CUA 2018: Early or Late: The CRPC Management Debate

Halifax, Nova Scotia ( Armen Aprikian, MD, started the CRPC management debate by highlighting the various stages of the prostate cancer disease course (from local to mCRPC) and noting the various treatment options at each stage of the disease. For purposes of this debate, the discussion centered on the M0 CRPC disease state, an unmet clinical need until the reporting of two large phase III trials earlier this year at GU ASCO. 

In the PROSPER trial1, 1,401 patients were randomized 2:1 to enzalutamide vs placebo, with a primary outcome of metastasis-free survival (MFS). Secondary endpoints were time to PSA progression, time to first use of new therapy, and overall survival (OS). Enzalutamide was associated with a 71% improvement of MFS (HR 0.29), as well as time to PSA progression (HR 0.07), and time to subsequent therapy (HR 0.21). At the interim analysis for OS, the HR was 0.80 (favoring enzalutamide), but was not statistically significant (p=0.15).

The SPARTAN trial randomized 1,207 men 2:1 to receive apalutamide vs placebo2. In the planned primary analysis at 378 events, median MFS was 40.5 months in the apalutamide group compared with 16.2 months in the placebo group (HR for metastasis or death 0.28, 95% CI 0.23-0.35). Time to symptomatic progression was significantly longer with apalutamide than with placebo (HR 0.45, 95%CI 0.32-0.63). The rate of adverse events leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7.0% in the placebo group. The conclusions from SPARTAN were that apalutamide decreased the risk of metastasis or death by 72% and prolonged the median MFS by more than two years in men with high-risk nmCRPC. Furthermore, the MFS benefit was consistent across all subgroups, and the results were supported by consistent improvement across all evaluable endpoints (time to metastasis, PFS, time to symptomatic progression, time to PSA progression, and PSA decline).

This debate focused on two scenarios relating to M0 CRPC: 

  1. Be it resolved that an improvement in MFS alone is sufficient to change practice in M0 CRPC
  2. Be it resolved that patient-reported outcomes (PROs) are as important as OS in CRPC
MFS and OS in CRPC

Kim Chi, MD, started the debate by stating that no, MFS alone is not sufficient to change practice for CRPC patients. He stated that the goals of treating incurable cancer are to live longer and relieve symptoms and improve quality of life. Chi’s argument is that improving MFS does not achieve either of these goals. 

Chi’s key points are as follows:

  1. MFS as an endpoint is a moving target – according to Chi, nmCRPC is not really non-metastatic, rather that it is defined by the current limits of detection. His opinion is that with the improvement of radiographic imaging, such as PSMA-PET scan, this disease space will shrink drastically as most patients will be noted with micro-metastatic disease. 
  2. MFS is not a clinically relevant or patient-centered benefit – Chi notes a patient from his practice that had sub-centimeter retroperitoneal lymphadenopathy, which by definition he was “non-metastatic”, however on repeat imaging 6 months later the lymph node had grown to subsequently classify the patient as metastatic, with no change whatsoever in symptoms. 
  3. MFS is not a surrogate for OS in nmCRPC – Chi notes that in both SPARTAN and PROSPER, there were large differences in the MFS curves, without any difference (and tight Kaplan-Meier curves) for OS. In his opinion, these curves for OS are highly unlikely to separate with further follow-up.
  4. Benefit < cost – Chi states that with no OS benefit and an inability to improve quality of life in nmCRPC, the direct and indirect monetary cost, as well as the side effects of treatment are not reconcilable. As he notes in both SPARTAN and PROSPER, although both medications were generally well tolerated, patients still reported a degree of bothersome side-effects.
Chi summarized that an improvement in MFS alone is not sufficient to change clinical practice for CRPC patients secondary to MFS in nmCRPC not being clinically relevant or patient-centered because it does not improve OS nor quality of life.

Bobby Sheyegan, MD,  then argued that MFS is sufficient to change clinical practice for CRPC. He notes that OS will always be the best endpoint, however clinical trials designed to show improvement in OS need (i) a large number of patients, (ii) long follow-up, (iii) significant funds, and that a (iv) high proportion of treatment in the placebo at the time of progression makes the OS results difficult to interpret. Shayegan highlighted a paper from 1989 noting surrogate endpoints in clinical trials, known as the Prentice criteria3. The Prentice rules for surrogacy note that a surrogate endpoint must capture any and all relationships between treatment and the true endpoint. Furthermore, there must be biologic plausibility, which Shayegan argues is certainly present for prostate cancer. Secondly, if biologic plausibility is less compelling, then one must establish statistically that the correlation with the true endpoint is sufficiently great to justify the surrogate endpoint as a basis for inference. Previous data from ICECaP suggest that MFS is a strong surrogate for OS in patients with localized prostate cancer. Additionally, there was a strong correlation between rPFS and OS for key mCRPC studies (COU-AA-302 and PREVAIL). Furthermore, post-hoc data from SPARTAN presented last month at ASCO demonstrated that MFS correlated with OS in this trial4

Shayegan summarized that MFS alone should be sufficient to change clinical practice in CRPC patients because:

  • MFS is a biologically plausible surrogate for OS
  • There is a strong correlation in localized prostate cancer
  • Post-hoc analyses of COU-AA-302 and PREVAIL show similar findings in mCRPC
  • Post-hoc analysis of SPARTAN shows a consistently strong association between MFS and OS in nmCRPC
PROs and OS in CRPC

Ricardo Rendon, MD, started his argument for PROs by noting that despite longer exposure, health-related quality of life was maintained in these asymptomatic patients, and there were no differences between the treatment groups in a perceived burden of toxicity. He also notes that PROs are important because they are obtained directly from the patient and not interpreted by the clinician. Furthermore, PROs are what the patient is actually experiencing: symptoms, health status and quality of life. Rendon argues that PROs are becoming increasingly important with regards to selecting a treatment, as patients with CRPC are living longer with incurable cancer. The goals of an incurable disease are to delay disease progression and provide timely palliation of symptoms and improve quality of life.

There have been many systematic reviews on PROs for prostate cancer patients, which Rendon summarizes:

  • PROs provide invaluable information for treating CRPC
  • Impact on systemic therapies on PROs has not been well studied
  • PRO results are published after and separately from the clinical trial primary end-points
  • Most studies were powered on the basis of the primary endpoint of OS or PFS
  • Future studies should consider the size of the study population needed to obtain meaningful PRO data
Rendon highlights that studies in other oncology disciplines have noted that patients receiving treatment randomized to a collection of PROs data actually had an improved OS compared to patients without PROs recorded (absolute difference 5 months).
Rendon summarized:

  • PROs are increasingly supported by regulatory authorities, industry, and academia
  • The importance of PROs in the setting of mCRPC is widely accepted
  • Providing active treatment to an asymptomatic population (nmCRPC) could have a negative impact
  • In other disciplines, PROs have been directly linked to survival outcomes
  • PROs are here to stay, and in this population, they are as valuable as OS
Naveen S. Basappa, MD, provided the counter argument to the utility of PROs, by starting his argument that you can’t beat a hard endpoint such as OS. In his practice, the most common question is “Doc, how long do I have to live”. By striving for survival outcomes, Basappa argues that we have an objective, quantifiable, and singular endpoints. He argues that PROs look at the quality of life and patient well-being, which may be difficult to objectively quantify and are based on subjective experience. Furthermore, there are 98 different tools available to assess several domains including quality of life, pain, and physical performance. So, which one do we use? 

Basappa argues that there is wide variability in reporting of PROs, based on the extremely wide confidence intervals noted in the PROs data for both SPARTAN and PROSPER. Looking at these trials, he states that although there was no statistical difference in OS, the HRs look appropriate and that it is too early to measure OS, however, all of the other endpoints are encouraging. Whereas with PROs data there was no detriment to therapy, which in his opinion means that the patients “tolerated” the treatment, albeit good PRO results may overlook important safety data.

Basappa concluded by stating:

  • OS is THE definitive endpoint and has the most value in influencing treatment decisions
  • PROs are objectified subjectivity and variability = unreliability
  • PROs are not informative enough in the CRPC setting to influence treatment decisions

1. Hussain M, Fizazi K, Saad F, et al. PROSPER: A phase 3, randomized, double-blind, placebo-controlled study of enzalutamide in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC). J Clin Oncol 2018;36(suppl 6S;abstr 3).
2. Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 2018;378(15):1408-1418.
3. Prentice RL. Surrogate endpoints in clinical trials: Definition and operational criteria. Stat Med 1989;8(4):431-440.
4. Smith MR, Mehra M, Nair S, et al. Association of MFS and OS in nonmetastatic CRPC. ASCO 2018 abstr 5032.

Moderator: Armen Aprikian, MD, McGill University, Montreal, Quebec, Canada
Speakers: Bobby Shayegan, McMaster University, Hamilton, Ontario, Canada; Kim Chi, University of British Columbia, Vancouver, British Columbia, Canada; Ricardo Rendon, Dalhousie University, Halifax, Nova Scotia, Canada; Naveen S. Basappa, MD, University of Alberta, Edmonton, Alberta, Canada

Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre Twitter: @zklaassen_md at the 73rd Canadian Urological Association Annual Meeting - June 23 - 26, 2018 - Halifax, Nova Scotia

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