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Non-Metastatic Metastases and Other Confusing Findings from the PROSPER and SPARTAN Trials

Last month we saw the final published data from the PROSPER study1, and coupled with the earlier published SPARTAN study2, we now have two complete and large phase III studies detailing the clinical activity of androgen-receptor inhibitors, enzalutamide and apalutamide in so-called “non-metastatic” castrate-resistant prostate cancer (nmCRPC) patients. I am impressed with the results of these two studies; both demonstrated a robust clinical effect in delaying or preventing the development of metastases in this patient population that I believe is clinically beneficial in patients who are likely to live long enough to die from metastatic prostate cancer.  While I appreciate the FDA approval of these agents to treat this patient population, I don’t like this term non-metastatic CRPC.

Non-metastatic CRPC implies these are cancer patients that are in an earlier stage of disease (presumably stage I-III since metastasis would make then stage IV).  However, from SPARTAN we know that most of these patients had either surgery or radiation therapy (76.6%) and both studies enrolled patients with relatively fast PSA doubling times (median 3.8 months for PROSPER and median < 5 months for SPARTAN).  Serum PSA at enrollment for SPARTAN was 7.9 ng/ml, while it was even higher for PROSPER at 11.1 ng/ml.  These data suggest that most patients enrolled harbored small volume metastases that were just not detectable by bone scan or CT scan.  This conjecture is supported by the short median times to radiographic metastasis in the placebo arms of both trials (16.2 months for SPARTAN and 14.7 months for PROSPER). My European colleagues tell me that they routinely perform more sensitive scans for staging (whole body MRI or Ga68 PSMA PET) and would expect positive findings in most patients with PSA levels above 8 ng/ml or doubling times < 5 months3,4.  I would rather we consider these patients to be low volume metastatic disease, recognizing that there may be a few localized CRPC patients in the mix, but the majority gets the name.

One of the more subtle and unexpected findings from PROSPER, at least to me, was where do these patients first metastasize to?  I had presumed, with baseline median PSA levels near or over 10 ng/ml and with doubling time < 5 months that these patients would ultimately progress with bone metastases.  After all, the vast majority of prostate cancer patients ultimately develop bone metastases.  So, I was surprised to see that of the patients in PROSPER who developed progression, 32% (of enzalutamide patients) and 35% (of placebo patients) developed bone metastases vs 50% and 58% who developed soft tissue metastases, respectively. Why is this important?  For one, it suggests that enzalutamide and apalutamide don’t change the pattern of metastases, despite delaying progression by a median of roughly 2 years. Second, that this population does not all progress the same.  For the majority with lymph node only metastases (soft tissue), additional hormonal manipulations and sipuleucel-T may be the right path forward, while for those with an osseous metastatic disease as the first site of metastasis, targeting the bone microenvironment (with drugs like radium-223 and denosumab) may be crucial.  SPARTAN revealed post-progression treatment patterns but did not break them down by the pattern of metastasis.  Friends, you’ve heard me say before, not all metastases are equal; we shouldn’t treat them the same, either.

  1. Hussain M, et al. N Engl J Med. 2018 Jun 28;378(26):2465-2474
  2. Smith MR, et al N Engl J Med. 2018 Apr 12;378(15):1408-1418
  3. Larbi A, et al. Prostate. 2016 Aug;76(11):1024-33.
  4. Zacho HD, et al. Clin Physiol Funct Imaging. 2017
Written by: Daniel J. George, MD, Medical Oncologist, Professor of Medicine, Professor of Surgery, Duke Cancer Institute, Durham, North Carolina

Published Date: July 24th, 2018

Further Related Content:
Watch: First presentation of SPARTAN - a phase 3 double-blind, randomized study of apalutamide (APA) versus placebo in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) - Eric Small
Watch: Changing the Landscape of nmCRPC - The SPARTAN Trial - Eric Small
Watch: Changing the Standard of Care in the M0 CRPC Patient: PROSPER - A Conversation with Cora Sternberg
Watch: Meeting an Unmet Need in the Nonmetastatic Castration-Resistant Prostate Cancer Patient Population - Maha Hussain