COMBAT-CRPC: COncurrent adMinistration of Bipolar Androgen Therapy and Nivolumab in men with mCRPC

[pjoshea13]

First, an interview of Mark Markowski by Charles Ryan:

urotoday.com/video-lectures...

... then the ASCO presentation by Markowski :

urotoday.com/conference-hig...

ASCO 2021: COMBAT-CRPC: COncurrent adMinistration of Bipolar Androgen Therapy and nivolumab in men with mCRPC

(UroToday.com) During bipolar androgen therapy (BAT), intramuscular testosterone is administered, which results in rapid cycling of serum T levels from supraphysiologic to near-castrate in men with metastatic castration resistant prostate cancer (mCRPC).1 It has previously been observed that anecdotal clinical responses to immune checkpoint blockade in mCRPC patients previously treated with BAT occur and it has been hypothesized that a BAT/ immune checkpoint blockade combination would be synergistic. At the American Society of Clinical Oncology (ASCO) 2021 Annual Meeting, Dr. Mark Markowski and colleagues reported the results of a prospective phase 2 study of men with mCRPC treated with BAT in combination with nivolumab.

This was a multi-center, single-arm, open-label phase 2 trial of men with mCRPC who received testosterone cypionate 400mg intramuscular (BAT) every 28 days and nivolumab 480mg IV every 28 days, during which time LHRH agonist treatment was continued. All patients received BAT as single-agent therapy for a 12-week lead-in prior to the addition of nivolumab. Eligible patients were those with asymptomatic mCRPC who had soft tissue disease amenable to biopsy and progressed on at least one prior novel AR targeted therapy. Up to one line of chemotherapy was allowed for the treatment of mCRPC disease. The trial design for this study is as follows:

ASCO_BAT.png

The primary endpoint for this trial was confirmed PSA50 response rate. Key secondary endpoints included safety, objective response rate, and radiographic progression-free survival (rPFS). The trial was designed to detect a 20% absolute increase in PSA50 response rate from the null of 25%.

There were 45 patients enrolled on study and treated. The confirmed PSA50 response rate was 40.0% (n = 18/45, 95% CI: 26-56%, p = 0.02 against the 25% null hypothesis). For patients with measureable disease, the objective response rate was 23.8% (n = 10/42):

ASCO_COMBAT-CRPC.png

Median rPFS on BAT and nivolumab was estimated at 5.7 months (95% CI 4.9-7.8 months), and 11.1% (n = 5/45) of patients were free from radiographic progression for 11 or more months. One patient achieved a complete radiographic response, which is ongoing (>13 months):

ASCO_radiographic_progression.png

The majority of adverse events were Grade <2. The most common adverse events were edema (20%), nausea (20%), and back pain (13%). Immune-related adverse events were generally mild (Grade <2) with only two grade 3 immune-related adverse events observed (pericarditis, lipase elevation).

Dr. Markowski concluded his presentation of this phase 2 trial assessing BAT plus nivolumab with the following take-home points:

BAT plus nivolumab was well-tolerated without concerning safety signals

The combination met the pre-specified primary endpoint of confirmed PSA50response in a heavily treated population

Durable responses were observed in a subset of patients

Biomarker analysis is ongoing to identify a molecular signature predictive of response

Clinical trial information: NCT03554317

Presented by: Mark C. Markowski, MD, PhD, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021

References:

Denmeade SR, Wang H, Agarwal N, et al. TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men with Castration-Resistant Metastatic Prostate Cancer. J Clin Oncol. 2021 Apr 20;39(12):1371-1382.

[Hidden]

Do you know how this compares to straight BAT? Do you think it might be applicable to SPT?

[pjoshea13 in reply to Hidden]

From:

"Supraphysiological Testosterone Therapy {SPT} as Treatment for Castration-Resistant Prostate Cancer" [1]:

"Cycling or not cycling—that is the question. While we currently do not have sufficient evidence whether BAT results in better clinical outcome than continuous SPT, it is possible that long-term continuous SPT and BAT could alter AR signaling differently. One would anticipate that continuous SPT might trigger more pronounced differentiation, potentially causing a change from a “low-T” oncogenic AR transcriptome to that of a more differentiating SPT transcriptome (24). Meanwhile, BAT might provide better efficacy if cell-cycle relicensing effects and DNA damage are the critical mechanism of action ..."

Denmeade's BAT is intermittent SPT, since he aims for T of ~2,000 ng/dL.

With his 28 day cycle, the patient is near-castrate on day 28, but does not spend any appreciable time at castrate levels.

Much of Denmeade's study has been on CRPC.

One could use the BAT concept:

- on castrate-sensitive men

- with half the T-cypionate aiming for high-normal T of only 1,000 ng/dL

- with an extra month in the cycle at castrate level

& this could be done in combination with any therapy that does not target the androgen receptor axis.

Even though I have used T for 16 years, I find Denmeade's BAT to be confusing. How significant are the double-strand breaks & how does he know they are occurring? I can see why men with CRPC would not need more than a 28-day cycle to begin with, but if they are resensitized to ADT, shouldn't a meaningful castration period be added to the cycle?

Men with CRPC are in need or more options, but CRPC is a consequence of treatment. We need a BAT protocol to prevent CRPC.

-Patrick

[1] ncbi.nlm.nih.gov/pmc/articl...

[Hidden in reply to pjoshea13]

My research led me to SPT. BAT also looks viable. Straight ADT has a rather dismal long-term lifespan and QoL track record.

I'm pleased that there are more and more doctors working on BAT. Not much is being done with SPT but maybe someday...

[pjoshea13 in reply to Hidden]

In my case, I know that continuous T would result in leg pain due to a lesion at S1, so SPT is out.

[MateoBeach in reply to pjoshea13]

Great thoughts and questions Patrick. I am HSPC and my PSA growth is very slow (indolent). So I find the 28 day cycling for original BAT to be not likely to optimize adaptive effects for AR sub-populations of PC cells. Of course this is all unproven and speculative. But I personally am betting my life on it. I am doing two. Months of Supra-Testosterone via 400 mg of T-cypionate every two weeks, and then two months of low to castrate T levels. Just a guess on my part subject to adjustment based on PSA response and imaging. I think BAT cycling should take PSADT into consideration for adaptive (Darwinian) effects which are founded in cell cycle temporal dynamics.

[Fiddler2004]

Wow... very interesting... thank you!