BERKELEY, CA (UroToday.com) - Prostate cancer (PCa) is the most common cancer in men in the United States, and it is the second leading cause of death in men with cancer.
In 2012, approximately 241 800 cases of PCa were newly diagnosed, and approximately 28 200 deaths occurred from PCa. Of the patients diagnosed with PCa, about 5-10% present with metastatic disease, and another 25% diagnosed with localized or locally advanced PCa will develop metastases during the course of the disease. In men with recurrent disease, androgen deprivation therapy (ADT) is used to lower testosterone to castrate levels, and this is an effective palliation therapy that lasts between 12-24 months. After this period, most men who receive ADT treatment will progress to castration-resistant prostate cancer (CRPC). For men with metastatic castration-resistant prostate cancer (mCRPC), fairly recent phase III trials have shown a median survival that ranges from 12.2 to 21.7 months.
Since the FDA approval of docetaxel in 2004 as first line treatment for metastatic PCa, it has become the standard treatment for patients with mCRPC, and it has shown a median survival benefit of 2 to 3 months compared to mitoxantrone and prednisone.
Sipuleucel-T is an autologous active cellular immunotherapy indicated for treatment of patients with asymptomatic or minimally symptomatic mCRPC. It is designed to stimulate an immune response against an antigen expressed in most prostate cancers, prostatic acid phosphatase. Treatment with this therapeutic cancer vaccine has shown improved survival but no change in time to disease progression in men with mCRPC.
After two prior phase III trials with sipuleucel-T in minimally symptomatic mCRPC, no change in time to progression (primary endpoint in both studies) was shown, but a preplanned secondary analysis suggested an improvement in overall survival (OS). This outcome resulted in the initiation of the randomized, double-blind, controlled, multicenter phase III Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial with OS as the primary endpoint. The IMPACT trial included 512 men with mCRPC, and the patient population in this trial was essentially the same as in the previous two smaller phase III trials, i.e., patients with good functional status and asymptomatic or minimally symptomatic mCRPC. The results of the IMPACT trial demonstrated a relative reduction of 22.5% in the risk of death for the sipuleucel-T group compared with the control group (hazard ratio (HR), 0.78; 95% confidence interval [CI], 0.61 to 0.98; P = 0.03), and median OS in the sipuleucel-T group vs. the control group was 25.8 months vs. 21.7 months, representing a 4.1-month median survival improvement. The estimated 36-month survival probability was 31.7% in the sipuleucel-T group vs. 23.0% in the control group.
In order to predict individual survival probabilities and to stratify mCRPC patients in randomized phase III trials, numerous prognostic variables have been identified and they include serum lactate dehydrogenase (LDH), prostate-speciﬁc antigen (PSA), serum alkaline phosphatase (ALP), Gleason score, Eastern Cooperative Oncology Group performance status (ECOG PS), hemoglobin (Hgb), and the presence of visceral disease. These prognostic factors were identified by Halabi et al. (J Clin Oncol. 2003), and in the IMPACT trial, subgroup analyses were performed based on 19 baseline characteristics that included all prognostic factors identified except visceral disease, which was an exclusion criteria in this trial. Across all of these subgroups, a consistent positive effect of sipuleucel-T on OS was observed. Baseline PSA appeared to be a potential predictive factor, and a trend toward a greater sipuleucel-T treatment effect in patients with baseline PSA at or below the median compared with baseline PSA above the median (HR, 0.685 vs 0.865) was shown. This trend suggests that sipuleucel-T may provide greater beneﬁt for patients with a lower disease burden. In this trial, prognostic and predictive value of the factors identiﬁed by Halabi, et al. was further explored in the IMPACT data set. PSA was the most powerful prognostic factor and in the IMPACT trial, baseline PSA was subdivided into quartiles to evaluate potential treatment effect patterns.
In the case of sipuleucel-T, antigen-presenting cells (APCs) are used to initiate a diverse, lasting, tumor-specific immune response. In order to achieve this, autologous peripheral-blood mononuclear cells (PBMCs) are isolated via leukapheresis and sent to a central facility where APCs are activated ex vivo with a recombinant fusion protein (PA2024). This recombinant fusion protein consists of a prostate antigen, prostatic acid phosphatase (PAP) that is fused to granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune-cell activator. The resulting cell product (sipuleucel-T) is reinfused into the patient. The control comprised cultured PBMCs without PA2024. The leukapheresis was performed at weeks 0, 2, and 4 and the patients received 3 infusions of either sipuleucel-T or the control approximately 3 days after each leukapheresis. Any patient in the control group who experienced disease progression during the IMPACT trial was able to enroll in an open-label salvage trial where they received treatment with APC8015F (manufactured from cryopreserved cells collected at each leukapheresis).
In this trial, the primary endpoint (OS) was defined as time from randomization until death from any cause. All randomized patients (n=512) were included in the exploratory analyses and they were categorized into subsets by baseline PSA quartiles, ECOG PS (0 vs 1), Gleason score (≤7 vs ≥8), and by the median values for other baseline prognostic variables (LDH, ALP, and Hgb). All of the variables identiﬁed by Halabi, et al. that were available for evaluation in the IMPACT trial (PSA, LDH, Hgb, ECOG PS, ALP, and Gleason score) turned out to be signiﬁcant independent prognostic factors for survival (P < 0.05), except for the Gleason score. The strongest independent prognostic factor was PSA (P < 0.0001). There was a trend toward greater OS beneﬁt in patients with better baseline prognostic features even though none of the variables were found to interact signiﬁcantly with treatment.
When subdivided by baseline PSA into quartiles, the analysis showed more favorable prognostic features for patients with lower levels of baseline PSA. As expected, improved estimated median survival times were seen in both the sipuleucel-T and control arms, in patients with lower baseline PSA values. In the sipuleucel-T arm, patients in the lowest baseline PSA quartile (≤22.1 ng/mL) showed an estimated median survival time of 41.3 vs 18.4 months in the highest baseline PSA quartile (>134.1 ng/mL). In the control arm, the estimated median survival time was 28.3 vs 15.6 months for patients in the lowest vs highest baseline PSA quartile. Patients with lower baseline PSA values did not only live longer, they also appeared to experience a greater beneﬁt from sipuleucel-T. Although there was evidence of a consistent treatment effect across all baseline PSA quartiles, it appeared to increase with decreasing baseline PSA, such that it was most favorable in the lowest baseline PSA quartile. For patients in the lowest baseline PSA quartile, the HR was 0.51 (95% CI, 0.31-0.85) compared with a HR of 0.84 (95% CI, 0.55-1.29) for patients in the highest baseline PSA quartile, representing a 49% reduction in the risk of death for sipuleucel-T patients compared to control patients in the lowest quartile and a 16% reduction in the risk of death in the highest quartile. The estimated improvement in median survival favoring the sipuleucel-T patients varied from 13.0 months in the lowest baseline PSA quartile to 2.8 months in the highest baseline PSA quartile. Finally, for sipuleucel-T patients, the estimated 36-month survival in the lowest baseline PSA quartile was 62.2% compared to 41.6% for control patients in the lowest quartile. This represents a 50% relative increase in the estimated 36-month survival for sipuleucel-T patients compared to control patients.
To summarize the key findings discussed above:
- The patient’s PSA levels were the strongest independent baseline prognostic factor for response to sipuleucel-T (P < 0.0001)
- Estimated median survival in sipuleucel-T arm was
- 41.3 months for patients in the lowest baseline PSA quartile (≤ 22.1 ng/mL)
- 18.4 months for patients in the highest baseline PSA quartile (> 134.1 ng/mL)
- Estimated median survival in control arm was
- 28.3 months for patients in the lowest baseline PSA quartile
- 15.6 months for patients in the highest baseline PSA quartile
- The HRs for OS were
- 0.51 for patients in the lowest baseline PSA quartile
- 0.84 for patients in the highest baseline PSA quartile
- Estimated improvements in median OS were
- 13.0 months for patients in the lowest baseline PSA quartile
- 2.8 months for patients in the highest baseline PSA quartile
- Estimated 36-month survival was
- 62.6 % for sipuleucel-T patients in the in the lowest baseline PSA quartile
- 41.6 % for control patients in the in the lowest baseline PSA quartile
In summary, it has previously been demonstrated that sipuleucel-T prolongs survival in men with mCRPC and that it is effective in multiple subgroups. This exploratory analysis in the IMPACT trial demonstrates a trend toward a more pronounced treatment effect in patients with better baseline characteristics, and this seemed most prominent with baseline PSA. These findings of an improved treatment effect with sipuleucel-T in patients with more favorable prognostic features are in line with the proposed mechanism of action of sipuleucel-T. Thus, patients with a lower cancer burden tend to experience less immunosuppression systemically and in the microenvironment of the tumor. Therefore, the anticipation is that patients earlier in the natural history of PCa would have a more robust and effective immunologic response to treatment with sipuleucel-T. Additionally, immunotherapies such as sipuleucel-T seem to have a delayed onset of action and are generating a sustained immune response. In light of these findings, treatment with immunotherapy earlier in the disease would allow more time for the patient to benefit from the therapy.
Treatment of mCRPC with other agents does not appear to demonstrate the same findings as seen with immunotherapy, i.e., a larger treatment effect with lower baseline PSA values. Instead, treatment with docetaxel, abiraterone acetate in pre- and post-chemo settings, and enzalutamide in post-chemo settings have shown trends toward a greater treatment effect with PSA above rather than below the median. Based on these findings, one hypothesis suggests that cytoreductive therapies may be more effective in patients with a greater disease burden while immunotherapy may be best used earlier in the disease when the disease burden is lower. To conclude, sipuleucel-T treatment demonstrated the greatest benefit in patients with better baseline prognostic factors and particularly in those patients with lower baseline PSA values. The findings in this exploratory analysis suggest that patients with less advanced disease may benefit the most from treatment with sipuleucel-T, providing a rationale for immunotherapy as an early step in the sequencing of treatment algorithms for mCRPC.
Schellhammer PF, Chodak G, Whitmore JB, Sims R, Frohlich MW, Kantoff PW
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Philip W. Kantoff, et al. (for the IMPACT Study Investigators). Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer. N Engl J Med. 2010; 363:411-22
Susan Halabi, et al. Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J Clin Oncol. 2003 Apr 1;21(7):1232-7.
Written by Anna Forsberg, medical director for UroToday.com. Anna received a BSc in zoology from Louisiana State University, and a BSc in biomedicine and MSc in clinical drug development from Uppsala University in Sweden. She has worked almost 20 years in the global pharmaceutical and medical device world, involved with clinical research management and as a Medical Science Liaison (MSL) before joining UroToday as Medical Director. Her focus in clinical research and as a MSL has mainly been in the fields of urology and oncology.
Urology. 2013 Apr 9. (Epub ahead of print)