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ASCO 2023

ASCO 2023: Discussant: Right Treatment, Right Setting for Systemic Therapy

(UroToday.com) The 2023 ASCO annual meeting included a prostate cancer session, featuring a discussant presentation by Dr. Joaquin Mateo discussing the right treatment in the right setting for systemic therapy. Dr. Mateo discussed two abstracts including “PANTHER: A prospective trial of apalutamide and abiraterone acetate plus prednisone in Black and White men with mCRPC” presented by Dr. Daniel George, and “STARTAR: A phase 2 salvage trial of androgen receptor inhibition with ADT and apalutamide with radiation therapy followed by docetaxel in men with PSA recurrent prostate cancer after radical prostatectomy” presented by Dr. Tian Zhang. Discussing PANTHER first, Dr. Mateo highlighted the author’s conclusions of this trial, which were as follows:

  • The Black patient cohort in PANTHER demonstrated numerically longer rPFS, TTP, OS, and greater PSA response rates than the White patient cohort
  • The Black patient cohort in PANTHER experienced numerically longer rPFS, TTP, and OS than the Black patient cohort in Abi Race, with similar baseline characteristics
  • Ancestry-related biologic differences in prostate cancer should be studied to understand mechanisms related to treatment outcomes

For context, Dr. Mateo notes that the Abi Race trial was the first prospective parallel cohort study of abiraterone acetate + prednisone in Black and White men with mCRPC and demonstrated greater PSA response, time to PSA progression, and toxicity rates among Black patients.1 PANTHER was a single arm phase 2 trial + indirect comparison with Abi Race, with patients being stratified by white or black assessing first-line treatment in mCRPC patients (docetaxel was allowed in the mHSPC space). Patients were treated with oral apalutamide (240 mg/d), abiraterone (1000 mg/d) and prednisone (10 mg/d) continuously until disease progression, unacceptable toxicity or 2 years. The primary endpoint was radiographic progression free survival.

The Black cohort in PANTHER had greater rPFS, time to PSA progression and overall survival than White patients. Compared to the previous study of abiraterone in mCRPC patients by Black and White cohorts (Abi Race), the Black cohort from PANTHER (abiraterone + apalutamide) demonstrated greater radiographic progression free survival, time to PSA progression, and overall survival, while the White cohort in PANTHER revealed similar outcomes to the Abi Race White cohort: 

ASCO 2023_Joaquin Mateo_0 

Dr. Mateo highlighted that this is likely a complex interplay of factors affecting race / patient outcomes, which includes germline DNA, tumor DNA, and tumor biology:

ASCO 2023_Joaquin Mateo_1 

Additionally, access to healthcare, dietary/lifestyle factors, comorbidities, and other factors we don’t understand that may be also contributing. Dr. Mateo concluded this section on PANTHER with the following thoughts:

  • Most clinical trials and genomic/transcriptomic/epigenomic landscape studies are disproportionately enriched for Caucasian patients receiving therapy at a few selected academic sites
  • We need external validity of data in a global, diverse, patient population (beyond race)
  • We need to work on increasing participation in clinical studies of non-Caucasian patients + dedicating specific studies to non-Caucasian population to fill the gap of knowledge + comparing real world evidence to clinical trial data
  • Precision medicine needs to be guided by the right map, otherwise it will get lost

Dr. Mateo then discussed the STARTAR trial, summarizing the author’s conclusions of this study by stating that multimodality therapy with short-course hormonal therapy with ADT + apalutamide + salvage IMRT followed by adjuvant docetaxel x 6 achieved a 3-year PSA progression free survival rate of 72% with an expected safety profile and testosterone recovery in 38/39 patients. STARTAR is a multicenter investigator initiated phase 2 trial for salvage treatment of PSA recurrent prostate cancer post-radical prostatectomy. Patients received ADT with apalutamide for 9 months, radiotherapy (66-74 Gy to the prostate bed +/- pelvic lymph nodes over 6-8 weeks) starting week 8, and then completed 6 cycles of concurrent docetaxel 75mg/m2 q3 weeks. The trial design for STARTAR is as follows:

ASCO 2023_Joaquin Mateo_2 

Median PSA was 0.58 ng/mL (range 0.21-3.40) and all patients achieved undetectable PSA nadirs. At 24 months and 36 months, progression free survival rates were 84% and 72%, respectively, with 95% patients recovering testosterone at 36 months: 

ASCO 2023_Joaquin Mateo_3 

Dr. Mateo emphasized that the standard of care for this patient in the salvage setting is ADT + radiotherapy, but with many remaining questions including when to start therapy, how long should we treat with ADT, should we treatment intensify (this is where STARTAR comes in), and are there patients we should/can watch and wait? With regards to treatment intensification, there are several studies that have looked at this:

  1. NRG Oncology/RTOG 0534 SPPORT2 - radiotherapy + 6 months of ADT: 81% 5-year progression free survival, increasing to 87% if radiotherapy is also given to the lymph nodes
  2. RADICALS-RT [3] – does not have the same high risk definition as STARTAR but more similar radiotherapy arm at biochemical relapse (87% 5-year PSA progression free survival)
  3. STREAM [4] – indirect comparator of this study, ADT + enzalutamide for 6 months showing that 87% of 38 patients were high risk or very high risk (21% N+) showing a 3-year progression free survival of 54%
  4. FORMULA 509 (presented at GU ASCO 2023), testing ADT + bicalutamide vs ADT + apalutamide + abiraterone for 6 months among high risk patients. The 3-year progression free survival in Arm A was 47%, compared to 67% in arm B.

Dr. Mateo concluded his presentation discussing STARTAR with some concluding points:

  • ADT + radiotherapy is standard of care in the post-prostatectomy, biochemical relapse setting, but there still is a need for better evidence (ie. when to start, duration of therapy)
  • “High-risk” relapse patients have a worse prognosis – ADT + radiotherapy may be insufficient for some of them – emerging data from ADT + ARSI trials needs to be confirmed for larger trials and/or longer follow-up. Currently, the role of docetaxel is unclear
  • We need to re-define risk populations incorporating new biomarkers (ie. molecular and imaging) to inform the design of new trials

 

Presented by: Joaquin Mateo, MD, PhD, Vall d'Hebron Institute of Oncology, Barcelona, Spain

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 2 – Tues, June 6, 2023. 

References:

  1. George DJ, Halabi S, Heath EI, et al. A prospective trial of abiraterone acetate plus prednisone in Black and White men with metastatic castrate-resistant prostate cancer. Cancer. 2021 Aug 15;127(160:2954-2965.
  2. Pollack A, Karrison TG, Balogh AG, et al. The addition of androgen deprivation therapy and pelvic lymph node treatment to prostate bed salvage radiotherapy (NRG Oncology/RTOG 0534 SPPORT): An international, multicentre, randomized phase 3 trial. Lancet. 2022 May 14;399(10338):1886-1901.
  3. Parker CC, Clarke NW, Cook AD, et al. Timing of radiotherapy after radical prostatectomy (RADICALS-RT): A randomized, controlled phase 3 trial. Lancet 2020;396(10260):1413-1421.
  4. Bitting RL, Healy P, George DJ, et al. Phase II trial of Enzalutamide and Androgen Deprivation Therapy with Salvage Radiation in men with high-risk prostate-specific antigen recurrent prostate cancer: The STREAM trial. Eur Urol Oncol. 2021 Dec;4(6):948-954.

   

ASCO 2023: PANTHER: A Prospective Trial of Apalutamide and Abiraterone Acetate plus Prednisone in Black and White Men with mCRPC
ASCO 2023: Primary Analysis of STARTAR: A Phase 2 Salvage Trial of ADT and Apalutamide with Radiation Therapy Followed by Docetaxel in Men with PSA Recurrent Prostate Cancer After Radical Prostatectomy