In this trial, the following men were eligible for inclusion:
- cM0 CRPC
- Pelvic nodes < 2 cm below the iliac bifurcation (N1) were allowed
- Rising PSA despite castration-resistant testosterone (testosterone <= 50 ng/dL)
- PSADT <= 10 months
1) PSADT: PSADT <6 months and 6-10 months)
2) Use of bone-targeted agents at baseline: Yes vs. No
3) Nodal disease: N0 or N1
1,207 patients were recruited across all the institutions. Men were randomized in a 2:1 fashion to either apalutamide 240 mg daily + ADT or placebo + ADT.
An important difference between the SPARTAN study design and PROSPER is that once a patient developed metastases, they were offered secondary treatment (at the discretion of their treating physician OR offered abiraterone + prednisone by study coordinators) and followed. The time from their first developed of metastases (hence become mCRPC) to the time they progressed on secondary therapy was defined as Progression-Free Survival-2, essentially a measure of time to progression as mCRPC.
Their endpoints were as follows:
Primary endpoint: Metastasis-free survival (MFS).
Secondary endpoints (assessed in an hierarchical manner – hence, each was only assessed if the prior endpoint demonstrated significant results!)
- Time to metastases
- Progression-free survival
- Time to symptomatic progression
- Overall survival
- Time to cytotoxic chemotherapy
- PFS-2 (defined in study design)
- Time to PSA progression
- Patient reported outcomes using FACT-P and EQ-5D-3L
- Median age for the group was 74
- Median PSADT was 4.4 and 4.5 – well below the cutoff of 10!
- In fact, 71% of both groups fell in the PSADT < 6 months stratification
- 16-17% of the groups were cN1
- Median duration of therapy was 18.4 months (Enza) vs. 11.1 months (placebo)
Dr. Small jumped directly to the primary outcome, MFS.
Focusing on the primary endpoint, MFS – the Kaplan-Meier curve split very early, and there was a 72% risk reduction in MFS favoring apalutamide. Median MFS was 40.5 months vs. 16.2 months (placebo), HR 0.28, p<0.0001. The benefit was seen in all subgroup analyses, except black men (HR 0.65, CI 0.23-1.72).
Similar findings were identified for all secondary endpoints – again this was a hierarchical analysis. Time to metastases and Progression-free survival were both significant (details below). Overall survival, as mentioned above, was an interim analysis – they had reached 24% of their target events, but there was already early evidence of benefit. The apalutamide arm median OS has not yet been reached, but median OS for placebo was 39.0 months (HR 0.70, p = 0.07). The curves do begin to split on the Kaplan-Meier survival analysis.
As mentioned above, the PFS2 analysis was unique to the SPARTAN trial. 165 men in the apalutamide arm (53% of the 314 men who discontinued apalutamide) and 217 men in the placebo arm (78% of the 279 who had discontinued placebo) received subsequent therapy for mCRPC (primarily abiraterone through the trial). 68% of the placebo arm patients and 48% of the apalutamide arm patients ended up receiving either enzalutamide or abiraterone for mCRPC.
Interestingly, men who had been treated with apalutamide had a 51% risk reduction in PFS2 compared to men treated with placebo (HR 0.49, p<0.0001). While not powered for this analysis, this highlights the fact that maybe early treatment of cM0 CRPC may help improve subsequent management of mCRPC and delay failure of therapy.
Lastly, he did briefly review patient-reported outcomes. As can be expected in a non-metastatic population, baseline scores were FACT-P and EQ-5D-3L were within normal range. Adding apalutamide to ADT did not significantly change either PRO during the course of the study.
In terms of adverse events, apalutamide was well tolerated. Grade 3-4 Adverse events were slightly higher in the apalutamide arm (45% vs. 34%), as were serious adverse events (25% vs. 23%). Treatment discontinuation due to adverse events (11% vs. 7%) was also slightly higher in the apalutamide arm. Importantly, seizures were rare, and were never Grade 3 or 4.
Summary of SPARTAN and PROSPER Studies
Presented by: Eric Jay Small, MD, FASCO
Authors: Eric Jay Small, Fred Saad, Simon Chowdhury, Boris A. Hadaschik, Julie Nicole Graff, David Olmos, Paul N. Mainwaring, Hiroji Uemura, Angela Lopez-Gitlitz, Geralyn Carol Trudel, Byron M. Espina, Youyi Shu, Youn C. Park, Wayne R. Rackoff, Margaret K. Yu, Matthew Raymond Smith, On Behalf of the SPARTAN investigators;
Author Affiliation(s): UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; Centre Hospitalier de l‘Université de Montréal/CRCHUM, Montréal, QC, Canada; Guy's and St Thomas' Hospital NHS Foundation Trust, London, United Kingdom; West German Cancer Center, University Hospital Essen, Essen, Germany; VA Portland Health Care System, Knight Cancer Institute, Oregon Health & Science University, Portland, OR; Spanish National Cancer Research Centre, Madrid and Hospitales Universitarios Virgen de la Victoria, Málaga, Spain; Paul Mainwaring Pty Ltd, Hamilton, Queensland, Australia; Yokohama City University Medical Center, Yokohama, Japan; Janssen Research & Development, LLC, Los Angeles, CA; Janssen Research & Development, LLC, Raritan, NJ; Massachusetts General Hospital Cancer Center/ Harvard Medical School, Boston, MA
Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto | @tchandra_uromd at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA
Matthew R. Smith, M.D., Ph.D., Fred Saad, M.D., Simon Chowdhury, M.B., B.S., Ph.D., et al, for the SPARTAN Investigators, Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. NEJMoa1715546. February 8, 2018 DOI: 10.1056.