatment can be challenging, and I’m not sure interpreting the curve presented in the SPARTAN paper is entirely intuitive. However, the comparison raises an important point about the possibility that we may be unable to make up for lost time after men develop metastatic disease. The idea that containing smaller amounts of cancer is more effective than containing more widespread disease is consistent across solid tumors, and this finding seems to support that. It raises the question of whether we should consider applying these AR directed therapies for M0CRPC to all patients rather than only those with a short PSADT, as well. If we can’t make up for lost time, and treatment with AR directed therapy is less durable in the mCRPC setting than the M0CRPC setting, should we consider applying earlier treatment to everyone? Only time and additional clinical trials will tell.

  1. Defining the long term complications from extreme androgen deprivation will be critical. Just as we learned that exposure to standard ADT puts men at risk for developing osteoporosis, cardiovascular disease, diabetes or cognitive change, we will need to assess these outcomes in men receiving long term intense androgen deprivation in the M0CRPC setting. Complications may develop more quickly, be more pronounced, or may even be novel. This is not to say that we should avoid using treatments that prolong life and improve quality of life as we saw in these studies, but to say that we should be vigilant regarding complications and prevent, reverse, or treat them to ensure the best outcomes for our patients.
  2. What we are doing to the biology of a patient’s disease is anyone’s guess, and next steps in treatment must be personalized. The earlier integration of more intense androgen deprivation means that we are altering selective pressure and potentially forcing cancers to develop a different spectrum of resistance mechanisms than we have previously. Recognizing this and developing strategies to sequence therapies in the mCRPC population after earlier use of apalutamide or enzalutamide will be important. Just as with each therapeutic advance in the past, we will need to think critically about resistance patterns and approaches to treatment that utilize alternate mechanisms of action to overcome them.
These landmark studies provide treatment options for a population that previous had nothing, enabling patients to live longer lives and have better quality of life without developing bone metastases as quickly. If we consider the points above, I believe the field will rationally and rapidly integrate the new M0CRPC data into our treatment algorithms. We will inevitably continue to learn about the complications of these therapies and the biology that results from treatment over the coming years, improving our support mechanisms and plans for drug sequencing along the way. Ultimately this progress will lead to patients living longer and better lives, improving patient outcomes, and bringing us one step closer to victory over prostate cancer once and for all.

Written by: Alicia Morgans, MD, MPH

Read More: 

First Presentation - SPARTAN: A Study of Apalutamide (ARN-509) in Men with Non-Metastatic Castration-resistant Prostate Cancer

First Presentation - PROSPER: Safety and Efficacy Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer (nmCRPC)
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