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Optimal Management of Metastatic Castration Sensitive Prostate Cancer

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Washington, DC (UroToday.com) Renowned medical oncologist Dr. Chris Sweeney provided an overview of the current landscape of metastatic castration sensitive prostate cancer (mCSPC) at the prostate cancer session at the SUO 2019 annual meeting.

Prior to 2014, there were only a handful of impactful clinical trials in this disease space, specifically those that stratified patients by disease volume. SWOG S8894 tested bilateral orchiectomy +/- flutamide, stratifying 1,387 patients by minimal vs extensive disease. The extensive disease was defined as appendicular skeletal involvement (+/- axial skeleton involvement), visceral metastases, or both.1 There was no significant difference between the two groups in regards to overall survival (OS) (p = 0.14). The estimated risk of death for flutamide as compared with placebo was HR 0.91 (90% CI 0.81 to 1.01). Furthermore, flutamide was not associated with enhanced benefits in patients with minimal disease. In 2008, MD Anderson Cancer Center conducted a trial of ADT +/- ketoconazole + doxorubicin alternating with vinblastine + estramustine, stratifying patients by high and low volume disease.2 Low volume disease in this trial was defined as two or less bone metastases and no visceral metastases. Among 286 patients, the median time to progression was 24 months (95% CI, 18 to 39 months) in the standard therapy arm, and 35 months (95% CI, 26 to 44 months) in the chemohormonal group (p = 0.39). At median follow-up of 6.4 years, overall survival was 5.4 years (95% CI, 4.7 to 7.8 years) in the standard therapy arm versus 6.1 years (95% CI, 5.1 to 10.1 years; p = 0.41). Chemotherapy significantly increased the burden of therapy, with 51% of patients experiencing an adverse event of grade 3 or worse, especially thromboembolic events.

Ultimately, patients with mCSPC have variable outcomes with testosterone suppression. Combining data from CHAARTED and GETUG15 (high volume disease being defined as visceral metastases and/or 4 or more bone metastases with at least one beyond the vertebra and pelvis), the median OS outcomes are as follows:

  • Prior local therapy and low volume disease: ~8 years
  • Prior local therapy and high volume disease: 4.5 years
  • De novo and low volume disease: 4.5 years
  • De novo and high volume disease: 3 years

There are interesting findings when assessing docetaxel in mCSPC by volume and de novo vs metachronous presentation. When looking at the initial OS data from CHAARTED, over a median follow-up of 28.9 months there was a significant survival advantage (13 months) to the early administration of docetaxel (HR 0.61, 95% CI 0.47 to 0.80).3 On follow-up analysis at a median of 53.7 months, the results are relatively stable with the docetaxel arm maintaining a survival advantage (10 months; (HR0.73, 95% CI 0.59 to 0.89).4 When stratifying by high volume, in the original analysis there was a 17 month advantage for docetaxel (HR 0.60, 95% CI 0.45 to 0.81), which is durable in the subsequent analysis (17 months, HR 0.60, 95% CI 0.50 to 0.79). However, this is clearly not the case in the low volume patients. In the original CHAARTED analysis the median OS was not reached (HR 0.60, 95% CI 0.32 to 1.13), and there is no clear benefit in the follow-up analysis (0 months; HR 1.04, 95% CI 0.70 to 1.55). The quality of life assessment for CHAARTED demonstrated that ADT alone in low volume patients had no change in the quality of life over 12 months, however, there was a decline for high volume patients, likely secondary to progression of disease. In patients receiving docetaxel, there was a decline in quality of life in low volume patients, however there was no decline in high volume patients.5

There are several points that may explain this heterogeneity in outcomes when assessing GETUG15, CHAARTED and STAMPEDE:

  • GETUG15 was conducted in an era with minimal access to agents other than docetaxel for castration resistant prostate cancer (CRPC)
  • CHAARTED is the only study with prospective stratification by volume
  • STAMPEDE had outlier or missing scan data on 25% of the patients in retrospective volume analysis
  • The bottom line is that some patients with low volume disease may benefit, but this effect is not large enough to see across all trials. Conversely, some patients with high volume disease may not benefit from docetaxel

Since 2014, there have been a plethora of trials assessing androgen receptor inhibition in patients with mCSPC. LATITUDE evaluated ADT + abiraterone compared to ADT alone among men with high-risk metastatic hormone-sensitive prostate cancer (mHSPC).6 High-risk was defined as meeting at least two of three criteria: (i) Gleason score ≥8, (ii) presence of ≥3 lesions on bone scan, or (iii) presence of measurable visceral lesions. Patients were randomized 1:1 to either ADT + abiraterone (n=597) or ADT + placebo (n=602). Over a median follow-up of 30.4 months, patients treated with ADT + abiraterone had a 38% risk reduction of death (HR 0.62, 95%CI 0.51-0.76) compared to ADT + placebo. Median OS was not yet reached in the ADT + abiraterone arm, compared to 34.7 months in the ADT + placebo arm. Using the CHAARTED definition for high volume, patients in LATITUDE were recently assessed for OS benefit stratified by disease volume. These results were presented at GU ASCO 2019 by Dr. Kim Chi – high volume patients had a survival advantage with ADT + abiraterone (16 months; HR 0.62, 95% CI 0.52 to 0.74), whereas there was no benefit in low volume patients (not reached; HR 0.72, 95% CI 0.47-1.10). The STAMPEDE abiraterone trial also recently assessed OS outcomes by volume of disease (95% de novo). Similar to LATITUDE, there was a survival advantage for ADT + abiraterone in the high risk patients (HR 0.54, 95% CI 0.41-0.70), however there was a benefit for low volume disease (HR 0.66, 95% CI 0.44-0.98).

At this year’s ASCO annual meeting, Dr. Sweeney’s team presented the first results of ENZAMET.7 ENZAMET is the first mCSPC trial to report OS data of enzalutamide plus testosterone suppression and outcomes if patients also received concurrent docetaxel. It was also the first study to include an active control arm (standard non-steroidal anti-androgen – bicalutamide, nilutamide, or flutamide). ENZAMET randomly assigned 1,125 patients: 562 in the non-steroidal anti-androgen and 563 in the enzalutamide arm. In the non-steroidal anti-androgen arm 44% of patients were planned for early docetaxel, compared to 45% in the enzalutamide arm; 53% of patients in the non-steroidal anti-androgen arm were high volume metastatic burden, compared to 52% in the enzalutamide arm. Overall survival was significantly prolonged in the enzalutamide arm compared to the non-steroidal anti-androgen arm (HR 0.67, 95% CI 0.52-0.86). Furthermore, time to PSA rise, clinical progression or death (HR 0.39, 95%CI 0.33-0.47) and time to clinical progression (HR 0.40, 95%CI 0.33-0.49) both favored enzalutamide. In the prespecified subgroup analysis of docetaxel (yes vs no), enzalutamide significantly improved time to clinical progression among men receiving docetaxel (HR 0.48, 95%CI 0.37-0.62), but did not improve OS (HR 0.90, 95%CI 0.62-1.31). In men not receiving docetaxel, enzalutamide improved clinical progression (HR 0.34, 95%CI 0.26-0.44) and OS (HR 0.53, 95%CI 0.37-0.75). There were 67% of patients in the enzalutamide arm that received one or more life-prolonging CRPC therapies, compared to 85% in the non-steroidal anti-androgen arm, thus the OS benefits noted in this trial are unlikely to be secondary to discrepancies in subsequent therapy.

Quality of life studies have also looked at the “Amides” in mCSPC. Patients on either apalutamide or enzalutamide reported a mild increase in fatigue. Looking at a composite variable called deterioration free survival (death, clinical progression, cessation of study treatment, or a 10-point decrease in quality of life score), deterioration free survival improved with enzalutamide because early impairments in specific aspects of health related quality of life did not outweigh the subsequent benefits of delayed clinical progression. Furthermore, the benefits at 3 years were smaller with early docetaxel than without docetaxel.

As follows is a summary of treatment benefit for overall survival in mCSPC:

SUO2019_Sweeney.png

Dr. Sweeney concluded his talk with several summary statements regarding deciding which systemic therapy for which patient with mCSPC:

  • Are they fit enough for chemo?
  • Do they have a low or high burden of mCSPC?
  • Determine which agents you can prescribe
  • Define treatment burden vs treatment benefit for a given subgroup
  • Engage the patient in treatment choice – some chemo fit patients with high volume disease may want to get chemo out of the way early

 

Presented by: Christopher Sweeney, MBBS, Professor of Medicine, Harvard Medical School, Dana Farber Cancer Institute, Boston, Massachusetts

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 20th Annual Meeting of the Society of Urologic Oncology (SUO), December 4 – 6, 2019, Washington, DC

 

References:

  1. Eisenberger MA, Blumenstein BA, Crawford ED, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 1998;339(15):1036-1042.
  2. Millikan RE, Wen S, Pagliaro LC, et al. Phase III trial of androgen ablation with or without three cycles of systemic chemotherapy for advanced prostate cancer. J Clin Oncol 2008;26(36):5936-5942.
  3. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med. 2015;373(8):737-746.
  4. Kyriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: Long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol 2018 Apr 10;36(11):1080-1087.
  5. Morgans AK, Chen YH, Sweeney CJ, et al. Quality of Life During Treatment with Chemohormonal Therapy: Analysis of E3805 Chemohormonal Androgen Ablation Randomized Trial in Prostate Cancer. J Clin Oncol 2018;36(11):1088-1095.
  6. Fizazi K, Tran N, Fein L, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2017;377(4):352-360.
  7. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med 2019 Jul 11;381(2):121-131.

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