ASCO 2021: Does the Treatment Sequence Matter? Resolving the Controversies

( In plenary program of the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Dr. Fleming discussed treatment sequencing in advanced prostate cancer within a session entitled “Beyond the Androgen Receptor: New Avengers in the Treatment of Castrate-Resistant Metastatic Cancer”.

Dr. Fleming began by providing a framework for sequencing. This is, importantly, not guided by definitive guidelines given the sparsity of head-to-head comparative data and varied trial enrollment criteria. However, the goal is to maximize the number of lines of life-prolonging therapy that a patient may receive.

Classically, this was dependent on the chronology of drug development and strongly influence by categorizations such as “pre-chemotherapy” or “post-chemotherapy”. However, changing criteria for progression and evolving imaging will influence treatment decisions moving forward. Additionally, there is an evolving justification for rationale treatment selection on a biologic basis, due to identified characteristics including androgen receptor mutation status, microsatellite instability, mismatch repair deficiency, homologous recombination repair, and PSMA.

He highlighted the extensively discussed prostate cancer clinical states models, highlighting the importance of lines of therapy, within each disease state but particularly within mCRPC. In 2021, the therapeutic landscape is complex with numerous treatment options in each disease state, many of which may be employed in a variety of different disease states and some of which may be indicated somewhat independent of disease state among patients with advanced prostate cancer.


Dr. Fleming then discussed factors to considering in sequencing of agents in metastatic castration resistant prostate cancer (mCRPC), highlighting the mnemonic “PM SAGAS”:

P – Prior therapies
M – Metastatic sites
S – Symptoms
A – Androgen indifference
G – Germline mutations
A – AR signaling defects
S – Somatic mutations

He then discussed the importance of considering prior therapies received for patients who are being treated for mCRPC. As alluded to above, many of the same agents used and indicated in mCRPC have subsequently been approved earlier in the disease process. For patients with metastatic castration sensitive prostate cancer, docetaxel, abiraterone acetate, enzalutamide, and apalutamide have proven survival benefits and are approved in this indication. Further, apalutamize, enzalutamide, and darolutamide have been approved in non-metastatic castration resistant prostate cancer on the basis of overall survival benefits in phase III registration trials. Clearly, patients who progress when receiving these agents earlier in their disease course are unlikely to benefit from treatment with the same agent again.

There are relatively limited data regarding treatment sequencing with a predominancy of retrospective and phase II prospective data. Together, these suggest cross-resistance is relatively common, particularly between androgen axis targeting agents. However, when these agents are used in sequence, he suggested that there may be a benefit in terms of PSA response when using abiraterone acetate followed by enzalutamide rather than the converse.

Dr. Fleming emphasized that, as highlighted above, there are a variety of treatment approaches. These, in turn, lead to varied practice patterns. Dr. Fleming discussed results of the CARD trial. Included patients had progressive mCRPC with prior docetaxel chemotherapy and novel hormonal agents (including abiraterone acetate and enzalutamide). Patients were randomized to receive the other novel hormonal agent or cabazitaxel.


The primary report of the CARD trial demonstrated improvement in both radiographic progression-free survival and overall survival (difference in median overall survival of 2.6 months) among patients who received third-line cabazitaxel, rather than a second androgen-axis targeting agent.

He then considered the effect of metastatic sites on sequencing. Certainly, it’s worth considering that different trials had different inclusion criteria. For example, patients with hepatic disease were not included in the IMPACT trial of sipuleucel-T. Similarly, approval for radium-223 is restricted to patients with bone-only disease. As a result, sites of metastatic disease may influence the treatment options available. Beyond that, it is important to consider the differing prognosis between node only, bony, and visceral metastasis, as well as differences in tumor biology and reliance of androgens.

Finally, he considered the effect of symptomatic disease on treatment sequencing. Many clinical trials, including IMPACT, COU-302, and PREVAIL, enrolled patients with a relatively limited disease burden and no or minimal cancer attributable symptoms. For patients with more advanced, and symptomatic disease, many of the same agents have proven benefit later in the disease process.

Dr. Fleming then concluded by highlighting the importance of previous treatment administered, metastatic site, and symptoms in guiding treatment choice. However, there is no definitive sequence and treatment needs to be personalized to patient, disease, and treatment considerations. As we move forward, treatment will be increasingly guided by a biologic understanding of disease.

Presented by: Mark T. Fleming, MD, Medical Oncologist, Virginia Oncology Associates

Written by: Christopher J.D. Wallis, MD, Ph.D., Urologic Oncology Fellow, Vanderbilt University Medical Center, Twitter: @WallisCJD at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting #ASCO21, June, 4-8, 2021